49 results on '"Gely-Pernot A"'
Search Results
2. The Acute Exposure of Human Adult Testis Tissue to Cannabinoids THC and CBD Does Not Impact Testosterone Production Nor Germ Cell Lineage
- Author
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Janaina da Silva, Juliette Dochez-Arnault, Chritèle Desdoits-Lethimonier, Nathalie Dejucq-Rainsford, and Aurore Gely-Pernot
- Subjects
cannabis ,leydig cells ,male infertility ,spermatogenesis ,Medicine ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Purpose: While an increased risk of developing germ cell tumors has been established in regular cannabis consumers, there is conflicting evidence about an association between cannabis use and testosterone levels in those regular consumers. In this context, we aimed to determine whether Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two major and beststudied cannabinoids present in cannabis, also the most used for therapeutic applications, can directly impact the steroidogenic function and germ cell lineage of the human adult testis. Materials and Methods: We used our well-characterized organotypic culture of human testis, in which adult testis explants were exposed to CBD, THC, or CBD/THC [ratio 1:1] from 10-9 to 10-5 M for up to either 48 hours or 9 days of culture. The testes were obtained from multi-organ donors (n=13; mean age: 55.15±5.62 y). Results: The testosterone production and the spatial distribution of Leydig cells did not change upon CBD and/or THC exposure versus controls after 48 hours or 9 days. The overall tissue morphology of the cannabinoids-exposed testis explants was similar to their control upon 24 hours or 9 days of exposure, a finding confirmed by morphometric analyses on short-term cultures. In line, the number of apoptotic cells was not affected by either 48 hours or 9 days of cannabinoids treatment versus mock. Cannabinoids had no impact on the number of proliferating cells nor on mRNA expression of genes encoding proteins involved in germ cell differentiation, meiosis, or Sertoli and Leydig functions after 24 hours exposure. Conclusions: Altogether, these findings show an absence of acute direct effects of exposure to cannabis-derived cannabinoids THC and CBD on testicular testosterone production and germ cells ex vivo. Further studies are warranted to explore an indirect impact of cannabinoids on testis functions through the hypothalamic-pituitary-testis axis, as well as the potential effects of long-term exposures.
- Published
- 2023
- Full Text
- View/download PDF
3. Expression of the endocannabinoid system and response to cannabinoid components by the human fetal testis
- Author
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J. Dochez-Arnault, C. Desdoits-Lethimonier, I. Matias, B. Evrard, M. Lagarrigue, M. Toupin, A. Lardenois, F. Chalmel, S. Mazaud-Guittot, N. Dejucq-Rainsford, and A. Gely-Pernot
- Subjects
Endocannabinoids ,CBD ,THC ,Human fetal exposure ,Endocrine disruptors ,Testis ,Medicine - Abstract
Abstract Background Cannabis consumption by pregnant women continues to increase worldwide, raising concerns about adverse effects on fetal growth and deleterious impacts on the newborn, in connection with evidence of placental transfer of cannabis compound. Cannabis action is mediated by the endocannabinoid system (ECS), which expression is well established in the brain but unknown in the developing testis. The fetal testis, whose endocrine function orchestrates the masculinization of many distant organs, is particularly sensitive to disruption by xenobiotics. In this context, we aimed to determine whether cannabis exposure has the potential to directly impact the human fetal testis. Methods We determined the expression of components of the ECS in the human fetal testis from 6 to 17 developmental weeks and assessed the direct effects of phytocannabinoids Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD) on the testis morphology and cell functions ex vivo. Results We demonstrate the presence in the human fetal testis of two key endocannabinoids, 2-arachidonylglycerol (2-AG) and to a lower level anandamide (AEA), as well as a range of enzymes and receptors for the ECS. Ex vivo exposure of first trimester testes to CBD, THC, or CBD/THC [ratio 1:1] at 10−7 to 10−5 M altered testosterone secretion by Leydig cells, AMH secretion by Sertoli cells, and impacted testicular cell proliferation and viability as early as 72 h post-exposure. Transcriptomic analysis on 72 h-exposed fetal testis explants revealed 187 differentially expressed genes (DEGs), including genes involved in steroid synthesis and toxic substance response. Depending on the molecules and testis age, highly deleterious effects of phytocannabinoid exposure were observed on testis tissue after 14 days, including Sertoli and germ cell death. Conclusions Our study is the first to evidence the presence of the ECS in the human fetal testis and to highlight the potential adverse effect of cannabis consumption by pregnant women onto the development of the male gonad.
- Published
- 2023
- Full Text
- View/download PDF
4. Developmental exposure to chlordecone induces transgenerational effects in somatic prostate tissue which are associated with epigenetic histone trimethylation changes
- Author
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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
- Full Text
- View/download PDF
5. Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features
- Author
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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
- Full Text
- View/download PDF
6. Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males
- Author
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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
- Full Text
- View/download PDF
7. Mapping competency in public health training – experience of the Europubhealth consortium.
- Author
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Grimaud, Olivier, Foucrier, Mathilde, Czabanowska, Kasia, Barnes, Sarah, Bauernfeind, Ariane, Clemens, Timo, Codd, Mary, Donneau, Anne-Françoise, Sowada, Christoph, Keller, Catherine, Gely-Pernot, Aurore, Mueller, Judith, Guevel, Marie-Renée, Bodeau-Livinec, Florence, and Théault, Laurence
- Subjects
CONSORTIA ,PUBLIC health education ,PUBLIC health ,WORLD health ,EDUCATIONAL objectives - Abstract
Background: Public health education aims at producing a competent workforce. The WHO-ASPHER framework proposes a set of relevant public health competencies organised in 10 sections (e.g. science practice, leadership, law policies and ethics etc). As part of the Europubhealth (EPH) consortium, eight universities collaborate for the delivery of a 2-year international public health master course. The training pathway includes a first "foundation" year, with a choice of four options (components), and a second "specialisation" year with a choice of seven components. In 2020, EPH consortium decided to use the WHO-ASPHER framework in order to map the competencies addressed and the level of proficiency targeted by each component of its master course. Methods: An 84-item questionnaire covering the whole WHO-ASPHER framework was sent to the 11 EPH component coordinators, asking them to rate the proficiency levels targeted at the end of their courses. Answers from each coordinator were summarised by calculating mean proficiency levels for each of the 10 competency sections. We used Bland & Altman plots to explore heterogeneity of answers and then calculated transformed scores to account for rating heterogeneity. We use tabulation and a heat map to explore patterns of proficiency levels across components. Results: There were differences in overall proficiency levels between years with, as expected, higher scores in year two. Year one components reached medium to high proficiency scores for the sections "science practice", "health promotion" and "communication" with scores ranging from 2.6 to 3 (on a 1-low to 4-high scale). When compared with year one on a heat-map, year two components displayed more contrasted profiles, typically aiming for high proficiency level (i.e. scores above 3.5) on 3 out of the 10 sections of competencies. Except for the "collaborations and partnership" section, the training pathways offered by the EPH master course seem to offer opportunities for a high proficiency level in all domains of competencies. Conclusions: The mapping proved a useful exercise to identify strengths and complementarities among the EPH consortium. The results suggest that the EPH master course is coherent and offers students opportunities to gain proficiency in most competencies relevant to public health practice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. Embryonic exposure to the widely-used herbicide atrazine disrupts meiosis and normal follicle formation in female mice
- Author
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Aurore Gely-Pernot, Souhila Saci, Pierre-Yves Kernanec, Chunxiang Hao, Frank Giton, Christine Kervarrec, Sergei Tevosian, Severine Mazaud-Guittot, and Fatima Smagulova
- Subjects
Medicine ,Science - Abstract
Abstract The widely-used herbicide atrazine (ATZ) is detected in ground and surface water in many countries. Several studies in animals have demonstrated that ATZ has endocrine-disrupting effects on male and female reproduction in many vertebrate species. In this study, we investigated the effects of ATZ exposure on meiosis, a key step in gametogenesis in mammals. The treatment was initiated before oocyte entry into meiosis, which occurs during the embryonic period in females. We found that embryonic exposure to ATZ increases the level of 8-oxo-guanine in the nucleus of meiotic cells, reflecting oxidative stress and affecting meiotic double-strand break repair, chromosome synapsis and crossover numbers. Finally, embryonic exposure to ATZ reduces the number of primordial follicles and increases the incidence of multi-oocyte follicles in adult mice. Our data demonstrate that embryonic exposure to ATZ disrupts prophase I of meiosis and affects normal follicle formation in female mice.
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- 2017
- Full Text
- View/download PDF
9. Preconception Generational Impacts Male
- Author
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Gely-Pernot, Aurore, primary
- Published
- 2018
- Full Text
- View/download PDF
10. Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features
- Author
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Legoff, Louis, Dali, Ouzna, D’Cruz, Shereen Cynthia, Suglia, Antonio, Gely-Pernot, Aurore, Hémery, Chloé, Kernanec, Pierre-Yves, Demmouche, Abbassia, Kervarrec, Christine, Tevosian, Sergei, Multigner, Luc, and Smagulova, Fatima
- Published
- 2019
- Full Text
- View/download PDF
11. The Acute Exposure of Human Adult Testis Tissue to Cannabinoids THC and CBD Does Not Impact Testosterone Production Nor Germ Cell Lineage.
- Author
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da Silva, Janaina, Dochez-Arnault, Juliette, Desdoits-Lethimonier, Chritèle, Dejucq-Rainsford, Nathalie, and Gely-Pernot, Aurore
- Subjects
CANNABINOIDS ,TETRAHYDROCANNABINOL ,LEYDIG cells ,MESSENGER RNA - Abstract
Purpose: While an increased risk of developing germ cell tumors has been established in regular cannabis consumers, there is conflicting evidence about an association between cannabis use and testosterone levels in those regular consumers. In this context, we aimed to determine whether Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two major and beststudied cannabinoids present in cannabis, also the most used for therapeutic applications, can directly impact the steroidogenic function and germ cell lineage of the human adult testis. Materials and Methods: We used our well-characterized organotypic culture of human testis, in which adult testis explants were exposed to CBD, THC, or CBD/THC [ratio 1:1] from 10-9 to 10-5 M for up to either 48 hours or 9 days of culture. The testes were obtained from multi-organ donors (n=13; mean age: 55.15±5.62 y). Results: The testosterone production and the spatial distribution of Leydig cells did not change upon CBD and/or THC exposure versus controls after 48 hours or 9 days. The overall tissue morphology of the cannabinoids-exposed testis explants was similar to their control upon 24 hours or 9 days of exposure, a finding confirmed by morphometric analyses on short-term cultures. In line, the number of apoptotic cells was not affected by either 48 hours or 9 days of cannabinoids treatment versus mock. Cannabinoids had no impact on the number of proliferating cells nor on mRNA expression of genes encoding proteins involved in germ cell differentiation, meiosis, or Sertoli and Leydig functions after 24 hours exposure. Conclusions: Altogether, these findings show an absence of acute direct effects of exposure to cannabis-derived cannabinoids THC and CBD on testicular testosterone production and germ cells ex vivo. Further studies are warranted to explore an indirect impact of cannabinoids on testis functions through the hypothalamic-pituitary-testis axis, as well as the potential effects of long-term exposures. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
12. Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males
- Author
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Gely-Pernot, Aurore, Hao, Chunxiang, Legoff, Louis, Multigner, Luc, D’Cruz, Shereen Cynthia, Kervarrec, Christine, Jégou, Bernard, Tevosian, Sergei, and Smagulova, Fatima
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- 2018
- Full Text
- View/download PDF
13. The STRA6 Receptor Is Essential for Retinol-binding Protein-induced Insulin Resistance but Not for Maintaining Vitamin A Homeostasis in Tissues Other Than the Eye
- Author
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Berry, Daniel C., Jacobs, Hugues, Marwarha, Gurdeep, Gely-Pernot, Aurore, O'Byrne, Sheila M., DeSantis, David, Klopfenstein, Muriel, Feret, Betty, Dennefeld, Christine, Blaner, William S., Croniger, Colleen M., Mark, Manuel, Noy, Noa, and Ghyselinck, Norbert B.
- Published
- 2013
- Full Text
- View/download PDF
14. Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis
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Raverdeau, Mathilde, Gely-Pernot, Aurore, Féret, Betty, Dennefeld, Christine, Benoit, Gérard, Davidson, Irwin, Chambon, Pierre, Mark, Manuel, and Ghyselinck, Norbert B.
- Published
- 2012
15. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.
- Author
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Aurore Gely-Pernot, Mathilde Raverdeau, Marius Teletin, Nadège Vernet, Betty Féret, Muriel Klopfenstein, Christine Dennefeld, Irwin Davidson, Gérard Benoit, Manuel Mark, and Norbert B Ghyselinck
- Subjects
Genetics ,QH426-470 - Abstract
All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.
- Published
- 2015
- Full Text
- View/download PDF
16. Developmental exposure to chlordecone induces transgenerational effects in somatic prostate tissue which are associated with epigenetic histone trimethylation changes
- Author
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Legoff, Louis, D’cruz, Shereen Cynthia, Lebosq, Morgane, Gely-Pernot, Aurore, Bouchekhchoukha, Katia, Monfort, Christine, Kernanec, Pierre-Yves, Tevosian, Sergei, Multigner, Luc, Smagulova, Fatima, École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 Pontchaillou [Rennes], Département Santé Environnement Travail et Génie Sanitaire (DSETGS), University of Florida [Gainesville] (UF), Atip-Avenir program (R13139NS), direction générale de la santé (R20153NN), 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 ), HAL UR1, Admin, and Département des sciences en santé environnementale (DEESSE)
- Subjects
Epigenetics ,Male ,Prostate ,[SDV]Life Sciences [q-bio] ,DOHaD ,PIN ,Epigenesis, Genetic ,[SDV] Life Sciences [q-bio] ,Environmental sciences ,Histones ,Transgenerational inheritance ,Mice ,Chlordecone ,Pregnancy ,Prenatal Exposure Delayed Effects ,Animals ,GE1-350 ,Female - Abstract
International audience; 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
17. Evaluation of the impact of cannabinoids used for recreational or therapeutic purposes on the male germ cell differentiation during development
- Author
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Dochez-Arnault, J., primary, da Silva, J., additional, Desdoits-Lethimoniers, C., additional, Kernanec, P.-Y., additional, Mazaud-Guittot, S., additional, Dejucq-Rainsford, N., additional, and Gely-Pernot, A., additional
- Published
- 2021
- Full Text
- View/download PDF
18. Evaluation of the impact of cannabinoids used for recreational or therapeutic purposes on the male germ cell differentiation during development
- Author
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A. Gely-Pernot, C. Desdoits-Lethimoniers, J. Dochez-Arnault, J. O. Da Silva, Séverine Mazaud-Guittot, P.-Y. Kernanec, N. Dejucq-Rainsford, École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 ), Universidade Federal de Vicosa (UFV), 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 ), Universidade Federal de Viçosa = Federal University of Viçosa (UFV), and Département Santé Environnement Travail et Génie Sanitaire (DSETGS)
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0303 health sciences ,[SDV]Life Sciences [q-bio] ,General Medicine ,Biology ,Toxicology ,Bioinformatics ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Recreation ,ComputingMilieux_MISCELLANEOUS ,030217 neurology & neurosurgery ,Germ cell ,030304 developmental biology - Abstract
International audience
- Published
- 2021
19. Spermatogonia Differentiation Requires Retinoic Acid Receptor γ
- Author
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Gely-Pernot, Aurore, Raverdeau, Mathilde, Célébi, Catherine, Dennefeld, Christine, Feret, Betty, Klopfenstein, Muriel, Yoshida, Shosei, Ghyselinck, Norbert B., and Mark, Manuel
- Published
- 2012
20. Transgenerational effects promoted by chlordecone are mediated via histone trimethylation in a limited regions in mouse genome
- Author
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Gely-Pernot, Aurore, Université de Rennes (UR), 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 Gely-Pernot, Aurore
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[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,ComputingMilieux_MISCELLANEOUS ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology - Abstract
International audience
- Published
- 2018
21. Effets transgénérationnels d’une exposition gestationnelle au Chlordécone sur la fonction de reproduction dans un modèle murin
- Author
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Gely-Pernot, Aurore, Gely-Pernot, Aurore, Université de Rennes (UR), 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 ), and École des Hautes Études en Santé Publique [EHESP] (EHESP)
- Subjects
[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,ComputingMilieux_MISCELLANEOUS ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology - Abstract
International audience
- Published
- 2018
22. Preconception generational impacts male
- Author
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Aurore Gely-Pernot, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UNIV-RENNES), Université de Rennes (UR), 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 ), and Gely-Pernot, Aurore
- Subjects
0303 health sciences ,Pregnancy ,030219 obstetrics & reproductive medicine ,Offspring ,media_common.quotation_subject ,Reproduction ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,Biology ,medicine.disease ,Developmental psychology ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,03 medical and health sciences ,0302 clinical medicine ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,medicine ,Epigenetics ,Inheritance ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,media_common ,Exposition (narrative) - Abstract
Although mammalian development is directly affected by exposition of the mother during pregnancy, there is this last decade increasing evidence for the preconceptional impact of the father on their offspring. This article provides a summary of the major factors able to impact male gametes and considers epigenetics changes as supporting the existence of inheritance of paternal background.
- Published
- 2018
23. Perinatal exposure to glyphosate and a glyphosate-based herbicide affect spermatogenesis in mice
- Author
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Thu Ha Pham, Lohann Derian, Fatima Smagulova, Pierre-Yves Kernanec, Christine Kervarrec, Bernard Jégou, Aurore Gely-Pernot, 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 ), Institut National de la Santé et de la Recherche Médicale, R13139NS, Atip-Avenir program, 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 Chard-Hutchinson, Xavier
- Subjects
Male ,0301 basic medicine ,Glyphosate ,Acceptable daily intake ,Apoptosis ,Endocrine Disruptors ,Toxicology ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Testis ,Testosterone ,media_common ,Sperm Count ,Age Factors ,Gene Expression Regulation, Developmental ,Cell Differentiation ,differentiation ,3. Good health ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,Prenatal Exposure Delayed Effects ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Toxicity ,Female ,Reproduction ,Roundup ,Offspring ,media_common.quotation_subject ,Glycine ,Gestational Age ,Biology ,Risk Assessment ,reproduction ,03 medical and health sciences ,Animal science ,Animals ,Infertility, Male ,No-Observed-Adverse-Effect Level ,Dose-Response Relationship, Drug ,Herbicides ,Gamma hydroxybutyrate ,Spermatogonia ,spermatogenesis ,030104 developmental biology ,Animals, Newborn ,chemistry ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Spermatogenesis ,030217 neurology & neurosurgery - Abstract
International audience; Glyphosate is the most widely used herbicide in the world. Several studies have investigated the effects of glyphosate and glyphosate-based-herbicides (GBHs) on male reproduction, but there is still little and conflicting evidence for its toxicity. In this study, we analyzed the effects of glyphosate, alone or in formula, on the male reproductive system. Pregnant mice were treated from E10.5 to 20 days postpartum (dpp) by adding glyphosate or a GBH (Roundup® 3 Plus) to their drinking water at 0.5 (the acceptable daily intake, ADI dose), 5 and 50 mg/kg/day. Male offspring derived from treated mice were sacrificed at 5, 20 and 35 days-old (d.o.) and 8 months-old (m.o.) for analysis. Our result showed that exposure to glyphosate, but not GBH, affect testis morphology in 20 d.o. and decrease serum testosterone concentrations in 35 d.o. males. We identified that the spermatozoa number decreased by 89% and 84% in 0.5 and 5 mg/kg/day of GBH and glyphosate groups, respectively. Moreover, the undifferentiated spermatogonia numbers were decreased by 60% in 5 mg/kg/day glyphosate group, which could be due to the alterations in the expression of genes involved in germ cell differentiation such as Sall4 and Nano3 and apoptosis as Bax and Bcl2. In 8 m.o. animals, a decreased testosterone level was observed in GBH groups. Our data demonstrate that glyphosate and GBHs could cause endocrine-disrupting effects on male reproduction at low doses. As glyphosate has effects at the ADI level, our data suggests that the current ADI for glyphosate could be overestimated.
- Published
- 2019
24. Perturbateurs endocriniens et reprotoxicité masculine: point sur les connaissances
- Author
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Aurore Gely-Pernot
- Subjects
Public Health, Environmental and Occupational Health - Abstract
Depuis le debut des annees 90, la sante reproductive des hommes et le role qu’une sous-classe de produits chimiques appelee « perturbateurs endocriniens » (PE) pourrait jouer dans la diminution de la qualite du sperme et dans l’augmentation de l’incidence des cancers des testicules et de malformations congenitales ont suscite de vives inquietudes. Les hommes sont exposes simultanement a un grand nombre de produits chimiques pouvant jouer un role dans ces troubles. Ils y seront exposes a l’âge adulte ou durant des phases particulaires de vulnerabilite que sont le developpement, l’enfance ou la puberte. Les testicules assurent deux grandes fonctions: la production des cellules sexuelles mâles et la production des steroides sexuels. Ces deux fonctions s’etablissent durant la vie fœtale et cette ontogenese est fondamentale, puisqu’elle conditionne la fertilite de l’individu adulte et la masculinisation des organes genitaux. Le lien entre reproduction masculine et perturbation endocrinienne a fait l’objet ces dernieres decennies d’un grand nombre d’etudes toxicologiques et epidemiologiques. Beaucoup de composes exogenes incluant des plastifiants, des pesticides, des fongicides, des medicaments ou encore des composes recreatifs ont ete teste au travers de modeles animaux ou humain, ex-vivo ou in-vivo, afin de demontrer le potentiel anti-androgenique de certaines molecules ou leur capacite a venir alterer la fonction des cellules de Sertoli, cellules somatiques du testicule, ou de la lignee germinale. Certains travaux ont egalement mis en lumiere la capacite de certain PE a avoir des effets transgenenerationnels par leur impact sur l’epigenome. Les methodes utilisees dans le cadre de ce domaine de recherche vont de methodes classiques (histologie, immunohistochimie…) a l’utilisation de methodes innovantes avec l’arrivee de donnees de sequencage a haut debit. Alors que le potentiel perturbateur endocrinien de certain compose est aujourd’hui clairement avere, apporter la preuve que le mecanisme interferant avec le systeme endocrinien est bien responsable de l’effet observe represente un veritable challenge. Ainsi l’etude des PE represente un enjeu majeur pour la recherche et les pouvoirs publics car les sources d’exposition sont nombreuses et difficiles a maitriser, tandis que les consequences biologiques de ces expositions sont encore mal apprehendees et complexes a etudier.
- Published
- 2020
25. Perinatal Exposure to Glyphosate and a Glyphosate-Based Herbicide Affect Spermatogenesis in Mice
- Author
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Pham, Thu Ha, primary, Derian, Lohann, additional, Kervarrec, Christine, additional, Kernanec, Pierre-Yves, additional, Jégou, Bernard, additional, Smagulova, Fatima, additional, and Gely-Pernot, Aurore, additional
- Published
- 2019
- Full Text
- View/download PDF
26. The embryonic exposure to widely-used herbicide atrazine causes the reproduction defects in a third generation after treatment
- Author
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Hao, Chunxiang, Gely-Pernot, Aurore, Kervarrec, Christine, Becker, Emmanuelle, Jégou, Bernard, Smagulova, Fatima, Gely-Pernot, Aurore, 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), 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 EHESP-Irset (EHESP-Irset)
- Subjects
[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,ComputingMilieux_MISCELLANEOUS ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology - Abstract
International audience
- Published
- 2016
27. Embryonic exposure to the widely-used herbicide atrazine disrupts meiosis and normal follicle formation in female mice
- Author
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Séverine Mazaud-Guittot, Christine Kervarrec, Chunxiang Hao, Sergei G. Tevosian, Pierre-Yves Kernanec, Frank Giton, Fatima Smagulova, Aurore Gely-Pernot, Souhila Saci, 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 ), 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), University of Florida [Gainesville] (UF), Chair of Excellence Program from the European University of Brittany, Atip-Avenir program from INSERM, China Scholarship Council (CSC), Atip-Avenir fellowship for young researchers, 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), 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 Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
- Subjects
0301 basic medicine ,media_common.quotation_subject ,Science ,010501 environmental sciences ,Biology ,01 natural sciences ,Article ,03 medical and health sciences ,Follicle ,Mice ,Meiosis ,Ovarian Follicle ,medicine ,Animals ,Gametogenesis ,0105 earth and related environmental sciences ,media_common ,Genetics ,Multidisciplinary ,Herbicides ,Incidence ,Synapsis ,Chromosome ,Oocyte ,Embryonic stem cell ,3. Good health ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Medicine ,Atrazine ,Female ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Reproduction - Abstract
The widely-used herbicide atrazine (ATZ) is detected in ground and surface water in many countries. Several studies in animals have demonstrated that ATZ has endocrine-disrupting effects on male and female reproduction in many vertebrate species. In this study, we investigated the effects of ATZ exposure on meiosis, a key step in gametogenesis in mammals. The treatment was initiated before oocyte entry into meiosis, which occurs during the embryonic period in females. We found that embryonic exposure to ATZ increases the level of 8-oxo-guanine in the nucleus of meiotic cells, reflecting oxidative stress and affecting meiotic double-strand break repair, chromosome synapsis and crossover numbers. Finally, embryonic exposure to ATZ reduces the number of primordial follicles and increases the incidence of multi-oocyte follicles in adult mice. Our data demonstrate that embryonic exposure to ATZ disrupts prophase I of meiosis and affects normal follicle formation in female mice.
- Published
- 2017
28. Perturbateurs endocriniens et reprotoxicité masculine: point sur les connaissances
- Author
-
Gély-Pernot, Aurore
- Published
- 2020
- Full Text
- View/download PDF
29. Retinoic acid instructs spermatogonia cell-fate through controlling expression of the SALL4A transcription factor
- Author
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Aurore Gely-Pernot, Mathilde Raverdeau, Marius Teletin, Nadege Vernet, Betty Féret, Muriel Klopfenstein, Christine Dennefeld, Irwin Davidson, Gerard Benoit, Manuel Mark, Ghyselinck, Norbert B., Université de Rennes (UNIV-RENNES), EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), 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 ), Département Santé Environnement Travail et Génie Sanitaire (DSETGS), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2016
30. Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice
- Author
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Pavel P. Khil, Christine Kervarrec, Emmanuelle Becker, Sergei G. Tevosian, Fatima Smagulova, Aurore Gely-Pernot, Chunxiang Hao, Bernard Jégou, Melissa Boudjema, 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 ), Genetics and Biochemistry Branch, National Institute of Health (NIH)-National Institute of Diabetes, Digestive and Kidney Diseases, University of Florida [Gainesville] (UF), École des Hautes Études en Santé Publique [EHESP] (EHESP), 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
0301 basic medicine ,Male ,Transcription, Genetic ,Germline ,Epigenesis, Genetic ,Histones ,Mice ,0302 clinical medicine ,Transcription (biology) ,Pregnancy ,Testis ,Cluster Analysis ,High-Throughput Nucleotide Sequencing ,Genomics ,Spermatozoa ,Cell biology ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,Meiosis ,Maternal Exposure ,Organ Specificity ,Prenatal Exposure Delayed Effects ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Atrazine ,Female ,RNA, Long Noncoding ,Protein Binding ,Chromatin Immunoprecipitation ,Biology ,Methylation ,03 medical and health sciences ,Genetics ,[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health ,Animals ,Position-Specific Scoring Matrices ,Epigenetics ,Nucleotide Motifs ,Enhancer ,Spermatogenesis ,Transcription factor ,Gene ,[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,Binding Sites ,Herbicides ,Gene Expression Profiling ,Environmental Exposure ,Molecular biology ,030104 developmental biology ,H3K4me3 ,Chromatin immunoprecipitation ,030217 neurology & neurosurgery - Abstract
International audience; The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.
- Published
- 2016
31. Spermatogonia Differentiation Requires Retinoic Acid Receptor γ
- Author
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Mathilde Raverdeau, Norbert B. Ghyselinck, Christine Dennefeld, Aurore Gely-Pernot, Shosei Yoshida, Muriel Klopfenstein, Manuel Mark, Betty Feret, Catherine Celebi, 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 ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, 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 Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Aging ,endocrine system ,medicine.medical_specialty ,Mice, 129 Strain ,Receptors, Retinoic Acid ,Spermiogenesis ,[SDV]Life Sciences [q-bio] ,Retinoic acid ,Biology ,Real-Time Polymerase Chain Reaction ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Testis ,medicine ,Animals ,Spermatogenesis ,DNA Primers ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Vitamin A Deficiency ,urogenital system ,Retinoic Acid Receptor alpha ,Gene Expression Regulation, Developmental ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,Sertoli cell ,Retinoic Acid Receptor γ ,Spermatogonia ,Mice, Inbred C57BL ,Meiosis ,Retinoic acid receptor ,Spermatogonia Differentiation ,medicine.anatomical_structure ,Seminiferous tubule ,chemistry ,Nuclear receptor ,Retinoic acid receptor alpha ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
International audience; Vitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (Aal) spermatogonia, as well as during the transition from Aal to A1 spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the Aal to A1 transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated by RARA, as indicated by the normal timing of appearance of meiotic cells in Rarg-null testes. Accordingly, RARG- and RARA-selective agonists are both able to stimulate Stra8 expression in wild-type prepubertal testes. Interestingly, inactivation of Rarg does not impair expression of the spermatogonia differentiation markers Kit and Stra8, contrary to vitamin A deficiency. This latter observation supports the notion that the RA-signaling pathway previously shown to operate in Sertoli cells also participates in spermatogonia differentiation.
- Published
- 2012
32. Embryonic exposure to the widely-used herbicide atrazine disrupts meiosis and normal follicle formation in female mice
- Author
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Gely-Pernot, Aurore, primary, Saci, Souhila, additional, Kernanec, Pierre-Yves, additional, Hao, Chunxiang, additional, Giton, Frank, additional, Kervarrec, Christine, additional, Tevosian, Sergei, additional, Mazaud-Guittot, Severine, additional, and Smagulova, Fatima, additional
- Published
- 2017
- Full Text
- View/download PDF
33. Evidence for a subventricular zone neural stem cell phagocytic activity stimulated by the vitamin K-dependent factor protein S
- Author
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Aurore Gely-Pernot, Aurélie Ginisty, Valérie Coronas, Patricia Arnault, Loubna Abaamrane, Franck Morel, Omar Benzakour, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, and Université de Tours-Université de Poitiers-Centre National de la Recherche Scientifique (CNRS)
- Subjects
MESH: Signal Transduction ,MESH: Neural Stem Cells ,animal diseases ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Subventricular zone ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Protein S ,Mice ,SOX2 ,Neural Stem Cells ,Phagocytosis ,Lateral Ventricles ,Proto-Oncogene Proteins ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,medicine ,Animals ,MESH: Animals ,Efferocytosis ,MESH: Phagocytosis ,MESH: Mice ,Tissue homeostasis ,Cells, Cultured ,MESH: Lateral Ventricles ,c-Mer Tyrosine Kinase ,Receptor Protein-Tyrosine Kinases ,Cell Biology ,Nestin ,MERTK ,Antigens, Differentiation ,Neural stem cell ,Cell biology ,MESH: Protein S ,MESH: Proto-Oncogene Proteins ,medicine.anatomical_structure ,Neuropoiesis ,nervous system ,MESH: Antigens, Differentiation ,Molecular Medicine ,MESH: Receptor Protein-Tyrosine Kinases ,Developmental Biology ,Signal Transduction ,MESH: Cells, Cultured - Abstract
Neural stem cells, whose major reservoir in the adult mammalian brain is the subventricular zone (SVZ), ensure neuropoiesis, a process during which many generated cells die. Removal of dead cells and debris by phagocytes is necessary for tissue homeostasis. Using confocal and electron microscopy, we demonstrate that cultured SVZ cells phagocytose both 1 and 2 µm latex beads and apoptotic cell-derived fragments. We determine by flow cytometry that phagocytic cells represent more than 10% of SVZ cultured cells. Phenotyping of SVZ cells using nestin, GFAP, Sox2, or LeX/SSEA and quantification of aldehyde dehydrogenase (ALDH) activity, reveals that cells with neural stem-cell features phagocytose and represent more than 30% of SVZ phagocytic cells. In vivo, nestin-, Sox2-, and ALDH-expressing neural stem-like cells engulfed latex beads or apoptotic cell-derived fragments that were injected into mice lateral brain ventricles. We show also that SVZ cell phagocytic activity is an active process, which depends both on cytoskeleton dynamic and on recognition of phosphatidylserine eat-me signal, and is stimulated by the vitamin K-dependent factor protein S (ProS). ProS neutralizing antibodies inhibit SVZ cell phagocytic activity and exposure of SVZ cells to apoptotic cell-derived fragments induces a transient Mer tyrosine kinase receptor (MerTK) phosphorylation. Conversely, MerTK blocking antibodies impair both basal and ProS-stimulated SVZ cell phagocytic activity. By revealing that neural stem-like cells act within the SVZ neurogenic niche as phagocytes and that the ProS/MerTK path represents an endogenous regulatory mechanism for SVZ cell phagocytic activity, the present report opens-up new perspectives for both stem cell biology and brain physiopathology. Stem Cells 2015;33:515–525
- Published
- 2015
34. Additional file 1: of The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine
- Author
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Gely-Pernot, Aurore, Chunxiang Hao, Becker, Emmanuelle, Stuparevic, Igor, Kervarrec, Christine, Chalmel, Frédéric, Primig, Michael, Jégou, Bernard, and Smagulova, Fatima
- Abstract
Supplementary material. (PDF 2459 kb)
- Published
- 2015
- Full Text
- View/download PDF
35. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor
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Muriel Klopfenstein, Christine Dennefeld, Irwin Davidson, Norbert B. Ghyselinck, Marius Teletin, Aurore Gely-Pernot, Mathilde Raverdeau, Manuel Mark, Gérard Benoit, Betty Féret, Nadège Vernet, 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), Département Santé Environnement Travail et Génie Sanitaire (DSETGS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 - Faculté des sciences et technologies (UCBL FST), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, This work was supported by grants from CNRS, INSERM, UNISTRA, Agence Nationale pour la Recherche (ANR 09-BLAN-0282, 10-BLAN-1239, 13-BSV2-0017), Fondation pour la Recherche Médicale (FDT20110922849, DEQ20071210544) and European community (FP7-PEOPLE-2012-IEF Marie Curie action, project #331687). It was also supported in part by the grant ANR-10-LABX-0030-INRT under the frame program Investissements d'Avenir labeled ANR-10-IDEX-0002-02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-09-BLAN-0282,NUREDIM,Bases structurales et implications biologiques in vivo des mécanismes de l'homodimérisation des récepteurs nucléaires non stéroïdiens(2009), ANR-10-BLAN-1239,molmechmeiosis,Mécanismes moléculaires contrôlant l'entrée en méiose chez les mammifères(2010), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), European Project: 331687,EC:FP7:PEOPLE,FP7-PEOPLE-2012-IEF,INVIVO_RA_NONCANON(2013), 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 Claude Bernard Lyon 1 - Faculté des sciences (UCBL FS)
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Male ,Cancer Research ,Cellular differentiation ,Sertoli cells ,Retinoic acid ,Epithelium ,chemistry.chemical_compound ,Mice ,Spermatocytes ,Cell differentiation ,Testes ,Genetics (clinical) ,[SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis ,Gene Expression Regulation, Developmental ,Sertoli cell ,Spermatids ,Cell biology ,DNA-Binding Proteins ,Meiosis ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Germ cell ,medicine.drug ,Research Article ,endocrine system ,lcsh:QH426-470 ,Tretinoin ,Biology ,Cell fate determination ,Retinoid X receptor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,medicine ,Germ cells ,Animals ,Humans ,Spermatogenesis ,Molecular Biology ,Transcription factor ,neoplasms ,Ecology, Evolution, Behavior and Systematics ,urogenital system ,organic chemicals ,Molecular biology ,biological factors ,Spermatogonia ,lcsh:Genetics ,Retinoid X Receptors ,chemistry ,Transcription Factors - Abstract
All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells., Author Summary Differentiation of spermatozoa from immature germ cells, called spermatogonia, critically depends on retinoic acid (ATRA), the active metabolite of vitamin A that acts though binding to nuclear receptors called RXR and RAR. To understand the mechanism by which ATRA control germ cell differentiation, we generated mice simultaneously lacking all RXR or all RAR specifically in spermatogonia. From their phenotypic analysis, we demonstrate that meiosis does not require a RAR/RXR-dependent pathway in germ cells and propose that this process is either ATRA-independent or requires an ATRA signal originating from somatic cells. We also show that RXR, in the form of dimers with RAR, can drive spermatogonia differentiation through binding to a regulatory region located in the Sall4 gene. This finding is significant, as the transcription factor encoded by Sall4 is known to regulate the expression of KIT, a key tyrosine kinase receptor which is frequently deregulated in testicular cancer.
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- 2015
36. The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine
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Gely-Pernot, Aurore, Hao, Chunxiang, Becker, Emmanuelle, Stuparevic, Igor, Kervarrec, Christine, Chalmel, Frédéric, Primig, Michael, Jégou, Bernard, Smagulova, Fatima, 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 ), University of Zagreb, École des Hautes Études en Santé Publique [EHESP] (EHESP), 11 IRSET Chaire d'excellence, Université Européenne de Bretagne (FR), China Scholarship Council (CN), R13139NS, Atip-Avenir 2013, 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
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Male ,Chromatin Immunoprecipitation ,Cell Survival ,Double-strand breaks ,Receptors, Cytoplasmic and Nuclear ,Apoptosis ,Epigenesis, Genetic ,GTP Phosphohydrolases ,Histones ,Mice ,ChIP-Seq ,Testis ,Genetics ,Animals ,Position-Specific Scoring Matrices ,DNA Breaks, Double-Stranded ,Testosterone ,Nucleotide Motifs ,Gonadal Steroid Hormones ,Binding Sites ,[SDV.TOX.ECO] Life Sciences [q-bio]/Toxicology/Ecotoxicology ,Sperm Count ,Herbicides ,Gene Expression Profiling ,Computational Biology ,High-Throughput Nucleotide Sequencing ,H3K4me3 ,Mitochondria ,Meiosis ,meiosis ,double-strand breaks ,gene-chip ,atrazine ,Atrazine ,[SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology ,Gene-Chip ,Research Article ,Genome-Wide Association Study ,Protein Binding ,Biotechnology - Abstract
Background Environmental factors such as pesticides can cause phenotypic changes in various organisms, including mammals. We studied the effects of the widely used herbicide atrazine (ATZ) on meiosis, a key step of gametogenesis, in male mice. Methods Gene expression pattern was analysed by Gene–Chip array. Genome-wide mapping of H3K4me3 marks distribution was done by ChIP-sequencing of testis tissue using Illumina technologies. RT-qPCR was used to validate differentially expressed genes or differential peaks. Results We demonstrate that exposure to ATZ reduces testosterone levels and the number of spermatozoa in the epididymis and delays meiosis. Using Gene-Chip and ChIP-Seq analysis of H3K4me3 marks, we found that a broad range of cellular functions, including GTPase activity, mitochondrial function and steroid-hormone metabolism, are affected by ATZ. Furthermore, treated mice display enriched histone H3K4me3 marks in regions of strong recombination (double-strand break sites), within very large genes and reduced marks in the pseudoautosomal region of X chromosome. Conclusions Our data demonstrate that atrazine exposure interferes with normal meiosis, which affects spermatozoa production. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2095-y) contains supplementary material, which is available to authorized users.
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- 2015
37. Atrazine exposure of adult mice affect spermatogenesis
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Michael Priming, Christine Kervarec, Igor Stuparević, Chunxiang Hao, Bernard Jégou, Fatima Smagulova, Bertrand Evrard, Aurore Gely-Pernot, and Frédéric Chalmel
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Andrology ,chemistry.chemical_compound ,chemistry ,General Medicine ,Atrazine ,Biology ,Affect (psychology) ,Spermatogenesis - Published
- 2014
38. Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice
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Hao, Chunxiang, primary, Gely-Pernot, Aurore, additional, Kervarrec, Christine, additional, Boudjema, Melissa, additional, Becker, Emmanuelle, additional, Khil, Pavel, additional, Tevosian, Sergei, additional, Jégou, Bernard, additional, and Smagulova, Fatima, additional
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- 2016
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39. Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis
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Norbert B. Ghyselinck, Manuel Mark, Pierre Chambon, Mathilde Raverdeau, Christine Dennefeld, Aurore Gely-Pernot, Irwin Davidson, Gérard Benoit, Betty Féret, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Mice, 129 Strain ,Receptors, Retinoic Acid ,Somatic cell ,Cell ,Retinoic acid ,Gene Expression ,Mice, Transgenic ,Tretinoin ,Spermatocyte ,Biology ,Aldehyde Dehydrogenase 1 Family ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Spermatocytes ,Paracrine Communication ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,In Situ Hybridization ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Sertoli Cells ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,Retinal Dehydrogenase ,Cell Differentiation ,Aldehyde Dehydrogenase ,Biological Sciences ,Sertoli cell ,Immunohistochemistry ,Molecular biology ,Spermatogonia ,Mice, Inbred C57BL ,Meiosis ,medicine.anatomical_structure ,chemistry ,MAFB ,Female ,Spermatogenesis ,030217 neurology & neurosurgery ,Germ cell - Abstract
Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle ( i ) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; ( ii ) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; ( iii ) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8 . Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male.
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- 2012
40. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor
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Gely-Pernot, Aurore, primary, Raverdeau, Mathilde, additional, Teletin, Marius, additional, Vernet, Nadège, additional, Féret, Betty, additional, Klopfenstein, Muriel, additional, Dennefeld, Christine, additional, Davidson, Irwin, additional, Benoit, Gérard, additional, Mark, Manuel, additional, and Ghyselinck, Norbert B., additional
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- 2015
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41. Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice.
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Chunxiang Hao, Gely-Pernot, Aurore, Kervarrec, Christine, Boudjema, Melissa, Becker, Emmanuelle, Khil, Pavel, Tevosian, Sergei, Jégou, Bernard, and Smagulova, Fatima
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- 2016
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42. Atrazine exposure of adult mice affect spermatogenesis
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Gely-Pernot, Aurore, primary, Hao, Chunxiang, additional, Kervarec, Christine, additional, Stuparevic, Igor, additional, Chalmel, Frederic, additional, Evrard, Bertrand, additional, Priming, Michael, additional, Jegou, Bernard, additional, and Smagulova, Fatima, additional
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- 2014
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43. An Endogenous Vitamin K-Dependent Mechanism Regulates Cell Proliferation in the Brain Subventricular Stem Cell Niche
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Gely-Pernot, Aurore, primary, Coronas, Valérie, additional, Harnois, Thomas, additional, Prestoz, Laetitia, additional, Mandairon, Nathalie, additional, Didier, Anne, additional, Berjeaud, Jean Marc, additional, Monvoisin, Arnaud, additional, Bourmeyster, Nicolas, additional, De Frutos, Pablo García, additional, Philippe, Michel, additional, and Benzakour, Omar, additional
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- 2012
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44. MOESM1 of Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features
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Legoff, Louis, Ouzna Dali, D’Cruz, Shereen, Suglia, Antonio, Gely-Pernot, Aurore, Hémery, Chloé, Pierre-Yves Kernanec, Abbassia Demmouche, Kervarrec, Christine, Tevosian, Sergei, Multigner, Luc, and Smagulova, Fatima
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3. Good health - Abstract
Additional file 1: Fig. S1. Gestational CD exposure increases H2Aub in embryonic ovaries. Fig. S2. Increased levels of H3K27me3 in meiotic cells following embryonic CD exposure. Fig. S3. Gestational exposure to CD leads to decrease in expression of developmental genes. Fig. S4. Gestational exposure to CD leads to decrease in expression of genes associated with signaling, transcription regulation and DNA repair in three-month-old ovaries. Fig. S5. Decrease in the levels of AMH in adult ovaries after gestational CD exposure. Fig. S6. Gestational exposure to CD leads to decrease in body and ovarian weights in 5-month-old animals. Fig. S7. CD induces increased H3K4me3 occupancy at ZBTB17 binding site. Table S1. H3K4me3 differential peaks identified in CD exposed ovaries. Table S2. Targets of ZFP57 identified by ChEA. Table S3. Targets of TRIM28 identified by ChEA. Table S4. Oligonucleotides used for RT-qPCR.
45. MOESM1 of Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features
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Legoff, Louis, Ouzna Dali, D’Cruz, Shereen, Suglia, Antonio, Gely-Pernot, Aurore, Hémery, Chloé, Pierre-Yves Kernanec, Abbassia Demmouche, Kervarrec, Christine, Tevosian, Sergei, Multigner, Luc, and Smagulova, Fatima
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3. Good health - Abstract
Additional file 1: Fig. S1. Gestational CD exposure increases H2Aub in embryonic ovaries. Fig. S2. Increased levels of H3K27me3 in meiotic cells following embryonic CD exposure. Fig. S3. Gestational exposure to CD leads to decrease in expression of developmental genes. Fig. S4. Gestational exposure to CD leads to decrease in expression of genes associated with signaling, transcription regulation and DNA repair in three-month-old ovaries. Fig. S5. Decrease in the levels of AMH in adult ovaries after gestational CD exposure. Fig. S6. Gestational exposure to CD leads to decrease in body and ovarian weights in 5-month-old animals. Fig. S7. CD induces increased H3K4me3 occupancy at ZBTB17 binding site. Table S1. H3K4me3 differential peaks identified in CD exposed ovaries. Table S2. Targets of ZFP57 identified by ChEA. Table S3. Targets of TRIM28 identified by ChEA. Table S4. Oligonucleotides used for RT-qPCR.
46. Os efeitos de químicos ambientais (cádmio) e farmacológicos (CBD e THC) no processo espermatogênico
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Silva, Janaina da, Gely-Pernot, Aurore, Melo, Fabiana Cristina Silveira Alves de, and Matta, Sérgio Luis Pinto da
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Toxicologia ambiental ,Canabidiol ,Tetra-hidrocanabinol ,Histologia ,Rotas de resultados adversos ,Toxicologia reprodutiva - Abstract
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Uma tendência significativa para um declínio mundial na fertilidade masculina humana tem sido relatada nos últimos anos. Enquanto isso, a exposição a químicos tem sido proposta para potencialmente contribuir para os distúrbios reprodutivos masculinos, em que químicos ambientais e farmacológicos/recreacionais podem induzir efeitos prejudiciais à saúde reprodutiva masculina. Entre uma variedade complexa de produtos químicos ambientais, o cádmio (Cd) é um dos metais pesados que se classifica entre os metais prioritários com importância para a saúde pública, uma vez que o Cd é considerado como um desregulador endócrino. Os seres humanos estão expostos diariamente ao Cd por meio de fontes ocupacionais (e.g. produção de baterias) e não ocupacionais (e.g. alimentos/água contaminados e fumaça de cigarro). Além disso, o consumo de cannabis para fins terapêuticos e recreativos está em ascensão. Neste contexto de produtos químicos e fertilidade masculina, a exposição aos compostos da cannabis, chamados fitocanabinoides (canabinoides), pode resultar em resultados adversos para a saúde reprodutiva masculina. Portanto, a presente tese teve como objetivo avaliar o impacto dessas duas tendências globais, cádmio e canabinoides presentes na cannabis, no processo espermatogênico. Já se sabe que o cádmio induz danos ao testículo. No entanto, os mecanismos pelos quais o cádmio promove o aparecimento de patologias testiculares e a relação entre dose, via e tempo de exposição e lesões são pouco conhecidos. Nesse sentido, realizamos uma revisão sistemática (Capítulo 1) para responder a essas questões. Depois de recuperar estudos originais em bancos de dados, organizamos os resultados em uma estrutura de Adverse Outcome Pathway (AOP). Além disso, uma análise de viés foi realizada. Nos 37 estudos selecionados, ficou claro que o cádmio induz histopatologias significativas em testículos de modelos murinos independente de via, de maneira dose e tempo-dependente. Os danos podem ser observados nas primeiras horas de exposição, principalmente danos vasculares, sugerindo que a falha na vascularização é o mecanismo primário envolvido. A AOP mostrou que potenciais eventos moleculares iniciais podem ser o mimetismo e a interferência com elementos essenciais desregulando proteínas (estruturais e antioxidantes), alteração na atividade da enzima de fosforilação oxidativa e alteração da expressão gênica, que levam à falha reprodutiva. No entanto, a análise de viés mostrou que as evidências atuais apresentam qualidade metodológica pobre. Em relação ao impacto dos canabinoides na saúde reprodutiva masculina, realizamos dois ensaios biológicos. Em um manuscrito (Capítulo 2), buscamos responder se os dois principais fitocanabinoides presentes na cannabis poderiam representar um perigo para o testículo humano adulto. Para isso, expusemos testículos humanos adultos ao Δ 9- tetrahidrocanabinol (THC), canabidiol (CBD), ou CBD/THC (proporção 1:1) nas concentrações de 10 -9 M a 10 -5 M por 48 horas, utilizando nosso modelo ex vivo único de cultura organotípica. Nossos achados não mostraram alteração na histologia testicular, produção de testosterona, número de células apoptóticas e proliferativas e expressão de genes que codificam importantes proteínas testiculares. Uma vez que alguns problemas reprodutivos masculinos foram hipotetizados como sendo de origem fetal, no último estudo (Capítulo 3) avaliamos se a exposição pré-natal ao CBD/THC poderia levar a distúrbios reprodutivos masculinos na vida adulta. Para isso, expomos camundongos fêmeas prenhas do dia de gestação 6,5 (E6,5) ao E15,5 a 5mg/kg/dia de CBD/THC (proporção 1:1), por gavagem. Observamos diminuição do peso testicular e alterações morfológicas testiculares, estas identificadas por análises morfométricas, na prole adulta. No entanto, essas alterações não foram acompanhadas por mudanças nos números de espermatogônias indiferenciadas e células de Sertoli. A análise da expressão gênica revelou um aumento na expressão de genes pró-apoptótico (Bax), de diferenciação de células germinativas (Sohlh1) e de regulação meiótica (Stra8). Não foram observadas alterações nos níveis séricos de testosterona. Em geral, nossos resultados demonstram que o cádmio, um poluente ambiental, pode afetar a saúde reprodutiva masculina de modelos murinos e conduzir à infertilidade masculina. Entretanto, os dois fitocanabinoides presentes na cannabis, THC e CBD, os quais são também utilizados como químicos farmacológicos, não causam efeitos agudos diretos na histofisiologia testicular usando nossa cultura organotípica bem caracterizada de testículo humano adulto. Porém, exposição pré-natal a uma mistura desses dois canabinoides derivados da canabis pode conduzir ao peso testicular diminuído de camundongos na vida adulta. Ainda, a exposição pré-natal pode acelerar a meiose e a diferenciação celular e induzir apoptose, baseado nos achados moleculares, provavelmente, contribuindo de forma compensatória para a diminuição do peso do testículo. Assim, em camundongos, exposição pré-natal a uma mistura de THC/CBD pode afetar a biologia testicular de proles adultas. No geral, os resultados apresentados por esta tese fornecem novos conhecimentos sobre a toxicologia reprodutiva e a saúde reprodutiva masculina, que podem ser considerados para preservar a fertilidade em toda a população. Palavras-chave: Toxicologia reprodutiva. Contaminante ambiental. Adverse Outcome Pathway. Δ 9 -tetrahidrocanabinol. Canabidiol. Cultura organotípica. A significant trend towards a worldwide decline in human male fertility has been reported over the last years. In the meantime, exposure to chemicals has been proposed to potentially contribute to male reproductive disorders, in which environmental and pharmacological/recreational chemicals might induce detrimental effects on male reproductive health. Among a complex variety of environmental chemicals, cadmium (Cd) is one of the heavy metals that rank among the priority metals that are of public health significance, since Cd is considered as an endocrine disruptor. Human beings are daily exposure to Cd through occupational (e.g. production of batteries) and non-occupational (e.g. contaminated food/water, cigarette smoke) sources. Furthermore, cannabis consumption for medical and recreational purposes is on the rise. In this context of chemicals and male fertility, exposure to cannabis compounds, called phytocannabinoids (cannabinoids), could result in adverse outcomes to male reproductive health. So, this present thesis aimed to assess the impact of these two global trends, cadmium and cannabinoids, in the spermatogenic process. It is already known that cadmium induces damage to the testis. However, the mechanisms that cadmium leads to testicular histopathologies and the relationship between dose, route, and time of exposure and injuries are poorly understood. In this sense, we conducted a systematic review (Chapter 1) to answer these questions. After retrieving original studies on databases, we organized the results into an Adverse Outcome Pathway (AOP) framework. Also, a bias analysis was performed. In the 37 studies selected, it was clear that cadmium induces significant histopathologies in the murine model’s testis regarding routes, in a dose- and time-dependent manner. The damages can be observed in the first hours of exposure, mainly vascular damages suggesting that vasculature failure is the primary mechanism involved. The AOP showed that potential molecular initiating events may mimic and interfere with essential elements disrupting proteins (structural and antioxidants), change in the oxidative phosphorylation enzyme activities, and gene expression alteration, which lead to reproductive failure. However, analysis of bias showed that the current evidence presents poor methodological quality. Regarding the cannabinoid impact on male reproductive health, we performed two biological essays. In one manuscript (Chapter 2), we aimed to answer whether the two main phytocannabinoids present in cannabis could represent a hazard for adult human testis. For that, we exposed adult human testis to Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), or CBD/THC (ratio 1:1) at the concentrations from 10 -9 M to 10 -5 M for 48 hours, by using our unique ex vivo model of organotypic culture. Our findings show no alteration in testis histology, testosterone production, number of apoptotic and proliferative cells, and expression of some genes encoding important testicular proteins. Since some male reproductive problems have been hypothesized to have a fetal origin, in the last study (Chapter 3), we assessed whether prenatal exposure to CBD and THC could lead to male reproductive disorders in adult life. For that, we exposed pregnant mice from embryogenic day 6.5 (E6.5) to E15.5 to 5mg/kg/day of CBD/THC (ratio 1:1), by gavage. Then, we observed decreased testicular weight and testicular morphological alterations identified by morphometric analyses in adult offspring. However, these alterations were not followed by changes in the undifferentiated spermatogonia and Sertoli cell numbers. The gene expression analysis revealed an increase in the expression of pro-apoptotic (Bax), germ cell differentiation (Sohlh1), and regulating meiotic (Stra8) genes. Alterations in the serum testosterone levels were not observed. In general, our findings demonstrate that cadmium, an environmental pollutant, can affect the male reproductive health of murine models and lead to male infertility. On the other hand, the two main cannabinoids present in cannabis, THC and CBD, which are also used as pharmacological chemicals, do not cause acute direct effects in the testicular histophysiology using our well-characterized organotypic culture of adult human testis. However, prenatal exposure to a mixture of these cannabis-derived cannabinoids can lead to decreased testis weight of mice in adult life. Also, prenatal exposure can accelerate meiosis and cellular differentiation and induce apoptosis, based on the molecular findings, probably, contributing compensatory to the decreased testis weight. So, in mice, prenatal exposure to a mixture of THC/CBD might affect the testis biology of adult offspring. Overall, the results presented by this thesis provide new insights into male repro-toxicology and reproductive health, which might be considered to preserve fertility across the population. Keywords: Repro-toxicology. Environmental contaminant. Adverse Outcome Pathway. Δ 9 - tetrahydrocannabinol. Cannabidiol. Organotypic culture.
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- 2021
47. Profils respiratoires et allergiques depuis la naissance et facteurs associés en population générale française : résultats de la cohorte ELFE (Etude Longitudinale Française depuis l'Enfance)
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KHAN, Sadia, Raherison, Chantal, Molimard, Mathieu, Le Meur-Rouillard, Nolwenn, Didier, Alain, and Gely-Pernot, Aurore
- Subjects
Phénotypes ,Scores prédictifs ,Asthme ,Sifflement ,Cohortes de naissances ,Trajectoires
48. Developmental exposure to chlordecone induces transgenerational effects in somatic prostate tissue which are associated with epigenetic histone trimethylation changes.
- Author
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Legoff L, D'Cruz SC, Lebosq M, Gely-Pernot A, Bouchekhchoukha K, Monfort C, Kernanec PY, Tevosian S, Multigner L, and Smagulova F
- Subjects
- Animals, Epigenesis, Genetic, Female, Histones metabolism, Male, Mice, Pregnancy, Prostate metabolism, Chlordecone toxicity, Prenatal Exposure Delayed Effects genetics
- 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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
49. The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine.
- Author
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Gely-Pernot A, Hao C, Becker E, Stuparevic I, Kervarrec C, Chalmel F, Primig M, Jégou B, and Smagulova F
- Subjects
- Animals, Apoptosis drug effects, Binding Sites, Cell Survival, Chromatin Immunoprecipitation, Computational Biology methods, DNA Breaks, Double-Stranded drug effects, GTP Phosphohydrolases metabolism, Gene Expression Profiling, Genome-Wide Association Study, Gonadal Steroid Hormones metabolism, High-Throughput Nucleotide Sequencing, Histones metabolism, Male, Mice, Mitochondria drug effects, Mitochondria genetics, Mitochondria metabolism, Nucleotide Motifs, Position-Specific Scoring Matrices, Protein Binding, Receptors, Cytoplasmic and Nuclear metabolism, Sperm Count, Testis drug effects, Testis metabolism, Testosterone blood, Atrazine pharmacology, Epigenesis, Genetic drug effects, Herbicides pharmacology, Meiosis drug effects, Meiosis genetics
- Abstract
Background: Environmental factors such as pesticides can cause phenotypic changes in various organisms, including mammals. We studied the effects of the widely used herbicide atrazine (ATZ) on meiosis, a key step of gametogenesis, in male mice., Methods: Gene expression pattern was analysed by Gene-Chip array. Genome-wide mapping of H3K4me3 marks distribution was done by ChIP-sequencing of testis tissue using Illumina technologies. RT-qPCR was used to validate differentially expressed genes or differential peaks., Results: We demonstrate that exposure to ATZ reduces testosterone levels and the number of spermatozoa in the epididymis and delays meiosis. Using Gene-Chip and ChIP-Seq analysis of H3K4me3 marks, we found that a broad range of cellular functions, including GTPase activity, mitochondrial function and steroid-hormone metabolism, are affected by ATZ. Furthermore, treated mice display enriched histone H3K4me3 marks in regions of strong recombination (double-strand break sites), within very large genes and reduced marks in the pseudoautosomal region of X chromosome., Conclusions: Our data demonstrate that atrazine exposure interferes with normal meiosis, which affects spermatozoa production.
- Published
- 2015
- Full Text
- View/download PDF
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