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1. Inverse association between plasma chlordecone concentrations and progression of alcoholic liver fibrosis: the role of liver metabolism

Author

Moana Gelu-Simeon, Marie-Josée Lafrance, Leah Michineau, Eric Saillard, Jean Pierre Thomé, Claude Emond, Michel Samson, and Luc Multigner

Subjects
Chlordecone, Persistent organic pollutants, Liver fibrosis, Reverse causality, Industrial medicine. Industrial hygiene, RC963-969, Public aspects of medicine, RA1-1270
Abstract

Abstract Background and Aims Chlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis. Methods This study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis. Results With a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34–0.95 for the highest vs. lowest tertile, p = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations. Conclusion According to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver. Trial registration ClinicalTrials.gov Identifier: NCT03373396.

Published
2024
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2. Looking for Pathogens in Dust from North Africa Arriving in the French West Indies Using Metabarcoding and Cultivable Analysis

Author

Yann Reynaud, Andric Gelasse, Luc Multigner, Philippe Quénel, Antoine Talarmin, and Stéphanie Guyomard-Rabenirina

Subjects
dust, French West Indies, metabarcoding, microbial pathogens, Biology (General), QH301-705.5
Abstract

Periodically, the French West Indies receive dust originating from North Africa (NA). Microorganisms associated with desert dust can be transported over long distances through the atmosphere and could represent a means for the remote colonization of new habitats by putatively pathogenic microorganisms. The aim of this study was to determine the diversity and frequency of microbial agents (bacteria, eukaryotes) in NA dusts and the potential threat toward human and/or animal health by comparing microbial air composition during dust events and in control samples. In 2017 and 2018, 16 samples were collected during seven NA dust episodes and there were 9 controls. The microbial composition of the samples was characterized using a cultivable approach and by metabarcoding analyses (16S and 18S). A greater bacterial load and greater diversity were observed during the dust events, and some genera were significantly associated with the events. Some, such as Geodermatophilus, can be considered signature species of NA dust. No pathogenic species were found with the cultivable approach, whereas the metabarcoding analyses highlighted the presence of several potentially pathogenic species or known human pathogens such as Naegleria fowleri.

Published
2024
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3. Prenatal and childhood chlordecone exposure, cognitive abilities and problem behaviors in 7-year-old children: the TIMOUN mother–child cohort in Guadeloupe

Author

Youssef Oulhote, Florence Rouget, Léah Michineau, Christine Monfort, Mireille Desrochers-Couture, Jean-Pierre Thomé, Philippe Kadhel, Luc Multigner, Sylvaine Cordier, and Gina Muckle

Subjects
Chlordecone, Organochlorine pesticides, Cognitive abilities, Behavior, Childhood, Guadeloupe, Industrial medicine. Industrial hygiene, RC963-969, Public aspects of medicine, RA1-1270
Abstract

Abstract Background Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, resulting in a widespread contamination. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual and fine motor developments during infancy and childhood, with greater susceptibility in boys. Objective To assess the associations between pre- and postnatal exposures to chlordecone and cognitive and behavioral functions in school-aged children from Guadeloupe. Methods We examined 576 children from the TIMOUN mother–child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children’s blood at age 7 years. Cognitive abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child’s mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex. Results Geometric means of blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children’s blood at age 7 years. A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with Cognitive abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. Associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls. Conclusions These results suggests that cognitive abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems.

Published
2023
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4. Prenatal and childhood exposure to chlordecone and adiposity of seven-year-old children in the Timoun mother–child cohort study in Guadeloupe (French West Indies)

Author

Nathalie Costet, Antoine Lafontaine, Florence Rouget, Léah Michineau, Christine Monfort, Jean-Pierre Thomé, Philippe Kadhel, Luc Multigner, and Sylvaine Cordier

Subjects
Adiposity, Obesity, Chlordecone, Organochlorine pesticides, Prenatal exposure, Childhood exposure, Industrial medicine. Industrial hygiene, RC963-969, Public aspects of medicine, RA1-1270
Abstract

Abstract Background Exposure to persistent environmental organic pollutants may contribute to the development of obesity among children. Chlordecone is a persistent organochlorine insecticide with estrogenic properties that was used in the French West Indies (1973–1993) and is still present in the soil and the water and food consumed by the local population. We studied the association between prenatal and childhood exposure to chlordecone and the adiposity of prepubertal children. Methods Within the Timoun Mother–Child Cohort Study in Guadeloupe (French West Indies), 575 children had a medical examination at seven years of age, including adiposity measurements. A Structural Equation Modeling approach was used to create a global adiposity score from four adiposity indicators: the BMI z-score, percentage of fat mass, sum of the tricipital and subscapular skinfold thickness, and waist-to-height ratio. Chlordecone concentrations were measured in cord blood at birth and in the children’s blood at seven years of age. Models were adjusted for prenatal and postnatal covariates. Sensitivity analyses accounted for co-exposure to PCB-153 and pp’-DDE. Mediation analyses, including intermediate birth outcomes, were conducted. Results Prenatal chlordecone exposure tended to be associated with increased adiposity at seven years of age, particularly in boys. However, statistical significance was only reached in the third quartile of exposure and neither linear nor non-linear trends could be formally identified. Consideration of preterm birth or birth weight in mediation analyses did not modify the results, as adjustment for PCB-153 and pp’-DDE co-exposures. Conclusion Globally, we found little evidence of an association between chlordecone exposure during the critical in utero or childhood periods of development and altered body-weight homeostasis in childhood. Nevertheless, some associations we observed at seven years of age, although non-significant, were consistent with those observed at earlier ages and would be worth investing during further follow-ups of children of the Timoun Mother–Child Cohort Study when they reach puberty.

Published
2022
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5. Inverse probability weighting to handle attrition in cohort studies: some guidance and a call for caution

Author

Marie-Astrid Metten, Nathalie Costet, Luc Multigner, Jean-François Viel, and Guillaume Chauvet

Subjects
Cohort studies, Attrition, Missing outcome, Selection bias, Inverse probability weighting, Complete-case analysis, Medicine (General), R5-920
Abstract

Abstract Background Attrition in cohort studies challenges causal inference. Although inverse probability weighting (IPW) has been proposed to handle attrition in association analyses, its relevance has been little studied in this context. We aimed to investigate its ability to correct for selection bias in exposure-outcome estimation by addressing an important methodological issue: the specification of the response model. Methods A simulation study compared the IPW method with complete-case analysis (CCA) for nine response-mechanism scenarios (3 missing at random – MAR and 6 missing not at random - MNAR). Eighteen response models differing by the type of variables included were assessed. Results The IPW method was equivalent to CCA in terms of bias and consistently less efficient in all scenarios, regardless of the response model tested. The most effective response model included only the confounding factors of the association model. Conclusion Our study questions the ability of the IPW method to correct for selection bias in situations of attrition leading to missing outcomes. If the method is to be used, we encourage including only the confounding variables of the association of interest in the response model.

Published
2022
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6. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author

Minh-Phuong Huynh-Le, Chun Chieh Fan, Roshan Karunamuni, Wesley K. Thompson, Maria Elena Martinez, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth Muir, Johanna Schleutker, Nora Pashayan, Jyotsna Batra, Henrik Grönberg, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Sune F. Nielsen, Børge G. Nordestgaard, Fredrik Wiklund, Catherine M. Tangen, Graham G. Giles, Alicja Wolk, Demetrius Albanes, Ruth C. Travis, William J. Blot, Wei Zheng, Maureen Sanderson, Janet L. Stanford, Lorelei A. Mucci, Catharine M. L. West, Adam S. Kibel, Olivier Cussenot, Sonja I. Berndt, Stella Koutros, Karina Dalsgaard Sørensen, Cezary Cybulski, Eli Marie Grindedal, Florence Menegaux, Kay-Tee Khaw, Jong Y. Park, Sue A. Ingles, Christiane Maier, Robert J. Hamilton, Stephen N. Thibodeau, Barry S. Rosenstein, Yong-Jie Lu, Stephen Watya, Ana Vega, Manolis Kogevinas, Kathryn L. Penney, Chad Huff, Manuel R. Teixeira, Luc Multigner, Robin J. Leach, Lisa Cannon-Albright, Hermann Brenner, Esther M. John, Radka Kaneva, Christopher J. Logothetis, Susan L. Neuhausen, Kim De Ruyck, Hardev Pandha, Azad Razack, Lisa F. Newcomb, Jay H. Fowke, Marija Gamulin, Nawaid Usmani, Frank Claessens, Manuela Gago-Dominguez, Paul A. Townsend, William S. Bush, Monique J. Roobol, Marie-Élise Parent, Jennifer J. Hu, Ian G. Mills, Ole A. Andreassen, Anders M. Dale, Tyler M. Seibert, UKGPCS collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, The IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, The Profile Study Steering Committee, and The PRACTICAL Consortium

Subjects
Science
Abstract

A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Published
2021
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7. In Utero Chlordecone Exposure and Thyroid, Metabolic, and Sex-Steroid Hormones at the Age of Seven Years: A Study From the TIMOUN Mother-Child Cohort in Guadeloupe

Author

Gülen Ayhan, Florence Rouget, Frank Giton, Nathalie Costet, Léah Michineau, Christine Monfort, Jean-Pierre Thomé, Philippe Kadhel, Sylvaine Cordier, Alejandro Oliva, and Luc Multigner

Subjects
chlordecone, endocrine disruptors, in utero exposure, hormones, children, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

BackgroundChlordecone is an endocrine-disrupting chemical with well recognized estrogenic and progestagenic properties. This organochlorine insecticide was extensively used in the French West Indies from 1973 to 1993 to control the banana root borer. Due to its poor degradation in the environment, permanently polluted soil is responsible for the current contamination of the food chain and human beings. We aimed to examine the relationship of in utero exposure to chlordecone and thyroid (thyroid stimulating hormone [TSH], free tri-iodothyronine [FT3], free thyroxine [FT4]), metabolic (insulin growth-factor 1, leptin, adiponectin), and sex-steroid (dehydroepiandrosterone [DHEA], total testosterone [TT], dihydrotestosterone [DHT], estradiol [E2]) hormone levels in children at the age of seven years who participated in TIMOUN, an ongoing birth cohort in Guadeloupe.MethodsChlordecone concentrations were measured in cord-blood at delivery. Thyroid, metabolic, and sex-steroid hormone levels were determined in the blood of children at seven years of age. Associations between in utero chlordecone exposure and hormone levels at seven years of age were assessed by multiple linear or logistic regression, controlling for confounding factors.ResultsAmong the study population (210 boys and 228 girls), chlordecone and hormone measurements were available for 124 boys and 161 girls. We found the third quartile of in utero chlordecone exposure relative to the lowest quartile to be associated with elevated TSH levels in girls and elevated DHEA, TT, and DHT levels in both sexes. Complementary non-linear analysis (spline regression) confirmed a significant non-linear trend for TSH in girls and DHEA and DHT in boys.ConclusionIn utero chlordecone exposure was associated with elevated levels of selected thyroid (TSH) and sex-steroid (DHEA, TT, and DHT) hormones at seven years in a non-monotonic dose response (inverted U) relationship. The implications for future health and reproductive function in puberty and adulthood should be determined.

Published
2021
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8. Developmental exposure to chlordecone induces transgenerational effects in somatic prostate tissue which are associated with epigenetic histone trimethylation changes

Author

Louis Legoff, Shereen Cynthia D'Cruz, Morgane Lebosq, Aurore Gely-Pernot, Katia Bouchekhchoukha, Christine Monfort, Pierre-Yves Kernanec, Sergei Tevosian, Luc Multigner, and Fatima Smagulova

Subjects
Chlordecone, Prostate, PIN, Transgenerational inheritance, Epigenetics, DOHaD, Environmental sciences, GE1-350
Abstract

Background: Chlordecone (CD), also known as Kepone, is an organochlorine insecticide that has been used in banana crops in the French West Indies. Due to long-term contamination of soils and water, the population is still exposed to CD. Exposure to CD in adulthood is associated with an increased risk of prostate cancer (PCa). Objectives: We examined the transgenerational effects of CD on murine prostate tissue. Methods: We exposed pregnant Swiss mice to CD. The prostates from directly exposed (F1) and non-exposed (F3) male progeny were analyzed. We used immunofluorescence, RNA-seq and ChIP-seq techniques for the comprehensive analyses of chromatin states in prostate. Results: We observed an increased prostatic intraepithelial neoplasia phenotype (PIN) in both F1 and F3 generations. Transcriptomic analysis in CD-derived F1 and F3 prostate using RNA-seq revealed that 970 genes in F1 and 218 in F3 genes were differentially expressed. The differentially expressed genes in both datasets could be clustered accordingly to common biological processes, “cell differentiation”, “developmental process”, “regulating of signaling”, suggesting that in both generations similar processes were perturbed. We detected that in both datasets several Hox genes were upregulated; in F1, the expression was detected mainly in Hoxb and Hoxd, and in F3, in Hoxa family genes. Using a larger number of biological replicates and RT-qPCR we showed that genes implicated in testosterone synthesis (Akr1b3, Cyp11a1, Cyp17a1, Srd5a1) were dramatically upregulated in PIN samples; Cyp19a1, converting testosterone to estradiol was elevated as well. We found a dramatic increase in Esr2 expression both in F1 and F3 prostates containing PIN. The PIN-containing samples have a strong increase in expression of self-renewal-related genes (Nanog, Tbx3, Sox2, Sox3, Rb1). We observed changes in liver, F1 CD-exposed males have an increased expression of genes related to DNA repair, matrix collagen and inflammation related pathways in F1 but not in F3 adult CD-derived liver.The changes in RNA transcription were associated with epigenetic changes. Specifically, we found a global increase in H3K4 trimethylation (H3K4me3) and a decrease in H3K27 trimethylation (H3K27me3) in prostate of F1 mice. ChIP-seq analysis showed that 129 regions in F1 and 240 in F3 acquired altered H3K4me3 occupancy in CD-derived prostate, including highest increase at several promoters of Hoxa family genes in both datasets. The alteration in H3K4me3 in both generations overlap 73 genes including genes involved in proliferation regulation, Tbx2, Stat3, Stat5a, Pou2f3 and homeobox genes Hoxa13, Hoxa9. Conclusions: Our data suggest that developmental exposure to CD leads to epigenetic changes in prostate tissue. The PIN containing samples showed evidence of implication in hormonal pathway and self-renewal gene expression that have the capacity to promote neoplasia in CD-exposed mice.

Published
2021
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9. Petroleum and Chlorinated Solvents in Meconium and the Risk of Hypospadias: A Pilot Study

Author

Florence Rouget, Adèle Bihannic, Sylvaine Cordier, Luc Multigner, Marie Meyer-Monath, Fabien Mercier, Patrick Pladys, and Ronan Garlantezec

Subjects
hypospadias, BTEX, petroleum solvents, chlorinated solvents, meconium, volatile organic compound, Pediatrics, RJ1-570
Abstract

Background: Hypospadias is a male congenital malformation that occurs in ~2 of 1,000 births. The association between hypospadias and fetal exposure to environmental chemicals has been studied, but the results are inconsistent. Although several petroleum and chlorinated solvents are suspected to have teratogenic effects, their role in the occurrence of hypospadias has been little studied and never using biomarkers of exposure. We aimed to evaluate the association between fetal exposure to petroleum and chlorinated solvents measured in meconium and the occurrence of hypospadias.Methods: We conducted a pilot case-control study in the maternity of the University Hospital of Rennes (France). Eleven cases of hypospadias and 46 controls were recruited between October 2012 and January 2014. Data from hospital records and maternal self-reported questionnaires, including socio-demographic characteristics and occupational and non-occupational exposure to chemicals, were collected. Meconium samples were collected using a standardized protocol. Levels of petroleum solvents (toluene, benzene, ethylbenzene, and p, m, and o xylene), certain metabolites (mandelic acid, hippuric acid, methylhippuric acid, S-phenylmercapturic acid, S-benzylmercapturic acid, and phenylglyoxylic acid), and two chlorinated solvents (trichloroethylene and tetrachloroethylene) were measured in meconium by gas and liquid chromatography, both coupled to tandem mass spectrometry. Associations between the concentration of each chemical and the occurrence of hypospadias were analyzed using exact logistic regressions adjusted for maternal age, educational level, pre-pregnancy body mass index, and alcohol, and tobacco consumption during pregnancy. Results are presented with odds ratios (ORs) and their 95% confidence intervals (CIs).Results: Quantification rates for petroleum and chlorinated solvents or metabolites ranged from 2.2% (for methylhippuric acid) to 77.1% (for trichloroethylene) of the meconium samples. We found a significant association between the quantification of phenylglyoxylic acid (metabolite of styrene and ethylbenzene) in the meconium and a higher risk of hypospadias (OR = 14.2, 95% CI [2.5–138.7]). The risk of hypospadias was non-significantly elevated for most of the other solvents and metabolites.Conclusion: This exploratory study, on a limited number of cases, suggests an association between petroleum solvents and hypospadias. Additional studies are needed to confirm these results and identify the determinants for the presence of these solvents in meconium.

Published
2021
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10. Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features

Author

Louis Legoff, Ouzna Dali, Shereen Cynthia D’Cruz, Antonio Suglia, Aurore Gely-Pernot, Chloé Hémery, Pierre-Yves Kernanec, Abbassia Demmouche, Christine Kervarrec, Sergei Tevosian, Luc Multigner, and Fatima Smagulova

Subjects
Genetics, QH426-470
Abstract

Abstract Chlordecone (CD) is an insecticide that was used in the French West Indies for several years to control the banana root borer pest. Given its nonsignificant degradation, it persists in the environment. CD is a carcinogenic compound with reproductive and developmental toxicity and is a recognized endocrine-disrupting chemical. In this study, we examined the effects of CD on female reproductive system of mice with the focus on epigenetic features in ovary. Our data show that gestational exposure to low dose of CD affects meiotic double-strand breaks repair in female embryos. In adult mice derived from CD-treated pregnant females, we observed delayed puberty, decreased number of primordial and increased number of atretic follicles. Gene expression analysis revealed that Rcbtb2 and Rbpms genes were not expressed in embryonic gonads. Estrogen signaling- and oocyte maturation-associated genes were downregulated in adult ovaries. The morphological changes were associated with altered epigenetic features: increased H2Aub and increased H3K27me3 and decreased H4ac and H3K4me3 in embryonic oocytes. The DNA damage-associated, γH2AX marks were detected in the follicles of treated but not control adult ovaries. We also found reduced H3K4me3 and H4ac in fully grown oocytes of the treated ovaries. The ChIP-seq analysis of H3K4me3 in adult ovaries showed that target genes of ZFP57 and TRIM28, which regulate pluripotency and imprinting, were significantly enriched in altered regions. Our study clearly demonstrates that gestational exposure to a low dose of CD impairs the function of female reproductive system and the changes are associated with altered epigenetic features.

Published
2019
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11. Landfills and preterm birth in the Guadeloupe archipelago (French West Indies): a spatial cluster analysis

Author

Marion Istvan, Florence Rouget, Léah Michineau, Christine Monfort, Luc Multigner, and Jean-François Viel

Subjects
Preterm birth, Environmental exposure, Landfill, Spatial clustering, French West Indies, Arctic medicine. Tropical medicine, RC955-962
Abstract

Abstract Background A high rate of preterm birth is observed in the Guadeloupe archipelago (French West Indies), raising the hypothesis of harmful environmental exposures, including landfilling. Our aim was to evaluate whether preterm births cluster around the three main open landfills located in this area. Methods The study population consisted of 911 women enrolled in the Timoun mother-child cohort (2004–2007). Home addresses during pregnancy and locations of landfills were geocoded. To test for the presence of preterm birth clusters around each dumpsite, we used a focused cluster test specifically designed to detect spatial clustering around point sources. Results A total of 144 (15.8%) preterm births were observed among 911 births. Using the term births (n = 767) as controls, a significant cluster was identified within 2 km around the Saint-François landfill with a relative risk (RR) of 4.82 (p = 0.04). No clusters were found around the other two landfills (RR = 2.01, p = 0.26 and RR = 1.06, p = 0.64, for La Gabarre and Baillif, respectively). Conclusion The paucity of data available on open landfill sites regarding waste quantities, composition, and changes over time precludes any site-specific interpretation because of the variable degree of possible emissions. This result has to be confirmed in other tropical island environments where waste management has become a major concern with the potential to negatively impact the environment and public health.

Published
2019
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12. Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males

Author

Aurore Gely-Pernot, Chunxiang Hao, Louis Legoff, Luc Multigner, Shereen Cynthia D’Cruz, Christine Kervarrec, Bernard Jégou, Sergei Tevosian, and Fatima Smagulova

Subjects
Medicine, Science
Abstract

Abstract Environmental factors can affect epigenetic events during germline reprogramming and impose distinctive transgenerational consequences onto the offspring. In this study, we examined the transgenerational effects of chlordecone (CD), an organochlorine insecticide with well-known estrogenic properties. We exposed pregnant mice to CD from embryonic day 6.5 to 15.5 and observed a reduction in spermatogonia (SG) numbers in F3, meiotic defects in spermatocytes and decrease in spermatozoa number in the first and third generation of male progeny. The RNA qRT-PCR expression analysis in F1 and transcriptomics analysis in F3 males using the whole testes revealed changes in the expression of genes associated with chromosome segregation, cell division and DNA repair. The expression of the master regulator of pluripotency, Pou5f1, decreased in foetal and increased in adult F1, but not in F3 adult testes. Analysis of histone H3K4me3 distribution revealed widespread changes in its occupancy in the genome of F1 and F3 generations. We established that 7.1% of altered epigenetic marks were conserved between F1 and F3 generations. The overlapping changes common to F1 and F3 include genes implicated in cell adhesion and transcription factor activities functions. Differential peaks observed in F1 males are significantly enriched in predicted ESR1 binding sites, some of which we confirmed to be functional. Our data demonstrate that CD-mediated impairment of reproductive functions could be transmitted to subsequent generations.

Published
2018
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13. Chronic epididymitis and Grade III varicocele and their associations with semen characteristics in men consulting for couple infertility

Author

Alejandro Oliva and Luc Multigner

Subjects
couple subfertility, epididymitis, male factor infertility, semen quality, varicocele, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Chronic epididymitis and varicocele are frequently observed genital disorders in men consulting for couple infertility, but their impact on semen characteristics at the time of infertility consultation is still a matter of debate. We investigated 652 male partners of couples who had their first infertility consultation between 1999 and 2015 in Argentina. Men with chronic epididymitis (n = 253), Grade III varicocele (n = 106), and both conditions (n = 125) were compared with a control group (n = 168) composed of men without these disorders or any other recognized causes of male infertility. We showed that men who presented isolated chronic epididymitis were more likely to have high percentages of low sperm motility and abnormal sperm morphology as well as a high number of white blood cells. Men with isolated Grade III varicocele had low sperm production and motility and an increased percentage of abnormal sperm morphology. Finally, men who simultaneously presented chronic epididymitis with Grade III varicocele had a low sperm motility and increased percentage of abnormal sperm morphology as well as a high number of white blood cells. Physical examination of the genital organs may identify common disorders, potentially involved as causal factors of patient's infertility. These disorders are associated with specific seminal profiles that should help in identifying the best treatment from the available therapeutic options, effectiveness, safety, and allowing as much as possible natural conception.

Published
2018
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14. Blood Pressure, Heart Rate Variability, and Adiposity in Caribbean Pre-pubertal Children

Author

Morgane Grandemange, Nathalie Costet, Matthieu Doyen, Christine Monfort, Léah Michineau, Marie-Béatrice Saade, Luc Multigner, Sylvaine Cordier, Patrick Pladys, and Florence Rouget

Subjects
blood pressure, heart rate variability (HRV), adiposity, children, pre pubertal, BMI, Pediatrics, RJ1-570
Abstract

Childhood obesity prevalence has increased over the last 30 years. The Heart Rate Variability (HRV) studies performed in adults suggest a possible relation between abnormal autonomic regulation and hypertension in the situation of overweight or obesity.Objective: The aims of this study were to explore the early relationships between adiposity and blood pressure and HRV in pre-pubertal children.Methods: Data were collected during the medical examination of the follow-up at 7 years of the TIMOUN mother-child cohort in Guadeloupe. Body Mass Index z-score (zBMI), sum of tricipital and subscapular skinfold thickness, percentage of fat mass, and Waist-to-Height Ratio were measured. A global corpulence score was computed using a Principal Component Analysis (PCA). Systolic Blood Pressure (SBP) and HRV parameters (cardiac holter monitoring) were collected under 2 conditions (calm and tachycardial period). Relations between HRV, SBP, each adiposity indicator and the corpulence score were studied with restricted cubic splines models, and linear regression models. The age at adiposity rebound (AR) was estimated from the individual growth curves.Results: 575 children were included in the SBP study (mean age: 7.7 years, from 85 to 99 months). SBP was linearly correlated with the corpulence score and the zBMI. An increase of 1 in the zBMI was associated with an increase of 2.3 (±0.28) mmHg in SBP. The effect-size of zBMI on SBP was higher in children with early age at AR. Compared to children with normal BMI, children with a zBMI 2SD, we observed a global increase in all HRV parameters (under tachycardial conditions), particularly the LF [β = 0.43 (±0.18)].Conclusion: In pre-pubertal period a positive correlation between adiposity excess and SBP was observed with significant changes of HRV in boys, arguing for an early abnormal autonomic regulation and for early preventive intervention in the infancy period, particularly in case of overweight or obesity. Thinness was associated with a reduction in almost all the HRV parameters studied, when compared to normal corpulence, suggesting a decrease in autonomic influence.

Published
2019
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15. The annual carnival in Guadeloupe (French West Indies) is associated with an increase in the number of conceptions and subsequent births nine months later: 2000 - 2011.

Author

Philippe Kadhel, Nathalie Costet, Teddy Toto, Eustase Janky, and Luc Multigner

Subjects
Medicine, Science
Abstract

The seasonal patterns of conceptions and births differ between geographic areas. Several potential determinants of this variation have been identified, including biological, environmental and behavioral elements, but festive events are rarely mentioned. We investigated the possible association between the carnival and seasonal fertility variations in the French West Indies. We ran a retrospective registry-based study. The data were extracted from the registry of all births on Guadeloupe between 2000 and 2011 (n = 74,412), and from the Maternity Birth Register of the University Hospital, for all pregnancies of at least 14 completed weeks of gestation (observable conceptions) with an outcome recorded between 2007 and 2010 (n = 8,425). We compared data during and outside the carnival period for each year, including 2009, when there was no carnival due to a 44-day general strike. In all years other than 2009, the weekly number of births was higher for pregnancies initiated during the carnival period than for pregnancies initiated at other times, and the weekly number of observable conceptions was higher during the carnival period than at other times. Our findings support the hypothesis that carnivals in the French West Indies are associated with an increase in the number of conceptions and subsequent births.

Published
2017
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16. Region 2 of 8q24 is associated with the risk of aggressive prostate cancer in Caribbean men of African descent from Guadeloupe (French West Indies)

Author

Geraldine Cancel-Tassin, Marc Romana, Cecile Gaffory, Pascal Blanchet, Olivier Cussenot, and Luc Multigner

Subjects
African Continental Ancestry Group, aggressiveness, Caribbean region, genetic predisposition to disease, prostatic neoplasms, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Multiple regions of the genome have been associated with the risk of prostate cancer in Caucasians, particularly including several polymorphisms located at 8q24. Region 2 of 8q24 has been repeatedly found to be associated with the risk of prostate cancer among men of African descent, although one study performed in the Caribbean island of Jamaica did not report this finding. In this study, the single nucleotide polymorphism rs16901979, located in region 2 of 8q24, was genotyped in 498 cases of histologically confirmed prostate cancer and 541 controls from the French Caribbean islands of Guadeloupe, where the population is largely of African descent. The AA genotype and the A allele at rs16901979 were associated with elevated risks of prostate cancer (odds ratios [ORs] = 1.84, 95% confidence interval [95% CI] = 1.26-2.69, P = 0.002 and OR = 1.36, 95% CI = 1.13-1.64, P = 0.001, respectively). Following stratification of the patients by disease aggressiveness, as defined by the Gleason score, the pooled genotypes AC + AA were associated with a higher risk of a Gleason score ≥7 at diagnosis (OR = 1.79, 95% CI = 1.17-2.73, P = 0.007). In summary, the A allele at rs16901979 was associated with the risk of prostate cancer in the Caribbean population of Guadeloupe, confirming its involvement in populations of African descent. Moreover, our study provides the first evidence of an association between this variant and the risk of aggressive prostate cancer.

Published
2015
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17. Polymorphisms of Estrogen Metabolism-Related Genes and Prostate Cancer Risk in Two Populations of African Ancestry.

Author

Laurent Brureau, Dieudonné Moningo, Elise Emeville, Séverine Ferdinand, Augustin Punga, Simon Lufuma, Pascal Blanchet, Marc Romana, and Luc Multigner

Subjects
Medicine, Science
Abstract

BACKGROUND:Estrogens are thought to play a critical role in prostate carcinogenesis. It has been suggested that polymorphisms of genes encoding enzymes involved in estrogen metabolism are risk factors for prostate cancer. However, few studies have been performed on populations of African ancestry, which are known to have a high risk of prostate cancer. OBJECTIVE:We investigated whether functional polymorphisms of CYP17, CYP19, CYP1B1, COMT and UGT1A1 affected the risk of prostate cancer in two different populations of African ancestry. METHODS:In Guadeloupe (French West Indies), we compared 498 prostate cancer patients and 565 control subjects. In Kinshasa (Democratic Republic of Congo), 162 prostate cancer patients were compared with 144 controls. Gene polymorphisms were determined by the SNaPshot technique or short tandem repeat PCR analysis. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS:The AA genotype and the A allele of rs4680 (COMT) appeared to be inversely associated with the risk of prostate cancer in adjusted models for both Afro-Caribbean and native African men. For the A allele, a significant inverse association was observed among cases with low-grade Gleason scores and localized clinical stage, in both populations. CONCLUSIONS:These preliminary results support the hypothesis that polymorphisms of genes encoding enzymes involved in estrogen metabolism may modulate the risk of prostate cancer in populations of African ancestry.

Published
2016
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18. Secular variations in sperm quality: fact or science fiction? Variações seculares na qualidade dos espermatozóides: fato ou ficção científica?

Author

Luc Multigner and Alejandro Oliva

Subjects
Infertilidade Masculina, Sêmen, Desreguladores Endócrinos, Male Infertility, Semen, Endocrine Disruptors, Medicine, Public aspects of medicine, RA1-1270
Abstract

The debate concerning the possible degradation in human sperm quality began in the 1970s, was revived at the beginning of the 1990s and has continued to mobilize the scientific community ever since. After the meta-analysis by Carlsen et al. (1992) showing a decline in human semen quality over the last 50 years, several groups investigated the sperm characteristics of more or less homogeneous groups of men who had provided semen at the same center for 10 to 20 years. A significant decrease in sperm concentration was reported in some studies, but not in others. Meanwhile, there is an increasing number of reports suggesting that physical and chemical factors introduced and spread by human activity in the environment may have contributed to sperm decline. At the end of the 20th century the debate on declining semen quality is not closed. The lack of certainty and the serious consequences that such a decline would have on the fertility of human populations make this an important public health issue at the start of the 21st century. For this reason, intensive research should be developed in both fundamental and epidemiological domains, particularly in South America, where industrial and agricultural pollution pose a serious threat to the population.O debate sobre o possível declínio na qualidade dos espermatozóides humanos começou nos anos 70, foi reativado no início dos anos 90 e continua mobilizando a comunidade científica desde então. Desde a meta-análise realizada por Carlsen et al. (1992), demonstrando um declínio na qualidade do sêmen humano ao longo dos últimos 50 anos, vários grupos investigaram as características dos espermatozóides de grupos mais ou menos homogêneos de homens que forneceram amostras de sêmen para o mesmo centro ao longo de 10 a 20 anos. Alguns estudos, mas não outros, relataram uma diminuição significativa na concentração de espermatozóides. Enquanto isso, há um número crescente de relatos sugerindo que fatores físicos e químicos antropogênicos possam ter contribuído para a deterioração dos espermatozóides. Até o final do século XX, ainda não havia se encerrado o debate sobre a queda na qualidade do sêmen humano. A falta de certeza e as graves conseqüências que tal declínio teriam sobre a fertilidade de populações humanas tornam esta questão prioritária para a saúde pública no início do século XXI. Portanto, é necessário um enorme esforço de pesquisa básica e epidemiológica, particularmente na América do Sul, onde a poluição industrial e agrícola representa uma grave ameaça à população.

Published
2002
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19. Copy number variation of GSTT1 and GSTM1 and the risk of prostate cancer in a Caribbean population of African descent.

Author

Elise Emeville, Cédric Broquère, Laurent Brureau, Séverine Ferdinand, Pascal Blanchet, Luc Multigner, and Marc Romana

Subjects
Medicine, Science
Abstract

Deletions of the glutathione S-transferase genes M1 and T1 (GSTM1 and GSTT1) have been studied as potential risk factors for prostate cancer. Conflicting results have been obtained. Moreover, most such studies could not discriminate heterozygous from homozygous carriers of the non-deleted alleles.We investigated whether copy number variation (CNV) of the GSTM1 and/or GSTT1 genes contribute to the risk of prostate cancer in the Caribbean population of African descent of Guadeloupe.In a population-based case-control study, we compared 629 prostate cancer patients and 622 control subjects. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Exact copy numbers of GSTM1 and GSTT1 were determined by real-time PCR.A higher copy number of GSTM1 was marginally associated with prostate cancer risk. Men with 2 and 3 or more GSTT1 genes were at higher risk of prostate cancer (OR: 1.55, 95% CI: 1.11-2.16 and OR: 4.89, 95% CI: 1.71-13.99, respectively; P(trend)

Published
2014
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20. Persistent organochlorine pollutants with endocrine activity and blood steroid hormone levels in middle-aged men.

Author

Elise Emeville, Frank Giton, Arnaud Giusti, Alejandro Oliva, Jean Fiet, Jean-Pierre Thomé, Pascal Blanchet, and Luc Multigner

Subjects
Medicine, Science
Abstract

BACKGROUND: Studies relating long-term exposure to persistent organochlorine pollutants (POPs) with endocrine activities (endocrine disrupting chemicals) on circulating levels of steroid hormones have been limited to a small number of hormones and reported conflicting results. OBJECTIVE: We examined the relationship between serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulphate, androstenedione, androstenediol, testosterone, free and bioavailable testosterone, dihydrotestosterone, estrone, estrone sulphate, estradiol, sex-hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone as a function of level of exposure to three POPs known to interfere with hormone-regulated processes in different way: dichlorodiphenyl dichloroethene (DDE), polychlorinated biphenyl (PCB) congener 153, and chlordecone. METHODS: We collected fasting, morning serum samples from 277 healthy, non obese, middle-aged men from the French West Indies. Steroid hormones were determined by gas chromatography-mass spectrometry, except for dehydroepiandrosterone sulphate, which was determined by immunological assay, as were the concentrations of sex-hormone binding globulin, follicle-stimulating hormone and luteinizing hormone. Associations were assessed by multiple linear regression analysis, controlling for confounding factors, in a backward elimination procedure, in multiple bootstrap samples. RESULTS: DDE exposure was negatively associated to dihydrotestosterone level and positively associated to luteinizing hormone level. PCB 153 was positively associated to androstenedione and estrone levels. No association was found for chlordecone. CONCLUSIONS: These results suggested that the endocrine response pattern, estimated by determining blood levels of steroid hormones, varies depending on the POPs studied, possibly reflecting differences in the modes of action generally attributed to these compounds. It remains to be investigated whether this response pattern is predictive of the subsequent occurrence of disease.

Published
2013
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21. Environment as a Risk Factor for Male Infertility

Author

Luc Multigner and Alejandro Oliva

Subjects
Technology, Medicine, Science
Abstract

Infertility affects 15% of couples in Western countries. Infertility is defined as the inability to conceive after 1 year of attempts without contraception, but it is not synonymous with sterility. Between 30 and 50% of infertile couples are infertile due to male reasons, mainly due to sperm production disorders. Although some risk factors, most of which are infectious, have been identified, there is still much uncertainty about the origins of male infertility.

Published
2001
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22. Secular variations in sperm quality: fact or science fiction?

Author

Luc Multigner and Alejandro Oliva

Subjects
Infertilidade Masculina, Sêmen, Desreguladores Endócrinos, Medicine, Public aspects of medicine, RA1-1270
Abstract

The debate concerning the possible degradation in human sperm quality began in the 1970s, was revived at the beginning of the 1990s and has continued to mobilize the scientific community ever since. After the meta-analysis by Carlsen et al. (1992) showing a decline in human semen quality over the last 50 years, several groups investigated the sperm characteristics of more or less homogeneous groups of men who had provided semen at the same center for 10 to 20 years. A significant decrease in sperm concentration was reported in some studies, but not in others. Meanwhile, there is an increasing number of reports suggesting that physical and chemical factors introduced and spread by human activity in the environment may have contributed to sperm decline. At the end of the 20th century the debate on declining semen quality is not closed. The lack of certainty and the serious consequences that such a decline would have on the fertility of human populations make this an important public health issue at the start of the 21st century. For this reason, intensive research should be developed in both fundamental and epidemiological domains, particularly in South America, where industrial and agricultural pollution pose a serious threat to the population.

23. Secular variations in sperm quality: fact or science fiction?

Author

Luc Multigner and Alejandro Oliva

Subjects
male infertility, semen, endocrine disruptors, Medicine, Public aspects of medicine, RA1-1270
Abstract

The debate concerning the possible degradation in human sperm quality began in the 1970s, was revived at the beginning of the 1990s and has continued to mobilize the scientific community ever since. After the meta-analysis by Carlsen et al. (1992) showing a decline in human semen quality over the last 50 years, several groups investigated the sperm characteristics of more or less homogeneous groups of men who had provided semen at the same center for 10 to 20 years. A significant decrease in sperm concentration was reported in some studies, but not in others. Meanwhile, there is an increasing number of reports suggesting that physical and chemical factors introduced and spread by human activity in the environment may have contributed to sperm decline. At the end of the 20th century the debate on declining semen quality is not closed. The lack of certainty and the serious consequences that such a decline would have on the fertility of human populations make this an important public health issue at the start of the 21st century. For this reason, intensive research should be developed in both fundamental and epidemiological domains, particularly in South America, where industrial and agricultural pollution pose a serious threat to the population.

24. Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review [version 1; peer review: 2 approved with reservations]

Author

Laurent Brureau, Luc Multigner, Freddie Hamdy, Pascal Blanchet, and Richard Bryant

Subjects
Systematic Review, Articles, Organochlorine pesticides, prostate cancer, biochemical recurrence, advanced disease
Abstract

Background: There is an increasing body of evidence linking the exposure of an individual to pesticides such as organochlorine pesticides (OPCs) and an increased risk of developing diseases such as cancer. Exposure to OPCs has been suggested to increase the risk of developing hormone-dependant cancers such as prostate cancer (PCa). However, there is a relative paucity of information about the influence of exposure to these pesticides on the evolution of PCa, including risk of tumour development, progression to metastasis, and disease recurrence following therapy. Methods: We used several databases such as PubMed MEDLINE Database, Web of Science, and Scopus, in order to conduct a systematic review of the available epidemiological data implicating an association between exposure to OCPs and biochemical recurrence (BCR) of PCa. We searched all peer-reviewed articles published up to July 31 st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case–control or cohort studies. Results: Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease. Only two studies didn’t demonstrate a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Another study identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa. Conclusion: This review confirmed a relative lack of high-quality evidence regarding this topic. However, the available evidence to date suggests the presence of a potential causal relationship between exposure to OPCs and PCa development and progression.

Published
2021
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25. Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Author

Fei Chen, Ravi K. Madduri, Alex A. Rodriguez, Burcu F. Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J. Saunders, Suhn K. Rhie, Jeannette T. Bensen, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Janet L. Stanford, Wei Zheng, Maureen Sanderson, Esther M. John, Jong Y. Park, Jianfeng Xu, Ying Wang, Sonja I. Berndt, Chad D. Huff, Edward D. Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T. Rentsch, Kelly Cho, Benjamin H. Mcmahon, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A. Sellers, Kosj Yamoah, Adam B. Murphy, Dana C. Crawford, Alpa V. Patel, William S. Bush, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M. Neslund-Dudas, Mariana C. Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B. Cook, Anand P. Chokkalingam, Ann W. Hsing, Phyllis J. Goodman, Thomas J. Hoffmann, Bettina F. Drake, Jennifer J. Hu, Jacob M. Keaton, Jacklyn N. Hellwege, Peter E. Clark, Mohamed Jalloh, Serigne M. Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O. Idowu, Olufemi Popoola, Akindele O. Adebiyi, Oseremen I. Aisuodionoe-Shadrach, Hafees O. Ajibola, Mustapha A. Jamda, Olabode P. Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E. Mensah, Halimatou Diop, Stephen K. Van Den Eeden, Pascal Blanchet, Jay H. Fowke, Graham Casey, Anselm J. Hennis, Alexander Lubwama, Ian M. Thompson, Robin Leach, Douglas F. Easton, Michael H. Preuss, Ruth J. Loos, Susan M. Gundell, Peggy Wan, James L. Mohler, Elizabeth T. Fontham, Gary J. Smith, Jack A. Taylor, Shiv Srivastava, Rosaline A. Eeles, John D. Carpten, Adam S. Kibel, Luc Multigner, Marie-Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A. Klein, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stefan Ambs, Todd L. Edwards, Stephen Watya, Stephen J. Chanock, John S. Witte, William J. Blot, J. Michael Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman, University of Southern California (USC), Keck School of Medicine [Los Angeles], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay

Subjects
Prostate cancer, MESH: Humans, Urology, MESH: Genetic Predisposition to Disease, MESH: Black People, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Male, Polygenic risk score, African ancestry, MESH: Risk Factors, MESH: Prostatic Neoplasms, MESH: Genome-Wide Association Study, Susceptibility loci, Aggressive prostate cancer
Abstract

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Published
2023

26. Exposome chimique et approches « non ciblées »

Author

Vincent Bessonneau, Luc Multigner, Jade Chaker, and Arthur David

Subjects
0303 health sciences, 03 medical and health sciences, General Medicine, 010501 environmental sciences, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology, 0105 earth and related environmental sciences
Abstract

Les avancées techniques en spectrométrie de masse à haute résolution (SMHR), concomitantes au développement d’outils bio-informatiques, permettent aujourd’hui la détection simultanée de plusieurs dizaines de milliers de signaux chimiques dans des matrices biologiques, correspondant à des molécules d’origine exogène (dont les xénobiotiques) et à des molécules endogènes. Ces nouvelles approches reposant sur la SMHR, dites « non ciblées » car sans a priori, représentent une opportunité unique pour caractériser à grande échelle l’exposition de populations humaines aux composés chimiques (ce que l’on appelle exposome chimique interne), et ainsi mieux appréhender leur rôle dans la survenue de maladies chroniques.

Published
2021

27. Prenatal and childhood chlordecone exposure, intellectual abilities and problem behaviors in 7-year-old children: the TIMOUN mother-child cohort in Guadeloupe

Author

Youssef Oulhote, Florence Rouget, Léah Michineau, Christine Monfort, Mireille Desrochers-Couture, Jean-Pierre Thomé, Philippe Kadhel, Luc Multigner, Sylvaine Cordier, and Gina Muckle

Abstract

Background:Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, therefore resulting in a widespread contamination of soils, water sources and foodstuff. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual recognition memory and fine motor development during infancy, and visual contrast sensitivity at school age, with greater susceptibility in boys. Objective:To assess the associations between pre- and postnatal exposures to chlordecone and intellectual and behavioral functions in school-aged children from Guadeloupe. Methods:We examined 576 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children’s blood at age 7 years. Intellectual abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child’s mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex. Results: Blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children’s blood at age 7 years (geometric means [GM]). A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with intellectual abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. In sex-stratified analyses, associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls. Conclusions: These results suggests that intellectual abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems. The persistence of these effects at later age remains to be elucidated.

Published
2022

28. Abstract 3508: Association between clonal hematopoiesis and risk of prostate cancer in a large sample of African ancestry men

Author

Anqi Wang, Yili Xu, Xin Sheng, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W. Fernandez, Akin Olupelumi Adebiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, Adam de Smith, Fei Chen, Burcu F. Darst, David V. Conti, and Christopher A. Haiman

Subjects
Cancer Research, Oncology
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with inflammation, which is a risk factor for cancer, including prostate cancer. We previously reported weak evidence of an association between CHIP and prostate cancer risk in men of European ancestry. However, little is known for African ancestry populations. We investigated the association of age-related CHIP with overall and aggressive prostate cancer risk in a large whole-exome sequencing study of 12,049 African ancestry men, including 7,176 prostate cancer cases (of which 3,283 had aggressive disease and 1,074 had metastatic disease) and 4,873 controls. Somatic variant calling was carried out using GATK Mutect2, and only variants with minor allele frequencies (MAF) 5% were included. Variants with a MAF ≥0.1% in gnomAD were excluded. CHIP variants were identified from a list of pre-specified mutations in 74 genes. Associations were tested using regression models adjusting for age, sub-study, and top 10 principal components, with statistical significance tested by the likelihood ratio test and applying a Bonferroni correction to account for multiple testing. In total, 998 variants in 57 CHIP genes were identified. Consistent with previous results, we observed a strong association between CHIP and age at blood draw. CHIP genes in aggregate were not statistically significantly associated with risks of total (OR=1.12, 95% CI=0.97-1.28), aggressive (OR=1.14, 95% CI=0.92-1.43) or metastatic (OR=1.17, 95% CI=0.91-1.49) prostate cancer. We observed that carriers of variants in DNMT3A, which is the gene that harbors the most CHIP driver mutations, had a nominally elevated risk of prostate cancer compared to non-carriers (OR=1.35, 95% CI=1.08-1.68, p=0.007). Additionally, carriers of variants in EZH2, which is implicated in cancer progression, showed a suggestive association with aggressive prostate cancer (OR=7.33, 95% CI=1.01-53.21, p=0.029). After adjusting for age at blood draw, CHIP genes in aggregate were not associated with age at prostate cancer diagnosis. However, we found that EZH2 variants carriers were diagnosed 12.9 years earlier on average than non-carriers (95% CI=6.1-19.7, adjusted p=0.01). A prostate cancer polygenic risk score (PRS) constructed using 269 risk variants was not associated with CHIP carrier status in aggregate (OR=0.99, 95% CI=0.92-1.06, p=0.70) or with any individual gene (all adjusted p>0.05). In summary, overall CHIP is not likely to be a risk factor of prostate cancer or aggressive disease in men of African ancestry. However, our results do confirm the association of CHIP in DNMT3A with prostate cancer risk as reported in previous studies in men of European ancestry. Future work will be needed to evaluate the biological causality of DNMT3A- and EZH2- related CHIP on prostate cancer. Citation Format: Anqi Wang, Yili Xu, Xin Sheng, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W. Fernandez, Akin Olupelumi Adebiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, Adam de Smith, Fei Chen, Burcu F. Darst, David V. Conti, Christopher A. Haiman. Association between clonal hematopoiesis and risk of prostate cancer in a large sample of African ancestry men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3508.

Published
2023

29. Abstract 1182: Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry

Author

Fei Chen, Burcu F. Darst, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A. Adjei, James Mensah, Pedro W. Fernandez, Akindele O. Adebiyi, Oseremen Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jo McBride, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, David V. Conti, and Christopher A. Haiman

Subjects
Cancer Research, Oncology
Abstract

Background: There is a growing body of evidence supporting the contributions of germline rare variants to the susceptibility of prostate cancer (PCa), especially aggressive PCa. Our previous exome sequencing analysis highlighted 36 aggressive PCa candidate genes in populations of European ancestry. Here we investigated whether rare germline pathogenic, likely pathogenic, or deleterious (P/LD/D) variants in these genes were associated with overall and aggressive PCa risk in men of African ancestry. Methods: This exome sequencing analysis consists of 7,176 prostate cancer cases and 4,873 controls from the Research on Prostate Cancer in Men of African Ancestry (RESPOND) study. Among the PCa cases, 3,283 are aggressive cases (tumor stage T3/T4, regional lymph node involvement, metastatic disease, Gleason score >= 8.0, prostate-specific antigen [PSA] level >= 20 ng/mL or PCa as the underlying cause of death) including 1,074 metastatic cases, and 1,752 are non-aggressive cases (Gleason score ⇐ 7.0, PSA < 20 ng/mL, and tumor stage T1/T2). P/LP/D variants analyzed were rare (minor allele frequency < 1% in controls) and had either a Variant Effect Predictor impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. The association between P/LP/D carrier status with risk of overall PCa, aggressive PCa, and metastatic PCa was evaluated in logistic regression models, adjusting for age and the top ten principal components. All statistical tests are two-sided. Results: Of the 36 PCa candidate genes, BRCA2 was the most frequently affected gene, with 1.7% of cases and 1.1% of controls harboring a germline P/LP/D variant, followed by MUTYH (1.5%/1.3%) ATM (0.93%/0.49%), MSH5 (0.70%/0.51%) and HOXB13 (0.70%/0.35%). Nominally significant associations with overall PCa were observed for ATM (OR=1.83, 95% CI=1.14-2.92, P=0.012), BRCA2 (OR=1.52, 95% CI=1.10-2.10, P=0.011), HOXB13 (OR=2.10, 95% CI=1.12-3.66, P=0.008), and PALB2 (OR=3.46, 95% CI=1.18-10.1, P=0.02). In case-case analyses (aggressive vs. non-aggressive cases), the association with aggressive PCa was nominally significant for ATM (OR=5.10, 95% CI=1.96-13.3, P=8.7 × 10−4) and BRCA2 (OR=2.00, 95% CI=1.19-3.38, P=0.009) and was suggestive for PALB2 (OR=2.99, 95% CI=0.83-10.7, P=0.09). Similar associations with metastatic PCa were also observed for these three genes. Conclusion: The associations of BRCA2, ATM, and PALB2 with overall PCa and aggressive PCa observed in men of African ancestry are consistent with findings from our previous study in men of European ancestry. These findings further support the importance of these genes in the consideration of screening and active surveillance for high-risk and advanced disease. Citation Format: Fei Chen, Burcu F. Darst, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A. Adjei, James Mensah, Pedro W. Fernandez, Akindele O. Adebiyi, Oseremen Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jo McBride, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, David V. Conti, Christopher A. Haiman. Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1182.

Published
2023

30. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Minh-Phuong, Huynh-Le, Roshan, Karunamuni, Chun Chieh, Fan, Lui, Asona, Wesley K, Thompson, Maria Elena, Martinez, Rosalind A, Eeles, Zsofia, Kote-Jarai, Kenneth R, Muir, Artitaya, Lophatananon, Johanna, Schleutker, Nora, Pashayan, Jyotsna, Batra, Henrik, Grönberg, David E, Neal, Børge G, Nordestgaard, Catherine M, Tangen, Robert J, MacInnis, Alicja, Wolk, Demetrius, Albanes, Christopher A, Haiman, Ruth C, Travis, William J, Blot, Janet L, Stanford, Lorelei A, Mucci, Catharine M L, West, Sune F, Nielsen, Adam S, Kibel, Olivier, Cussenot, Sonja I, Berndt, Stella, Koutros, Karina Dalsgaard, Sørensen, Cezary, Cybulski, Eli Marie, Grindedal, Florence, Menegaux, Jong Y, Park, Sue A, Ingles, Christiane, Maier, Robert J, Hamilton, Barry S, Rosenstein, Yong-Jie, Lu, Stephen, Watya, Ana, Vega, Manolis, Kogevinas, Fredrik, Wiklund, Kathryn L, Penney, Chad D, Huff, Manuel R, Teixeira, Luc, Multigner, Robin J, Leach, Hermann, Brenner, Esther M, John, Radka, Kaneva, Christopher J, Logothetis, Susan L, Neuhausen, Kim, De Ruyck, Piet, Ost, Azad, Razack, Lisa F, Newcomb, Jay H, Fowke, Marija, Gamulin, Aswin, Abraham, Frank, Claessens, Jose Esteban, Castelao, Paul A, Townsend, Dana C, Crawford, Gyorgy, Petrovics, Ron H N, van Schaik, Marie-Élise, Parent, Jennifer J, Hu, Wei, Zheng, Ian G, Mills, Ole A, Andreassen, Anders M, Dale, Tyler M, Seibert, collaborators, UKGPCS, BioResource), APCB (Australian Prostate Cancer, Investigators, NC-LA PCaP, Collaborators, IMPACT Study Steering Committee and, Investigators, Canary PASS, Committee, Profile Study Steering, Consortium, PRACTICAL, and Clinical Chemistry

Subjects
SELECTION, Male, Cancer Research, Urology, LASSO, Polymorphism, Single Nucleotide, Risk Assessment, Cancer screening, Cancer epidemiology, SDG 3 - Good Health and Well-being, Risk Factors, Humans, Genetic Predisposition to Disease, prostate cancer, multi-ancestry datasets, Cancer genetics, Early Detection of Cancer, Prostatic Neoplasms/diagnosis, Cancer och onkologi, Science & Technology, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Prostatic Neoplasms, Urology & Nephrology, Prostate-Specific Antigen, Prostate-Specific Antigen/genetics, Oncology, Cancer and Oncology, Life Sciences & Biomedicine
Abstract

Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. Methods In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. Results The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43–15.16] in ProtecT, 7.07 [6.58–7.60] in African ancestry, 10.31 [9.58–11.11] in Asian ancestry, and 11.18 [10.34–12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11–0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15–0.22) and 0.26 (0.19–0.33), respectively. Conclusions We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022

31. A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry

Author

Luc Multigner, William J. Blot, Alexander Lubwama, Stephen Watya, Peter E. Clark, Lucy Xia, Sara S. Strom, Adam S. Kibel, Jong Y. Park, Adam B. Murphy, Jennifer Cullen, Christopher A. Haiman, Florence Menegaux, Shiv Srivastava, Loreall Pooler, Mariana C. Stern, Anand P. Chokkalingam, Eric A. Klein, Wei Zheng, Thomas A. Sellers, Anselm Hennis, Dana C. Crawford, James L. Mohler, Jack A. Taylor, Esther M. John, Robin J. Leach, Sonja I. Berndt, Laurent Brureau, John D. Carpten, Susan Gundell, David V. Conti, Barbara Nemesure, Rosalind A. Eeles, Graham Casey, Pascal Blanchet, Benjamin A. Rybicki, Chad D. Huff, Maureen Sanderson, Stephen J. Chanock, Melinda C. Aldrich, Jay H. Fowke, Jennifer J. Hu, Diptasri Mandal, Sue A. Ingles, Kosj Yamoah, Kathleen A. Cooney, K. Govindasami, Ian M. Thompson, Patrick C. Walsh, Xin Sheng, Zsofia Kote-Jarai, Janet L. Stanford, Marie-Élise Parent, Christine Neslund-Dudas, Jianfeng Xu, William S. Bush, Phyllis J. Goodman, Meredith Yeager, Burcu F. Darst, Gary J. Smith, Victoria L. Stevens, Rick A. Kittles, Elaine A. Ostrander, Olivier Cussenot, Gyorgy Petrovics, Elizabeth T. H. Fontham, William B. Isaacs, Peggy Wan, Geraldine Cancel-Tassin, Susan M. Gapstur, Bettina F. Drake, Jeannette T. Bensen, University of Southern California (USC), Centre de Recherche pour les Pathologies Prostatiques. (CeRePP / UA 3104), CEREPP, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], U19 CA148537, U19 CA214253, R01 CA165862, and K99 CA246063, National Cancer Institute at the National Institutes of Health, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, medicine.medical_specialty, Urology, Family history, Population, 030232 urology & nephrology, Black People, Familial prostate cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Familial clustering, Risk Assessment, Article, Germline, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Internal medicine, Genetics, Humans, Medicine, education, Genetic variant, Aged, education.field_of_study, business.industry, Genetic Variation, Prostatic Neoplasms, 8q24, Middle Aged, medicine.disease, Health equity, 3. Good health, Disease Hotspot, Germ Cells, Prostate cancer screening, African ancestry, 030220 oncology & carcinogenesis, Health disparities, business
Abstract

International audience; Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age

Published
2020

32. Persistent organochlorine pesticides in periprostatic adipose tissue from men with prostate cancer: Ethno-geographic variations, association with disease aggressiveness

Author

Jean-Philippe Antignac, Sandy Figiel, Michèle Pinault, Pascal Blanchet, Franck Bruyère, Romain Mathieu, Souhil Lebdai, Georges Fournier, Jerome Rigaud, Karine Mahéo, Philippe Marchand, Ingrid Guiffard, Emmanuelle Bichon, Bruno le Bizec, Luc Multigner, Gaëlle Fromont, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Nantes (CHU Nantes), and The authors thank 'Canceropole Grand Ouest', 'Region Bretagne', 'Region Pays-de-Loire' and 'Region 'Centre-Val-de-Loire', for financial support.

Subjects
Male, Prostate cancer, Persistent organic pollutants, Prostatic Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Exposure, Adipose Tissue, [SDE]Environmental Sciences, Hydrocarbons, Chlorinated, Organochlorine pesticides, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Fatty acids, Pesticides, Mirex, General Environmental Science
Abstract

International audience; Although several studies have examined the relationship between organochlorine pesticides (OCPs) and prostate cancer (PCa) risk, no data are available concerning the association between OCPs concentrations in periprostatic adipose tissue (PPAT), which reflects cumulative exposure, and PCa aggressiveness. Moreover, no previous study has compared OCPs exposure in two distinct ethno-geographical populations. The objectives were to analyze OCPs in PPAT of PCa patients from either Mainland France or French West Indies in correlation with features of tumor aggressiveness, after adjusting for potential confounders such age, BMI, and polyunsaturated fatty acid (PUFA) content of PPAT. PPAT was analyzed in 160 patients (110 Caucasians and 50 African-Caribbeans), 80 with an indolent tumor (ISUP group 1 + pT2), and 80 with an aggressive tumor (ISUP group more than 3 + pT3). The concentrations of 29 OCPs were measured in PPAT concomitantly with the characterization of PUFA content. Exposure patterns of OCPs differed according to the ethno-geographical origin. Most OCPs were found at higher concentration in Caucasian patients, whereas pp’-DDE content was twice as high in African-Caribbeans. Chlordecone was only detected in PPAT from African-Caribbean patients. Most OCP concentrations were positively correlated with age, and some with BMI. After adjusting for age, BMI, and PUFA composition of PPAT, no significant association was found between OCPs content and risk of aggressive disease, except of mirex which appeared inversely associated with aggressive features of PCa in Caucasian patients. These results highlight a significant ethno-geographic variation in internal exposure to OCPs, which likely reflects differences in consumption patterns. The inverse relationship observed between mirex concentration and markers of PCa aggressiveness need to be further investigated.

Published
2023

33. Metabolic syndrome and prostate cancer in Afro-Caribbean men

Author

Florian Lefebvre, Anne Blanchet‐Deverly, Leah Michineau, Pascal Blanchet, Luc Multigner, Laurent Brureau, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), French National Health Directorate (Grant No.: R20153NN), and Chard-Hutchinson, Xavier

Subjects
Male, Urology, [SDV]Life Sciences [q-bio], Black People, metabolic syndrome, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Prevalence, Humans, 030212 general & internal medicine, Obesity, Guadeloupe, 2. Zero hunger, Prostate, Prostatic Neoplasms, Middle Aged, Prostate-Specific Antigen, prostate cancer, radical prostatectomy, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Neoplasm Grading, Afro-Caribbean
Abstract

International audience; INTRODUCTION AND OBJECTIVES: Metabolic syndrome (MetS) is a group of risk factors that increases the likelihood of developing cardiovascular diseases. Although suggested, the relationship between MetS and prostate cancer (PCa) is still inconclusive. Very few studies have addressed this question in populations of African descent, which are disproportionately affected by PCa. This study aimed to assess the prevalence of MetS among incident cases of Afro-Caribbean PCa and estimate its association with adverse clinicopathological features and the risk of biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: We included 285 consecutive patients with incident cases of PCa attending the University Hospital of Guadeloupe (French West Indies). MetS was evaluated at the time of diagnosis by collecting information on blood pressure, glycaemic status, triglyceride and high-density lipoprotein cholesterol levels, and obesity through various surrogates, including two waist circumference indicators (≤94 cm, ≥102 cm), the waist-to-hip ratio (≥0.95), and body mass index (BMI; ≥30 kg/m(2) ). We followed 245 patients who underwent RP as primary treatment of localized PCa. RESULTS: The prevalence of MetS varied greatly, from 31.6% to 16.4%, when a waist circumference ≥94 cm or BMI were used as obesity surrogates, respectively. No significant associations were found between MetS, regardless of the obesity criteria employed, and the risk of adverse pathological features or BCR. CONCLUSIONS: The high variability in MetS resulting from the diversity of obesity criteria used may explain the discordant associations reported in the literature. Further studies using strict and uniform criteria to define MetS on homogeneous ethnic groups are encouraged to clarify the association, if any, between MetS and PCa outcomes.

Published
2021

34. Visuospatial processing and fine motor function among 7-years old Guadeloupe children pre- and postnatally exposed to the organochlorine pesticide chlordecone

Author

Mireille Desrochers-Couture, Sylvaine Cordier, Florence Rouget, Léah Michineau, Christine Monfort, Jean-Pierre Thomé, Philippe Kadhel, Luc Multigner, Gina Muckle, Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Université de Liège, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Chard-Hutchinson, Xavier, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Male, Insecticides, [SDV]Life Sciences [q-bio], 010501 environmental sciences, Toxicology, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Tremor, Humans, Guadeloupe, Motor function, 0105 earth and related environmental sciences, Organochlorine pesticide, General Neuroscience, Environmental Exposure, Childhood, 3. Good health, [SDV] Life Sciences [q-bio], Visual processing, Motor Skills, Chlordecone, Prenatal Exposure Delayed Effects, Female, Psychomotor Disorders, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: Chlordecone is an organochlorine that was largely used as an insecticide to control a species of root borers, the Banana weevil (Cosmopolites sordidus), in the French West Indies, Guadeloupe and Martinique. Its molecules have been shown to be very persistent in the environment as pollution in soils leading to contamination of water sources and foodstuff will last for several decades. Our team previously reported associations between prenatal chlordecone exposure and poorer fine motor development at two points in time during infancy. OBJECTIVE: To document whether effects of prenatal exposure to chlordecone previously reported persists until middle-childhood, and whether deleterious effects are observed in domain of visual processing. Associations with postnatal exposure and sex-specific vulnerabilities were also investigated. METHODS: We examined 410 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children’s blood at age 7 years. Fine motor function was assessed using the Bruininks Oseretsky Test of Motor Proficiency Second Edition (BOT-2). The Computerized Adaptive Testing System (CATSYS) was used to evaluated postural hand tremor, while non-verbal visuospatial processing was measured using the Stanford Binet copying (S-B copying) test. We used adjusted multiple linear regressions to test the relationship between children’s scores and both continuous and categorical blood chlordecone concentrations, adding child sex as a moderator in continuous models. RESULTS: Cord chlordecone concentrations are associated with a regular frequency pattern of subtle hand tremors in both hands, and not related to visual processing and fine motor precision. Chlordecone concentrations in blood sample collected at testing time are associated with poorer visual processing when copying geometric figures, but not significantly related to poorer fine movement precision in tasks requiring pencil, scissors and paper. No sex-specific vulnerability was reported in any of the outcomes. CONCLUSIONS: These results at school aged expand those previously reported in the same cohort during infancy at age 7- and 18 months, and corroborate the negative effects of chlordecone exposure on fine motor function in absence of intoxication. Our results support the need to continue public health efforts aimed at reducing exposure especially among women of child bearing age and young children.

Published
2021

35. Chlordecone: development of a physiologically based pharmacokinetic tool to support human health risks assessments

Author

Claude Emond, Luc Multigner, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Montréal (UdeM), École des Hautes Études en Santé Publique [EHESP] (EHESP), French Agency for Biodiversity (AFB) [R17148NN], and Chard-Hutchinson, Xavier

Subjects
PBPK, Insecticides, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, West Indies, Pharmacokinetic, Musa, General Medicine, Toxicology, Rats, [SDV] Life Sciences [q-bio], Soil, Chlordecone, French West Indies, Animals, Humans, Soil Pollutants, Pesticides
Abstract

Chlordecone (CD; Kepone™) is a carcinogenic organochlorine insecticide with neurological, reproductive, and developmental toxicity that was widely used in the French West Indies (FWI) from 1973 to 1993 to fight banana weevils. Although CD has not been used there for more than 25 years, it still persists in the environment and has polluted the waterways and soil of current and older banana fields. Today, human exposure to CD in the FWI mainly arises from consuming contaminated foodstuffs. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model in the rat and extrapolate it to humans based on available pharmacokinetic data in the literature. A comparison of simulations using the rat model with published experimental datasets showed reasonable predictability for single and repetitive doses, and, thus, it was extrapolated to humans. The human PBPK model, which has seven compartments, is able to simulate the blood concentrations of CD in human populations and estimate the corresponding external dose using the reverse dosimetry approach. The human PBPK model will make it possible to improve quantitative health risk assessments for CD contamination and reassess the current chronic toxicological reference values to protect the FWI population.

Published
2021

36. [Chemical exposome and non-targeted approaches]

Author

Arthur, David, Jade, Chaker, Luc, Multigner, Vincent, Bessonneau, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), and Département Santé Environnement Travail et Génie Sanitaire (DSETGS)

Subjects
Exposome, Chronic diseases, [SDV]Life Sciences [q-bio], [SDE]Environmental Sciences, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Environmental Exposure, Expositions chimiques, Chemical exposures, Maladies chroniques, Mass Spectrometry
Abstract

The technological advances in high-resolution mass spectrometry (HRMS), associated with the development of bioinformatics tools, allows the simultaneous detection of tens of thousands of chemical signals in biological matrices, including exogenous (i.e. xenobiotics) and endogenous molecules. These novel approaches based on HRMS, called "non-targeted" approaches, provide a unique opportunity to capture exposures to a wide range of chemicals (i.e. the internal chemical exposome) in populations, and to better understand the links between chemical exposures and the occurrence of chronic diseases.Exposome chimique et approches « non ciblées » - Un changement de paradigme pour évaluer l’exposition des populations aux contaminants chimiques.Les avancées techniques en spectrométrie de masse à haute résolution (SMHR), concomitantes au développement d’outils bio-informatiques, permettent aujourd’hui la détection simultanée de plusieurs dizaines de milliers de signaux chimiques dans des matrices biologiques, correspondant à des molécules d’origine exogène (dont les xénobiotiques) et à des molécules endogènes. Ces nouvelles approches reposant sur la SMHR, dites « non ciblées » car sans a priori, représentent une opportunité unique pour caractériser à grande échelle l’exposition de populations humaines aux composés chimiques (ce que l’on appelle exposome chimique interne), et ainsi mieux appréhender leur rôle dans la survenue de maladies chroniques.

Published
2021

37. Prostate cancer risk stratification improved across multiple ancestries with new polygenic hazard score

Author

Christopher J. Logothetis, Manolis Kogevinas, Piet Ost, Jong Y. Park, Minh-Phuong Huynh-Le, Johanna Schleutker, Jose E. Castelao, Apcb, Stella Koutros, Canary Pass Investigators, Rosalind A. Eeles, Robin J. Leach, David E. Neal, Janet L. Stanford, Ana Vega, Roshan Karunamuni, Radka Kaneva, Olivier Cussenot, Azad Hassan Abdul Razack, Anders M. Dale, Gyorgy Petrovics, Wei Zheng, Sue A. Ingles, William J. Blot, Esther M. John, Chun Chieh Fan, Ruth C. Travis, Lorelei A. Mucci, Robert J. Hamilton, Wesley K. Thompson, Luc Multigner, Demetrius Albanes, Artitaya Lophatananon, Fredrik Wiklund, Marie-Élise Parent, Christopher A. Haiman, Frank Claessens, Florence Menegaux, Susan L. Neuhausen, Alicja Wolk, Maria Elena Martinez, Kathryn L. Penney, Catherine M. Tangen, Tyler M. Seibert, Jennifer J. Hu, Hermann Brenner, Sune F. Nielsen, Jyotsna Batra, Marija Gamulin, Ian G. Mills, Nc-La PCaP Investigators, Christiane Maier, Barry S. Rosenstein, Stephen Watya, Aswin George Abraham, Manuel R. Teixeira, Lui Asona, Yong-Jie Lu, Kim De Ruyck, Paul A Townsend, Sonja I. Berndt, Eli Marie Grindedal, Ole A. Andreassen, Catharine M L West, Ron H.N. van Schaik, Zsofia Kote-Jarai, Lisa F. Newcomb, Kenneth Muir, Børge G. Nordestgaard, Karina Dalsgaard Sørensen, Chad D. Huff, Jay H. Fowke, Henrik Grönberg, Dana C. Crawford, Adam S. Kibel, Robert J. MacInnis, Cezary Cybulski, and Nora Pashayan

Subjects
Oncology, Prostate cancer risk, medicine.medical_specialty, business.industry, Proportional hazards model, Hazard ratio, Single-nucleotide polymorphism, medicine.disease, Prostate cancer, Prostate cancer screening, Internal medicine, Cohort, medicine, Genetic risk, business
Abstract

IntroductionProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2021

38. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

Author

Jennifer Cullen, Brandon A. Mahal, Maria Elena Martinez, Robin J. Leach, Brent S. Rose, Marie-Élise Parent, Catherine M. Tangen, Pascal Blanchet, Tyler M. Seibert, Jong Y. Park, Jennifer J. Hu, Geraldine Cancel-Tassin, Rosalind A. Eeles, Chun Chieh Fan, Esther M. John, Roshan Karunamuni, James L. Mohler, Jack A. Taylor, Melinda C. Aldrich, Artitaya Lophatananon, Luc Multigner, Ole A. Andreassen, Thérèse Truong, Marc Romana, Florence Menegaux, Ian M. Thompson, Laurent Brureau, Kenneth Muir, Olivier Cussenot, Dana C. Crawford, Adam S. Kibel, Gyorgy Petrovics, Asona Lui, Elizabeth T. H. Fontham, Bettina F. Drake, Jeannette T. Bensen, Ian G. Mills, William S. Bush, Hui-Yi Lin, Zsofia Kote-Jarai, Wesley K. Thompson, Maureen Sanderson, Anders M. Dale, Wei Zheng, Jay H. Fowke, Phyllis J. Goodman, William J. Blot, Minh-Phuong Huynh-Le, Collaborators, UKGPCS, Consortium, PRACTICAL, University of California [San Diego] (UC San Diego), University of California, The institute of cancer research [London], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), This study was funded in part by grants from the University of California (#C21CR2060), the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), the Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority., University of California (UC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité)

Subjects
Male, Multifactorial Inheritance, Cancer Research, Urology, Genetic genealogy, 030232 urology & nephrology, Black People, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Risk Assessment, White People, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genotype, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, 1000 Genomes Project, Prostate cancer risk, Proportional hazards model, business.industry, Prostatic Neoplasms, 3. Good health, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Relative risk, business, Chromosomes, Human, Pair 8, Demography
Abstract

Background We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Materials and methods Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. Results CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. Conclusion We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Published
2021

39. In utero exposure to chlordecone affects histone modifications and activates LINE-1 in cord blood

Author

Louis, Legoff, Shereen Cynthia, D'Cruz, Katia, Bouchekhchoukha, Christine, Monfort, Christian, Jaulin, Luc, Multigner, Fatima, Smagulova, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), R13139NS, Atip-Avenir, ARED/INSERM fellowship, R20024NN, French National Health Directorate Grant, Chard-Hutchinson, Xavier, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, DNA Methylation, Fetal Blood, Epigenesis, Genetic, Histone Code, Histones, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Long Interspersed Nucleotide Elements, Chlordecone, Pregnancy, Cell Line, Tumor, Prenatal Exposure Delayed Effects, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Humans, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Female, sense organs, Cordocentesis, Promoter Regions, Genetic, Research Articles, Research Article
Abstract

In utero exposure to chlordecone affects chromatin and leads to activation of retroelements. This study shows the changes induced by chlordecone in human umbilical cord blood and blood-derived cell line., Environmental factors can induce detrimental consequences into adulthood life. In this study, we examined the epigenetic effects induced by in utero chlordecone (CD) exposure on human male cord blood as well as in blood-derived Ke-37 cell line. Genome-wide analysis of histone H3K4me3 distribution revealed that genes related to chromosome segregation, chromatin organization, and cell cycle have altered occupancy in their promoters. The affected regions were enriched in ESR1, SP family, and IKZF1 binding motifs. We also observed a global reduction in H3K9me3, markedly in repeated sequences of the genome. Decrease in H3K9me3 after CD exposure correlates with decreased methylation in LINE-1 promoters and telomere length extension. These observations on human cord blood were assessed in the Ke-37 human cell line. H3K4me3 and the expression of genes related to immune response, DNA repair, and chromatin organization, which were affected in human cord blood were also altered in CD-exposed Ke-37 cells. Our data suggest that developmental exposure to CD leads to profound changes in histone modification patterns and affects the processes controlled by them in human cord blood.

Published
2021

40. A cohort study of banana plantation workers in the French West Indies: first mortality analysis (2000–2015)

Author

Mounia El-Yamani, Amandine Vaidie, Leah Michineau, Danièle Luce, Luc Multigner, Julien Dugas, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), Santé publique France - French National Public Health Agency [Saint-Maurice, France], General Social Security Funds (Caisses Generales de Securite Sociale) of Guadeloupe, and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, West Indies, occupational cohort, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, Population, standardized mortality ratio (SMR), Organochlorine insecticide, 010501 environmental sciences, 01 natural sciences, Cohort Studies, pesticides 1, Neoplasms, Occupational Exposure, French West Indies, Humans, Environmental Chemistry, Medicine, banana plantations, Pesticides, Lung cancer, education, Stomach cancer, 0105 earth and related environmental sciences, West indies, education.field_of_study, business.industry, Musa, General Medicine, Banana plantation, medicine.disease, mortality, Pollution, 3. Good health, Occupational Diseases, Cohort, Female, business, Demography, Cohort study
Abstract

International audience; Chlordecone, an organochlorine insecticide, was widely used in the French West Indies banana plantations. We set up a cohort of banana plantation workers who worked between 1973 and 1993, the period of authorized use of chlordecone. Vital status and causes of death were collected from French national registries. Workers were followed up from 1 January 2000 to 31 December 2015. Cause-specific mortality in the cohort was compared to that of the general population of the French West Indies by computing standardized mortality ratios (SMRs). A total of 11,112 workers (149,526 person-years, 77% men) were included in the mortality analysis, and 3647 deaths occurred over the study period. There was a slight deficit in all-cause mortality, which was statistically significant in men (SMR = 0.93, 95% CI 0.89-0.96), but not in women (SMR = 0.96, 95% CI 0.89-1.04). All-cancer mortality did not differ significantly from that of the general population (men SMR = 0.96, 95% CI 0.90-1.03; women SMR = 1.04, 95% CI 0.89-1.21). Significant excesses of deaths were observed for stomach cancer in women (SMR = 1.94, 95% CI 1.24-2.89) and pancreatic cancer in women farm owners (SMR = 2.31, 95% CI 1.06-4.39). Mortality from prostate cancer was similar to that of the general population in the whole cohort (SMR = 1.00; 95% CI 0.89-1.13) and non-significantly elevated among farm workers (SMR = 1.10, 95% CI 0.87-1.36). Non-significant increases in mortality were also observed for lung cancer in women, leukemia in men, and non-Hodgkin lymphoma in both genders.

Published
2019

41. Chlordecone exposure and risk of congenital anomalies: the Timoun Mother-Child Cohort Study in Guadeloupe (French West Indies)

Author

Sylvaine Cordier, Philippe Kadhel, Jean-Pierre Thomé, Jean-François Viel, Christine Monfort, Florence Rouget, Luc Multigner, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Liège, DGS RMC11129NNA, French General Health Directorate, and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Congenital anomalies, Insecticides, [SDV]Life Sciences [q-bio], West Indies, Health, Toxicology and Mutagenesis, Population, Mothers, Physiology, 010501 environmental sciences, Organochlorine, Logistic regression, 01 natural sciences, Persistence (computer science), Cohort Studies, Pregnancy, Cryptorchidism, French West Indies, Humans, Environmental Chemistry, Medicine, Child, education, Guadeloupe, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, West indies, 2. Zero hunger, Endocrine-disrupting chemicals, education.field_of_study, business.industry, Confounding, General Medicine, Odds ratio, Newborn, Pollution, 3. Good health, Chlordecone, 13. Climate action, Malformations, Gestation, Undescended testes, Female, business, Cohort study
Abstract

Chlordecone is an organochlorine pesticide that was extensively used to control the banana root borer population in the French West Indies until 1993. Its persistence in soil has led to widespread pollution of the environment, and human beings, including pregnant women, are still exposed to this chemical. High levels of exposure to chlordecone during gestation have been shown to cause congenital anomalies, including undescended testes in rodents. We assessed the associations between chlordecone concentrations in maternal and cord plasma and the risk of congenital anomalies in the Timoun Mother-Child Cohort Study (2004-2007) that included 1068 pregnant women in Guadeloupe. Odds ratios were estimated using unconditional logistic regression analysis, controlling for confounding factors. The median plasma concentrations in maternal and cord plasma were 0.39 μg/L and 0.20 μg/L, respectively. Thirty-six children were diagnosed with malformations according to the European Registration of Congenital Anomalies guidelines and 25 with undescended testes. There was no association between maternal or cord plasma concentration of chlordecone and the risk of overall malformations nor undescended testes. These results suggest that prenatal exposure to the currently observed environmental levels of chlordecone in French West Indies does not increase the risk of birth defects.

Published
2019

42. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author

Florence Menegaux, William J. Blot, Henrik Grönberg, Luc Multigner, Sune F. Nielsen, Stella Koutros, Frank Claessens, Manuela Gago-Dominguez, Kathryn L. Penney, Tyler M. Seibert, Cezary Cybulski, Jennifer J. Hu, Hermann Brenner, Radka Kaneva, Sue A. Ingles, Catherine M. Tangen, Ian G. Mills, Janet L. Stanford, Karina Dalsgaard Sørensen, Ruth C. Travis, Marie-Élise Parent, Monique J. Roobol, Nora Pashayan, Jyotsna Batra, Maria Elena Martinez, Anders M. Dale, Wei Zheng, Kay-Tee Khaw, Chad D. Huff, Chun Chieh Fan, Paul A. Townsend, Kim De Ruyck, Yong-Jie Lu, Eli Marie Grindedal, Hardev Pandha, Sonja I. Berndt, Susan L. Neuhausen, Alicja Wolk, Apcb, Wesley K. Thompson, Maureen Sanderson, Demetrius Albanes, Stephen N. Thibodeau, Christiane Maier, Kenneth Muir, Robin J. Leach, Børge G. Nordestgaard, Ole A. Andreassen, Fredrik Wiklund, Graham G. Giles, Zsofia Kote-Jarai, Catharine M L West, Minh-Phuong Huynh-Le, Manolis Kogevinas, Manuel R. Teixeira, Jong Y. Park, Johanna Schleutker, Marija Gamulin, Freddie C. Hamdy, William S. Bush, Barry S. Rosenstein, Stephen Watya, Roshan Karunamuni, Richard M. Martin, Nc-La PCaP Investigators, Ana Vega, Adam S. Kibel, Lisa A. Cannon-Albright, Azad Hassan Abdul Razack, Esther M. John, Christopher J. Logothetis, Jay H. Fowke, Nawaid Usmani, David E. Neal, Canary Pass Investigators, Rosalind A. Eeles, Robert J. Hamilton, Lisa F. Newcomb, Jenny L Donovan, Olivier Cussenot, Lorelei A. Mucci, University of California [San Diego] (UC San Diego), University of California, The institute of cancer research [London], University of Manchester [Manchester], University of Turku, Centre for Cancer Genetic Epidemiology [Cambridge], Department of Oncology-University of Cambridge [UK] (CAM), University College of London [London] (UCL), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), This study was funded in part by a grant from the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), United States Department of Defense (#W81XWH-13-1-0391), University of California CRCC C21CR2060, the Research Council of Norway (#223273), K.G. Jebsen Stiftelsen, and South East Norway Health Authority. RM Martin is supported in part by the National Institute for Health Research Bristol Biomedical Research Centre. The CAP trial is funded by Cancer Research UK and the UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326, C18281/A15064, and C18281/A24432). R.M. Martin was supported by a Cancer Research UK (C18281/A19169) program grant (the Integrative Cancer Epidemiology Programme). Funding for the PRACTICAL consortium member studies is detailed in the Supplementary Information., University of California (UC), University of Cambridge [UK] (CAM)-Department of Oncology, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Huynh-Le, Minh-Phuong [0000-0002-5025-4709], Fan, Chun Chieh [0000-0001-9437-2128], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Pashayan, Nora [0000-0003-0843-2468], Batra, Jyotsna [0000-0003-4646-6247], Grönberg, Henrik [0000-0002-1073-2753], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Wiklund, Fredrik [0000-0002-4623-0544], Giles, Graham G [0000-0003-4946-9099], Wolk, Alicja [0000-0001-7387-6845], Travis, Ruth C [0000-0002-9571-0763], Zheng, Wei [0000-0003-1226-070X], West, Catharine ML [0000-0002-0839-3449], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Park, Jong Y [0000-0002-6384-6447], Vega, Ana [0000-0002-7416-5137], Teixeira, Manuel R [0000-0002-4896-5982], Multigner, Luc [0000-0003-3205-8568], Cannon-Albright, Lisa [0000-0003-2602-3668], Gamulin, Marija [0000-0003-2431-7910], Bush, William S [0000-0002-9729-6519], Roobol, Monique J [0000-0001-6967-1708], Andreassen, Ole A [0000-0002-4461-3568], Seibert, Tyler M [0000-0002-4089-7399], Apollo - University of Cambridge Repository, and Clinical Chemistry

Subjects
0301 basic medicine, Oncology, Male, Multifactorial Inheritance, Aging, Multivariate analysis, Ethnic Groups/genetics, General Physics and Astronomy, UKGPCS collaborators, Prostate cancer, 0302 clinical medicine, Urologi och njurmedicin, Ethnicity, risk factors, PRACTICAL Consortium, genetics, Stage (cooking), AgedEthnic Groups / genetics, Cancer, Multidisciplinary, Manchester Cancer Research Centre, Prostatic Neoplasms/genetics, Prostate Cancer, Hazard ratio, APCB, Middle Aged, Hazard, Health equity, 3. Good health, Multidisciplinary Sciences, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, polygenic hazard score (PHS1), prostate cancer, ICEP, Medical Genetics, Urologic Diseases, medicine.medical_specialty, hazard, precision medicine, Science, Prostatic Neoplasms / genetics, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ethnic Groups, survival, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Medical research, SDG 3 - Good Health and Well-being, Internal medicine, NC-LA PCaP Investigators, Genetic model, medicine, Urology and Nephrology, Humans, Neoplasm Invasiveness, Multifactorial Inheritance/genetics, Medicinsk genetik, Aged, Canary PASS Investigators, Science & Technology, IMPACT Study Steering Committee and Collaborators, business.industry, Profile Study Steering Committee, ResearchInstitutes_Networks_Beacons/mcrc, Prostatic Neoplasms, General Chemistry, medicine.disease, Multifactorial Inheritance / genetics, 030104 developmental biology, Multivariate Analysis, Self Report, business, Biomarkers
Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p, A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Published
2021

43. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

Author

Marc Romana, Pascal Blanchet, Hui Yi Lin, Catherine M. Tangen, William J. Blot, Florence Menegaux, Marie-Élise Parent, Jennifer Cullen, Robin J. Leach, Geraldine Cancel-Tassin, Wesley Thompson, Adam S. Kibel, Chun Chieh Fan, Melinda C. Aldrich, Artitaya Lophatananon, Kenneth Muir, Minh-Phuong Huynh-Le, Brandon A. Mahal, Ole A. Andreassen, Thérèse Truong, Jong Y. Park, Ian M. Thompson, Dana C. Crawford, Olivier Cussenot, Gyorgy Petrovics, Luc Multigner, Elizabeth T. H. Fontham, James L. Mohler, Maria Elena Martinez, Jay H. Fowke, Jack A. Taylor, Esther M. John, Phyllis J. Goodman, Zsofia Kote-Jarai, Roshan Karunamuni, Maureen Sanderson, Ian G. Mills, Tyler M. Seibert, Jennifer J. Hu, Anders M. Dale, William S. Bush, Wei Zheng, Asona Lui, Bettina F. Drake, Jeannette T. Bensen, Rosalind A. Eeles, Laurent Brureau, and Brent S. Rose

Subjects
0303 health sciences, Proportional hazards model, Genetic genealogy, Single-nucleotide polymorphism, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Relative risk, Genetic variation, Genotype, SNP, 1000 Genomes Project, 030304 developmental biology, Demography
Abstract

We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Genotypic data were obtained from PRACTICAL consortium for 6,253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with performance of PHS46+African. A calibration factor (CF) was formulated using estimated Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our dataset with 1000 Genomes, we identified statistically significant associations between continental and calibration groupings. In conclusion, we identified PCs within 8q24 SNP window that were strongly associated with performance of PHS46+African. Further research to improve clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry

Published
2021

44. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Brian D. Carter, Gert De Meerleer, Michael B. Cook, Paul A. Townsend, Kim De Ruyck, Edward J. Saunders, Christopher A. Haiman, Atushi Takahashi, Sonja I. Berndt, Florence Menegaux, Cezary Cybulski, Barbara Nemesure, Loic Le Marchand, Sune F. Nielsen, Demetrius Albanes, Robert J. Hamilton, Ninghan Feng, Stella Koutros, Stephen J. Chanock, Wei Zheng, Thomas A. Sellers, Rick A. Kittles, Craig C. Teerlink, Stephen N. Thibodeau, Marija Gamulin, Artitaya Lophatananon, Niclas Håkansson, Fredrik Wiklund, Roberta McKean-Cowdin, Yuan Chun Ding, Nora Pashayan, Timothy J. Key, Børge G. Nordestgaard, Shannon K. McDonnell, Jong Y. Park, Laura Fachal, Martin Andreas Røder, Johanna Schleutker, Edward Giovannucci, Anssi Auvinen, Hardev Pandha, Maria Elena Martinez, Mitchell J. Machiela, Gill Barnett, Melissa C. Southey, Graham G. Giles, Barry S. Rosenstein, Stephen Watya, Bernd Holleczek, Pascal Blanchet, Agnieszka Michael, William J. Blot, James L. Mohler, Jack A. Taylor, Sarah L. Kerns, Adam S. Kibel, Piet Ost, Ana Vega, Richard M. Martin, Jennifer J. Hu, Nicholas Mancuso, Yukihide Momozawa, Robert J. MacInnis, Sue A. Ingles, Maureen Sanderson, Kai Uwe Saum, Markus Aly, Robert Szulkin, Davor Lessel, Hermann Brenner, Yves Akoli Koudou, Jan Lubinski, Mina Torres, Anselm Hennis, Eli Marie Grindedal, Csilla Sipeky, Susan L. Neuhausen, Alison M. Dunning, Alicja Wolk, Adam B. Murphy, Brandi Weaver, Mariana C. Stern, Paula Paulo, Stephanie J. Weinstein, Xueying Mao, Tobias Nordström, Neil Fleshner, Tokhir Dadaev, Teuvo L.J. Tammela, Jay H. Fowke, Tomislav Kuliš, Steven Joniau, Yudong Wu, Rosalind A. Eeles, Shan Chao Zhao, Kenneth Muir, Mark N. Brook, Hidewaki Nakagawa, Freddie C. Hamdy, Karina Dalsgaard Sørensen, Linda Steele, Alisha Chou, Dominika Wokołorczyk, Peggy Wan, Martin Eklund, Laurent Brureau, Lisa A. Cannon-Albright, Lilit C. Moss, Daniel J. Schaid, Luc Multigner, Benjamin A. Rybicki, Xin Sheng, Constance Turman, Ron H.N. van Schaik, Radka Kaneva, Zsofia Kote-Jarai, Frank Claessens, Katarina Cuk, Kay-Tee Khaw, Chad D. Huff, Henrik Grönberg, Kathryn L. Penney, Geraldine Cancel-Tassin, Eric A. Klein, Masashi Fujita, Jennifer Cullen, Michael Borre, Jenny L Donovan, Dana C. Crawford, Antonio Gómez-Caamaño, David V. Conti, Manuel Luedeke, Maya Ghoussaini, Janet L. Stanford, Peter Kraft, Ian M. Thompson, Koichi Matsuda, Soo-Hwang Teo, Christopher J. Logothetis, Robin J. Leach, Monique J. Roobol, Manuel R. Teixeira, Jose Esteban Castelao, Sara S. Strom, Vanio Mitev, Stig E. Bojesen, David J. Hunter, Wayne D. Tilley, Jyotsna Batra, Gerald L. Andriole, Christine Neslund-Dudas, Sara Lindström, Guido Jenster, Catherine M. Tangen, William S. Bush, Maren Weischer, Chavdar Slavov, Thomas J. Schnoeller, Javier Llorca, Claire Aukim-Hastie, Nawaid Usmani, Lisa G. Horvath, Daniel W. Lin, Esther M. John, Burcu F. Darst, Milan S. Geybels, Phyllis J. Goodman, Lynne R. Wilkens, Ali Amin Al Olama, Lorelei A. Mucci, Peter Iversen, Christiane Maier, Victoria L. Stevens, Andreia Brandão, Graham Casey, Neil G. Burnet, Ann W. Hsing, Hongwei Zhang, Laura E. Beane Freeman, Susan M. Gapstur, Sara Benlloch, James E. Mensah, Marie-Élise Parent, Jianfeng Xu, Bettina F. Drake, Jeannette T. Bensen, Azad Hassan Abdul Razack, Edward D. Yeboah, David E. Neal, John D. Carpten, Ruth C. Travis, Thomas J. Hoffmann, Thomas Van den Broeck, Jeri Kim, Ali Sahimi, Gemma Castaño-Vinyals, Alexander Lubwama, Leire Moya, Elio Riboli, Douglas F. Easton, Suzanne K. Chambers, Yong-Jie Lu, Melinda C. Aldrich, Manuela Gago-Dominguez, John S. Witte, Matthew Parliament, Gail P. Risbridger, Samantha E.T. Larkin, Lisa F. Newcomb, Fredrick R. Schumacher, Shiv Srivastava, Jasmine Lim, Meir J. Stampfer, Harry Ostrer, Judith A. Clements, Thérèse Truong, Catharine M L West, Zan Sun, Olivier Cussenot, Gyorgy Petrovics, Lovise Maehle, Elizabeth T. H. Fontham, William B. Isaacs, Hui Yi Lin, Rohit Varma, Elaine A. Ostrander, Manolis Kogevinas, Robert N. Hoover, Sandeep Singhal, Antonio Finelli, and Stephen K. Van Den Eeden

Subjects
0303 health sciences, business.industry, Published Erratum, MEDLINE, Genome-wide association study, Computational biology, Biology, medicine.disease, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Meta-analysis, Genetics, medicine, Susceptibility locus, 06 Biological Sciences, 11 Medical and Health Sciences, Personalized medicine, Genetic risk, business, 030217 neurology & neurosurgery, 030304 developmental biology, Developmental Biology
Abstract

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

Published
2021

45. Prenatal exposure to glycol ethers and visual contrast sensitivity in 6-year-old children in the PELAGIE mother-child cohort

Author

Luc Multigner, Charline Warembourg, Hélène Tillaut, Florent Le Gléau, Christine Monfort, Cécile Chevrier, Florence Rouget, Dave Saint-Amour, Sylvaine Cordier, Ronan Garlantézec, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), LABOCEA Laboratoire [Plouzané, France], EHESP-Irset (EHESP-Irset), ANR-2010-PRSP-007, Agence Nationale de la Recherche, Fondation de France, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, 2009/1/61, France and the French Agency for Food, Environmental and Occupational Health & Safety, National Public Health Agency (Santé publique France), France, Ministry of Labor, France, ANR-10-PRSP-0007,PEPSY(2010), Jonchère, Laurent, PROGRAMME DE RECHERCHE EN SANTE PUBLIQUE - - PEPSY2010 - ANR-10-PRSP-0007 - PRSP - VALID, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)

Subjects
medicine.medical_specialty, Offspring, Vision, Metabolite, [SDV]Life Sciences [q-bio], Urine, 010501 environmental sciences, Development, 01 natural sciences, Propylene glycol methyl ether, Glycols, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Internal medicine, Prenatal exposure, medicine, Humans, 030212 general & internal medicine, Contrast sensitivity, Child, Children, Glycol ethers, 0105 earth and related environmental sciences, business.industry, Public Health, Environmental and Occupational Health, medicine.disease, Mother-Child Relations, Confidence interval, [SDV] Life Sciences [q-bio], Endocrinology, chemistry, Quartile, Prenatal Exposure Delayed Effects, Female, business, Ethers
Abstract

International audience; BACKGROUND: Maternal occupational exposure to organic solvents during pregnancy has been associated with decreased visual function in offspring. Glycol ethers (GEs) belong to oxygenated solvents and are widely used both in occupational and domestic contexts. OBJECTIVES: We aimed to assess associations between prenatal GEs exposure and contrast sensitivity in children. METHODS: Six GE alkoxy carboxylic acidic metabolites (methoxyacetic acid [MAA], ethoxyacetic acid [EAA], ethoxyethoxyacetic acid [EEAA], butoxyacetic acid [BAA], phenoxyacetic acid [PhAA], and 2-methoxypropionic acid [2-MPA]) were measured in first morning void urine samples collected from 220 early-pregnancy women, in the mother-child PELAGIE cohort (France). Trained investigators administered the Functional Acuity Contrast Test (FACT) to the 6-year-old children, providing scores for 5 spatial frequencies (1.5-18 cycles per degree (cpd)). We standardized biomarker urinary concentrations on urine sampling conditions. Values below the LOD were imputed based on log-normal distribution, generating five datasets for multiple imputation. Linear regression models were adjusted for potential confounders. RESULTS: GE metabolites were detected in 70-98% of maternal urine samples. Phenoxyacetic acid (PhAA) had the highest median concentration (0.33 mg/L), and 2-methoxypropionic acid (2-MPA) the lowest (0.01 mg/L). Children with higher prenatal PhAA concentrations had poorer FACT scores at various spatial frequencies (fourth vs. first quartile: β(18cpd) = -0.90 (95% confidence interval CI = -1.64, -0.16), β(12cpd) = -0.92 (95%CI = -1.55, -0.29) and β(1.5cpd) = -0.69 (95%CI = -1.19, -0.20)). The 2-MPA log-scale concentration was negatively associated with the FACT score at the 3-cpd stimulus. DISCUSSION: PhAA is the metabolite of ethylene glycol monophenyl ether present in many cosmetics. 2-MPA is the metabolite of an isomer of propylene glycol methyl ether commonly present in household and industrial cleaning products. Although evidence of biological plausibility is lacking, the study suggests adverse impact of ubiquitous prenatal exposure to some GE on visual functioning among children.

Published
2021

46. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Paul A. Townsend, Edward J. Saunders, Hidewaki Nakagawa, Manuel R. Teixeira, Graham Casey, Demetrius Albanes, Christine Neslund-Dudas, Sara Lindström, William S. Bush, Maren Weischer, Lisa A. Cannon-Albright, Rick A. Kittles, Peggy Wan, Martin Eklund, Stephen N. Thibodeau, Burcu F. Darst, Fredrik Wiklund, Nicholas Mancuso, Jeri Kim, Jong Y. Park, Johanna Schleutker, Maureen Sanderson, Samantha E.T. Larkin, Radka Kaneva, Hongwei Zhang, Daniel J. Schaid, Luc Multigner, Marie-Élise Parent, Robert Szulkin, Fredrick R. Schumacher, Geraldine Cancel-Tassin, Jianfeng Xu, Gill Barnett, Melissa C. Southey, Yuan Chun Ding, Alexander Lubwama, Maria Elena Martinez, Manolis Kogevinas, Linda Steele, Laurent Brureau, Shiv Srivastava, Maya Ghoussaini, Alison M. Dunning, Adam B. Murphy, Kenneth Muir, Edward Giovannucci, Mitchell J. Machiela, James L. Mohler, Jack A. Taylor, Robert N. Hoover, Sandeep Singhal, Chavdar Slavov, Guido Jenster, Frank Claessens, Neil Fleshner, Sara Benlloch, Gert De Meerleer, Michael B. Cook, Zan Sun, Harry Ostrer, Pascal Blanchet, Lynne R. Wilkens, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jay H. Fowke, Agnieszka Michael, Yves Akoli Koudou, Victoria L. Stevens, Kathryn L. Penney, Ana Vega, Xin Sheng, Ron H.N. van Schaik, Zsofia Kote-Jarai, Kim De Ruyck, Christopher A. Haiman, Atushi Takahashi, Florence Menegaux, Judith A. Clements, Stephen K. Van Den Eeden, Brian D. Carter, Wayne D. Tilley, Antonio Finelli, Jennifer J. Hu, Hermann Brenner, Thomas Van den Broeck, Shan Chao Zhao, Azad Hassan Abdul Razack, Edward D. Yeboah, Sonja I. Berndt, Barbara Nemesure, Mark N. Brook, David V. Conti, Katarina Cuk, Teuvo L.J. Tammela, Ali Sahimi, Stephen J. Chanock, Loic Le Marchand, Gemma Castaño-Vinyals, Sune F. Nielsen, Sara S. Strom, Ann W. Hsing, Roberta McKean-Cowdin, David J. Hunter, Ian M. Thompson, Børge G. Nordestgaard, Jyotsna Batra, Paula Paulo, Masashi Fujita, Jennifer Cullen, Susan M. Gapstur, Sarah L. Kerns, Lorelei A. Mucci, Neil G. Burnet, Xueying Mao, Hui Yi Lin, Rohit Varma, Marija Gamulin, Wei Zheng, Thomas A. Sellers, Adam S. Kibel, Robert J. Hamilton, Leire Moya, Ninghan Feng, Laura E. Beane Freeman, James E. Mensah, Catherine M. Tangen, Shannon K. McDonnell, Matthew Parliament, Davor Lessel, Gail P. Risbridger, Mina Torres, Janet L. Stanford, Bettina F. Drake, Soo-Hwang Teo, Robert J. MacInnis, Stig E. Bojesen, Jeannette T. Bensen, William J. Blot, Stella Koutros, Robin J. Leach, Graham G. Giles, Piet Ost, Artitaya Lophatananon, Laura Fachal, Tomislav Kuliš, Peter Kraft, Monique J. Roobol, Elaine A. Ostrander, Niclas Håkansson, Anselm Hennis, Yukihide Momozawa, Anssi Auvinen, Koichi Matsuda, Steven Joniau, Lisa G. Horvath, Javier Llorca, Claire Aukim-Hastie, Bernd Holleczek, Daniel W. Lin, Gerald L. Andriole, John D. Carpten, Eli Marie Grindedal, Rosalind A. Eeles, Elio Riboli, Constance Turman, Martin Andreas Røder, Yong-Jie Lu, Tobias Nordström, Kai Uwe Saum, Esther M. John, Melinda C. Aldrich, Peter Iversen, Henrik Grönberg, John S. Witte, Andreia Brandão, Eric A. Klein, Olivier Cussenot, Barry S. Rosenstein, Stephen Watya, Jan Lubinski, Douglas F. Easton, Dana C. Crawford, Gyorgy Petrovics, Thomas J. Schnoeller, Richard M. Martin, Stephanie J. Weinstein, Jose Esteban Castelao, Suzanne K. Chambers, Tokhir Dadaev, Karina Dalsgaard Sørensen, Antonio Gómez-Caamaño, Lisa F. Newcomb, Csilla Sipeky, Lovise Maehle, Brandi Weaver, Susan L. Neuhausen, Christiane Maier, Alicja Wolk, Vanio Mitev, Thérèse Truong, Manuel Luedeke, Jenny L Donovan, Mariana C. Stern, Catharine M L West, Manuela Gago-Dominguez, Elizabeth T. H. Fontham, William B. Isaacs, David E. Neal, Christopher J. Logothetis, Alisha Chou, Jasmine Lim, Benjamin A. Rybicki, Kay-Tee Khaw, Meir J. Stampfer, Chad D. Huff, Thomas J. Hoffmann, Michael Borre, Freddie C. Hamdy, Nawaid Usmani, Cezary Cybulski, Craig C. Teerlink, Milan S. Geybels, Nora Pashayan, Timothy J. Key, Phyllis J. Goodman, Hardev Pandha, Ruth C. Travis, Yudong Wu, Dominika Wokołorczyk, Lilit C. Moss, University of Southern California (USC), Keck School of Medicine [Los Angeles], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], The institute of cancer research [London], U01CA194393, National Institutes of Health, NA, Achievement Rewards for College Scientists Foundation, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Urology, Clinical Chemistry, Darst, Burcu F [0000-0002-6205-4632], Chou, Alisha [0000-0001-7521-6373], Schumacher, Fredrick R [0000-0002-3073-7463], Dadaev, Tokhir [0000-0002-8268-0438], Brook, Mark N [0000-0002-8969-2378], Hoffmann, Thomas J [0000-0001-6893-4449], Takahashi, Atushi [0000-0001-7099-8767], Matsuda, Koichi [0000-0001-7292-2686], Fujita, Masashi [0000-0002-1457-6233], Muir, Kenneth [0000-0001-6429-988X], Stevens, Victoria L [0000-0003-0259-4407], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Auvinen, Anssi [0000-0003-1125-4818], Giles, Graham G [0000-0003-4946-9099], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Bojesen, Stig E [0000-0002-4061-4133], Røder, Martin Andreas [0000-0002-0019-5333], Batra, Jyotsna [0000-0003-4646-6247], Tilley, Wayne [0000-0003-1893-2626], Risbridger, Gail P [0000-0003-3089-4028], Gronberg, Henrik [0000-0002-1073-2753], Eklund, Martin [0000-0001-5032-5266], Nordström, Tobias [0000-0003-4915-7546], Pashayan, Nora [0000-0003-0843-2468], Dunning, Alison M [0000-0001-6651-7166], Travis, Ruth C [0000-0002-9571-0763], Riboli, Elio [0000-0001-6795-6080], Park, Jong Y [0000-0002-6384-6447], Weinstein, Stephanie J [0000-0002-3834-1535], Kraft, Peter [0000-0002-4472-8103], Ostrander, Elaine A [0000-0001-6075-9738], Wolk, Alicja [0000-0001-7387-6845], Håkansson, Niclas [0000-0001-7673-5554], Machiela, Mitchell J [0000-0001-6538-9705], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Zheng, Wei [0000-0003-1226-070X], Mensah, James E [0000-0003-4133-1722], Lu, Yong-Jie [0000-0001-6174-6621], West, Catharine ML [0000-0002-0839-3449], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Truong, Thérèse [0000-0002-2943-6786], Vega, Ana [0000-0002-7416-5137], Gómez-Caamaño, Antonio [0000-0002-9773-4590], Fachal, Laura [0000-0002-7256-9752], Kerns, Sarah L [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Teixeira, Manuel R [0000-0002-4896-5982], Brandão, Andreia [0000-0003-0938-1543], Cannon-Albright, Lisa [0000-0003-2602-3668], Multigner, Luc [0000-0003-3205-8568], Klein, Eric A [0000-0002-1783-0698], Murphy, Adam B [0000-0001-9977-3473], Michael, Agnieszka [0000-0002-7262-6227], Ost, Piet [0000-0002-2203-4848], Xu, Jianfeng [0000-0002-1343-8752], Teo, Soo-Hwang [0000-0002-0444-590X], Lessel, Davor [0000-0003-4496-244X], Kulis, Tomislav [0000-0002-0895-5691], Joniau, Steven [0000-0003-3195-9890], Bush, William S [0000-0002-9729-6519], Crawford, Dana C [0000-0002-6437-6248], Roobol, Monique J [0000-0001-6967-1708], Jenster, Guido [0000-0002-8658-2552], Van Den Eeden, Stephen K [0000-0002-5599-8387], Easton, Douglas F [0000-0003-2444-3247], Chanock, Stephen J [0000-0002-2324-3393], Wiklund, Fredrik [0000-0002-4623-0544], Eeles, Rosalind A [0000-0002-3698-6241], Haiman, Christopher A [0000-0002-0097-9971], and Apollo - University of Cambridge Repository

Subjects
Male, 8Q24, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Prostate cancer, 0302 clinical medicine, Risk Factors, Epidemiology, IMPUTATION, Odds Ratio, Prostatic Neoplasms/diagnosis, 0303 health sciences, education.field_of_study, Continental Population Groups, Manchester Cancer Research Centre, Middle Aged, Càncer--Aspectes genètics, 3. Good health, ODDS RATIOS, 06 Biological Sciences, 11 Medical and Health Sciences, medicine.medical_specialty, Population, Biology, prostate cancer, meta-analysis, SEQUENCE, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, education, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, ResearchInstitutes_Networks_Beacons/mcrc, Racial Groups, Prostatic Neoplasms, Molecular Sequence Annotation, Odds ratio, medicine.disease, BRCA2, Pròstata--Càncer, Genetic Loci, 030217 neurology & neurosurgery, Imputation (genetics), Genètica, Demography, Developmental Biology, Genome-Wide Association Study
Abstract

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Published
2021

47. In Utero Chlordecone Exposure and Thyroid, Metabolic, and Sex-Steroid Hormones at the Age of Seven Years: A Study From the TIMOUN Mother-Child Cohort in Guadeloupe

Author

Léah Michineau, Nathalie Costet, Sylvaine Cordier, Luc Multigner, Gülen Ayhan, Frank Giton, Jean-Pierre Thomé, Philippe Kadhel, Florence Rouget, Alejandro Oliva, Christine Monfort, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), CHU Pointe-à-Pitre/Abymes [Guadeloupe], CHU Pontchaillou [Rennes], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Liège, Universidad Nacional de Rosario [Argentina], Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Chard-Hutchinson, Xavier, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
endocrine system, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Dehydroepiandrosterone, Physiology, 010501 environmental sciences, 01 natural sciences, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Endocrinology, Thyroid-stimulating hormone, children, medicine, Testosterone, Original Research, 030304 developmental biology, 0105 earth and related environmental sciences, 2. Zero hunger, 0303 health sciences, chlordecone, hormones, business.industry, Leptin, Thyroid, RC648-665, in utero exposure, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, endocrine disruptors, In utero, Dihydrotestosterone, business, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Hormone
Abstract

BackgroundChlordecone is an endocrine-disrupting chemical with well recognized estrogenic and progestagenic properties. This organochlorine insecticide was extensively used in the French West Indies from 1973 to 1993 to control the banana root borer. Due to its poor degradation in the environment, permanently polluted soil is responsible for the current contamination of the food chain and human beings. We aimed to examine the relationship of in utero exposure to chlordecone and thyroid (thyroid stimulating hormone [TSH], free tri-iodothyronine [FT3], free thyroxine [FT4]), metabolic (insulin growth-factor 1, leptin, adiponectin), and sex-steroid (dehydroepiandrosterone [DHEA], total testosterone [TT], dihydrotestosterone [DHT], estradiol [E2]) hormone levels in children at the age of seven years who participated in TIMOUN, an ongoing birth cohort in Guadeloupe.MethodsChlordecone concentrations were measured in cord-blood at delivery. Thyroid, metabolic, and sex-steroid hormone levels were determined in the blood of children at seven years of age. Associations between in utero chlordecone exposure and hormone levels at seven years of age were assessed by multiple linear or logistic regression, controlling for confounding factors.ResultsAmong the study population (210 boys and 228 girls), chlordecone and hormone measurements were available for 124 boys and 161 girls. We found the third quartile of in utero chlordecone exposure relative to the lowest quartile to be associated with elevated TSH levels in girls and elevated DHEA, TT, and DHT levels in both sexes. Complementary non-linear analysis (spline regression) confirmed a significant non-linear trend for TSH in girls and DHEA and DHT in boys.ConclusionIn utero chlordecone exposure was associated with elevated levels of selected thyroid (TSH) and sex-steroid (DHEA, TT, and DHT) hormones at seven years in a non-monotonic dose response (inverted U) relationship. The implications for future health and reproductive function in puberty and adulthood should be determined.

Published
2021

48. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Author

Ian M. Thompson, Roshan Karunamuni, Elizabeth T.H. Fontham, Tyler M. Seibert, Jennifer J. Hu, Jong Y. Park, Phyllis J. Goodman, Ian G. Mills, Luc Multigner, James L. Mohler, Jack A. Taylor, Anders M. Dale, Wei Zheng, Chun Fan, Bettina F. Drake, Jeannette T. Bensen, Florence Menegaux, Supriya Srivastava, Laurent Brureau, Wesley K. Thompson, Hui Yi Lin, Jay H. Fowke, Maureen Sanderson, Zsofia Kote-Jarai, Rosalind A. Eeles, Geraldine Cancel-Tassin, William Blot, Minh-Phuong Huynh-Le, Catherine M. Tangen, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Ole A. Andreassen, Thérèse Truong, Jennifer Cullen, Robin J. Leach, Esther M. John, Artitaya Lophatananon, Pascal Blanchet, Marc Romana, Kenneth Muir, William S. Bush, Marie-Élise Parent, Dana C. Crawford, Adam S. Kibel, University of California [San Diego] (UC San Diego), University of California (UC), Healthlytix [San Diego], The Royal Marsden, The institute of cancer research [London], University of Manchester [Manchester], University of Warwick [Coventry], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Vanderbilt University School of Engineering [Nashville] (VUSE), GeneDx [Gaithersburg, MD, USA], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Washington University in Saint Louis (WUSTL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, H. Lee Moffitt Cancer Center and Research Institute, Louisiana State University (LSU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), The University of Texas at San Antonio (UTSA), Stanford University, Vanderbilt University [Nashville], Case Western Reserve University [Cleveland], eResearch Collaboratory [Quebec City], McGill University = Université McGill [Montréal, Canada], University of Miami Leonard M. Miller School of Medicine (UMMSM), School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Oslo (UiO), KG Jebsen Stiftelsen, National Institute of Biomedical Imaging and BioengineeringUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) [K08EB026503], Research Council of NorwayResearch Council of Norway [223273], South East Norway Health Authority, U.S. Department of DefenseUnited States Department of Defense [W81XWH-13-1-0391], Chard-Hutchinson, Xavier, collaborators, UKGPCS, Consortium, PRACTICAL, University of California, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP)

Subjects
Male, Cancer Research, Multifactorial Inheritance, Genotyping Techniques, [SDV]Life Sciences [q-bio], Age at diagnosis, Genome-wide association study, Prostate cancer, 0302 clinical medicine, Genotype, genome wide association study, 0303 health sciences, education.field_of_study, genotypic ancestry, Age Factors, Middle Aged, prostate cancer, Hazard, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, polygenic risk, Genetic genealogy, Population, Black People, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, medicine, genomics, Humans, Genetic Predisposition to Disease, education, Proportional Hazards Models, 030304 developmental biology, Genetic association, health disparities, Models, Genetic, Proportional hazards model, business.industry, African, Prostatic Neoplasms, medicine.disease, Case-Control Studies, business, Demography
Abstract

IntroductionPolygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population.Material and MethodsAnonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach.ResultsThree SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).ConclusionsWe identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.

Published
2021

49. Prenatal and childhood exposure to chlordecone and sex-typed toy preference of 7-year-old Guadeloupean children

Author

Gina Muckle, Nadine Forget-Dubois, Sylvaine Cordier, Philippe Kadhel, Christine Monfort, Jean-Pierre Thomé, Florence Rouget, Luc Multigner, Mireille Desrochers-Couture, Leah Michineau, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), Université de Liège, DGS RMC11129NNA, French General Health Directorate, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
Male, Insecticides, West Indies, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Population, 010501 environmental sciences, Breast milk, Organochlorine, 01 natural sciences, Cohort Studies, chemistry.chemical_compound, Pregnancy, French West Indies, Humans, Environmental Chemistry, Medicine, Child, education, Guadeloupe, Child development, 0105 earth and related environmental sciences, education.field_of_study, Endocrine-disrupting chemicals, Milk, Human, business.industry, Confounding, Infant, Newborn, General Medicine, Pollution, Preference, 3. Good health, Sexual dimorphism, [SDV] Life Sciences [q-bio], chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Chlordecone, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Demography, Toxicant, Cohort study
Abstract

International audience; Chlordecone was used intensively as an insecticide in the French West Indies. Because of its high persistence, the resulting contamination of food and water has led to chronic exposure of the general population as evidenced by its presence in the blood of people of Guadeloupe, in particular in pregnant women and newborns, and in maternal breast milk. Chlordecone is recognized as a reproductive and developmental toxicant, is neurotoxic and carcinogenic in rodents, and is considered as an endocrine-disrupting compound with well-established estrogenic and progestogenic properties both in vitro and in vivo. The question arises of its potential consequences on child neurodevelopment following prenatal and childhood exposure, in particular on behavioral sexual dimorphism in childhood. We followed 116 children from the TIMOUN mother–child cohort study in Guadeloupe, who were examined at age 7. These children were invited to participate in a 7-min structured play session in which they could choose between different toys considered as feminine, masculine, or neutral. The play session was video recorded, and the percentage of the time spent playing with feminine or masculine toys was calculated. We estimated associations between playtime and prenatal exposure to chlordecone (assessed by concentration in cord blood) or childhood exposure (determined from concentrations in child blood obtained at the 7-year follow-up), taking into account confounders and co-exposures to other environmental chemicals. We used a two-group regression model to take into account sex differences in play behavior. Our results do not indicate any modification in sex-typed toy preference among 7-year-old children in relation with either prenatal or childhood exposure to chlordecone.

Published
2020

50. Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts

Author

Luc Multigner, Rita Rahban, Serge Nef, M Istvan, Eric Stettler, Alfred Paul Senn, B Dananche, Ronan Garlantézec, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Genève = University of Geneva (UNIGE), Swiss Centre for Applied Human Toxicology: SCAHT and the ‘Fondation privée des Hôpitaux Universitaires de Genève’, FABER Foundation, Swiss National Science Foundation (SNSF): NFP 50 ‘Endocrine Disruptors: Relevance to Humans, Animals and Ecosystems’, Medical Services of the Swiss Army (DDPS) and Media support, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and University of Geneva [Switzerland]

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Cross-sectional study, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Fertility, Semen, Endocrine Disruptors, endocrine disrupting, Endocrine Disruptors/toxicity, male infertility, Male infertility, 03 medical and health sciences, Semen quality, fluids and secretions, 0302 clinical medicine, Pregnancy, Environmental health, Occupational Exposure, medicine, Humans, ddc:576.5, Child, semen parameters, Ecosystem, Maternal Exposure/adverse effects, 030304 developmental biology, media_common, 0303 health sciences, 030219 obstetrics & reproductive medicine, business.industry, Occupational Exposure/adverse effects, Rehabilitation, Confounding, Obstetrics and Gynecology, Odds ratio, medicine.disease, Confidence interval, Semen Analysis, Cross-Sectional Studies, Reproductive Medicine, Maternal Exposure, Female, business
Abstract

STUDY QUESTION Is there a relationship between maternal occupational exposure to endocrine-disrupting chemicals (EDCs) during pregnancy and the semen quality of their sons? SUMMARY ANSWER Our results suggest an association between maternal occupational exposure to potential EDCs, especially to pesticides, phthalates and heavy metals, and a decrease in several semen parameters. WHAT IS KNOWN ALREADY Sexual differentiation, development and proper functioning of the reproductive system are largely dependent on steroid hormones. Although there is some animal evidence, studies on maternal exposure to EDCs during pregnancy and its effect on the semen quality of sons are scarce and none have focused on maternal occupational exposure. STUDY DESIGN, SIZE, DURATION A cross-sectional study aiming to evaluate semen quality was carried out among Swiss conscripts aged 18 to 22 years between 2005 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS Conscript and parent questionnaires were completed prior to the collection of a semen sample. Semen parameters were categorised according to the guidelines of the World Health Organization (WHO). Data on maternal employment during pregnancy were provided by the parent questionnaire. Maternal occupational exposure to potential EDC categories was defined using a job-exposure matrix (JEM). Logistic regressions were used to analyse the relationship between maternal occupational exposure to EDCs and each semen parameter adjusted for potential confounding factors. Results are presented using odds ratios and 95% confidence intervals. MAIN RESULTS AND THE ROLE OF CHANCE In total, 1,737 conscripts provided a conscript and parent questionnaire, as well as a semen sample; among these 1,045 of their mothers worked during pregnancy. Our study suggests an association between occupational exposure of mothers during pregnancy to potential EDCs and low semen volume and total sperm count, particularly for exposure to pesticides (OR 2.07, 95% CI 1.11–3.86 and OR 2.14, 95% CI 1.05–4.35), phthalates (OR 1.92, 95% CI 1.10–3.37 and OR 1.89, 95% CI 1.01–3.55), and heavy metals (OR 2.02, 95% CI 1.14–3.60 and OR 2.29, 95% CI 1.21–4.35). Maternal occupational exposure to heavy metals was additionally associated with a low sperm concentration (OR 1.89, 95% CI 1.06–3.37). LIMITATIONS, REASONS FOR CAUTION Several limitations should be noted, such as the indirect method for maternal occupational exposure assessment during the pregnancy (JEM) and the cross-sectional design of the study. WIDER IMPLICATIONS OF THE FINDINGS Our observations reinforce the need to inform pregnant women of potential hazards during pregnancy that could impair their child’s fertility. Additional studies are needed to confirm the involvement of EDCs. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Swiss Centre for Applied Human Toxicology: SCAHT and the ‘Fondation privée des Hôpitaux Universitaires de Genève’. The collection of human biological material used for this study was supported by the FABER Foundation, the Swiss National Science Foundation (SNSF): NFP 50 ‘Endocrine Disruptors: Relevance to Humans, Animals and Ecosystems’, the Medical Services of the Swiss Army (DDPS) and Medisupport. The authors declare they have no competing financial interests. TRIAL REGISTRATION NUMBER N/A

Published
2020

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