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Objective This study tested for an association between early cancer-related biomarkers and low-to-moderate exposure to fumes from welding mild steel. Methods Male, non-smoking participants from southern Sweden were recruited and examined (N=338, 171 welders and 167 controls); of these, 78 welders and 96 controls were examined on two occasions six years apart. Exposure to welding fumes was evaluated by measuring respirable dust, welding years, and cumulative exposure. DNA methylation of CpG sites within the cancer-related genes AHRR, F2RL3, and B3GNTL1 was measured by pyrosequencing and relative mitochondrial DNA copy number and telomere length were measured by qPCR in whole-blood samples. Multivariate models were used for longitudinal analysis. Results Median exposure to respirable dust was 0.7 mg/m3 at both timepoints, adjusted for use of personal protective equipment. Compared with controls, welders showed a significant decrease over time in DNA methylation of B3GNTL1 CpG1 and CpG4 [adjusted for age, body mass index, and smoking: β=-0.66, standard error (SE)=0.28; β=-0.48, SE=0.24, respectively]. In addition, exposure to respirable dust and cumulative exposure was associated with a decrease in methylation of F2RL3 CpG2 among all welders (adjusted β=-0.67, SE=0.23 and β=-0.03, SE=0.02, respectively). No significant associations were found for AHRR, mitochondrial DNA copy number, or telomere length. Conclusion Low-to-moderate exposure to welding fumes was associated with a small effect on selected early epigenetic biomarkers of cancer. The direction of the methylation pattern (lower methylation of specific CpG sites) indicates early lung cancer-related changes associated with mild steel welding. [ABSTRACT FROM AUTHOR]

Background: Maternal status of long-chain PUFAs (LC-PUFAs) may be related to fetal growth. Maternal fish consumption exposes the mother to the neurotoxicant methylmercury (MeHg), which, in contrast, may restrict fetal growth.Objective: Our aim was to examine relations between maternal LC-PUFA status at 28 wk and birth outcomes (birth weight, length, and head circumference), controlling for MeHg exposure throughout pregnancy, in the Seychelles Child Development Study Nutrition Cohort 2. Our secondary aim was to examine the influence of maternal variation in genes regulating the desaturation of LC-PUFAs [fatty acid desaturase (FADS)] on birth outcomes.Methods: From nonfasting blood samples collected at 28 wk of gestation, we measured serum total LC-PUFA concentrations and FADS1 (rs174537, rs174561), FADS1-FADS2rs3834458, and FADS2rs174575 genotypes, with hair total mercury concentrations assessed at delivery. Data were available for n = 1236 mother-child pairs. Associations of maternal LC-PUFAs, MeHg, and FADS genotype with birth outcomes were assessed by multiple linear regression models, adjusting for child sex, gestational age, maternal age, BMI, alcohol use, socioeconomic status, and parity.Results: In our cohort of healthy mothers, neither maternal LC-PUFA status nor MeHg exposure were significant determinants of birth outcomes. However, when compared with major allele homozygotes, mothers who were heterozygous for the minor allele of FADS1 (rs174537 and rs174561, GT compared with TT, β = 0.205, P = 0.03; TC compared with CC, β = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, β = 0.197, P = 0.04) had infants with a greater head circumference (all P < 0.05). Homozygosity for the minor allele of FADS2 (rs174575) was associated with a greater birth weight (GG compared with CC, β = 0.109, P = 0.04).Conclusions: In our mother-child cohort, neither maternal LC-PUFA status nor MeHg exposure was associated with birth outcomes. The observed associations of variation in maternal FADS genotype with birth outcomes should be confirmed in other populations. [ABSTRACT FROM AUTHOR]

Objectives: Exposure to high-molecular-weight polycyclic aromatic hydrocarbons (PAHs) may cause cancer in chimney sweeps and creosote-exposed workers, however, knowledge about exposure to low-molecular-weight PAHs in relation to cancer risk is limited. In this study, we aimed to investigate occupational exposure to the low-molecular-weight PAHs phenanthrene and fluorene in relation to different cancer biomarkers.Methods: We recruited 151 chimney sweeps, 19 creosote-exposed workers and 152 unexposed workers (controls), all men. We measured monohydroxylated metabolites of phenanthrene and fluorene in urine using liquid chromatography coupled to tandem mass spectrometry. We measured, in peripheral blood, the cancer biomarkers telomere length and mitochondrial DNA copy number using quantitative PCR; and DNA methylation of F2RL3 and AHRR using pyrosequencing.Results: Median PAH metabolite concentrations were higher among chimney sweeps (up to 3 times) and creosote-exposed workers (up to 353 times), compared with controls (p<0.001; adjusted for age and smoking). ∑OH-fluorene (sum of 2-hydroxyfluorene and 3-hydroxyfluorene) showed inverse associations with percentage DNA methylation of F2RL3 and AHRR in chimney sweeps (B (95% CI)=-2.7 (-3.9 to -1.5) for F2RL3_cg03636183, and -7.1 (-9.6 to -4.7) for AHRR_cg05575921: adjusted for age and smoking), but not in creosote-exposed workers. In addition, ∑OH-fluorene showed a 42% mediation effect on the inverse association between being a chimney sweep and DNA methylation of AHRR CpG2.Conclusions: Chimney sweeps and creosote-exposed workers were occupationally exposed to low-molecular-weight PAHs. Increasing fluorene exposure, among chimney sweeps, was associated with lower DNA methylation of F2RL3 and AHRR, markers for increased lung cancer risk. These findings warrant further investigation of fluorene exposure and toxicity. [ABSTRACT FROM AUTHOR]

Chimney sweeps have higher incidence and mortality of cardiovascular disease (CVD), likely related to their exposure to polycyclic aromatic hydrocarbons (PAH). In order to identify underlying mechanisms of PAH-related CVD, we here investigated whether PAH exposure was associated with levels of putative CVD-related proteins in serum among currently working chimney sweeps. We enrolled 116 chimney sweeps and 125 unexposed controls, all nonsmoking male workers from Sweden. We measured monohydroxylated PAH metabolites in urine by liquid chromatography coupled to tandem mass spectrometry and a panel of 85 proteins in serum using proximity extension assay. Linear regression analysis adjusted for age and body mass index showed that 25 proteins were differentially expressed between chimney sweeps and the controls (p  <  .05, adjusted for false discovery rate). Of the 25 proteins, follistatin (FS), prointerleukin-16 (IL-16), and heat shock protein beta-1 (HSP 27) showed positive associations with the monohydroxylated metabolites of PAH in a dose-response manner (p  <  .05). Pathway and gene ontology analyses demonstrated that the differentially expressed proteins were mainly involved in inflammatory response and immunological functions, such as leukocyte migration, cell movement of leukocytes, and adhesion of immune cells. In conclusion, we found a number of putative CVD-related proteins differentially expressed, between PAH-exposed and unexposed individuals, and mainly involved in inflammation and immune function. Our data warrant protective measures to reduce PAH exposure and longitudinal investigations of the protein profile in chimney sweeps and other occupational groups exposed to PAH. [ABSTRACT FROM AUTHOR]

Exposure to some polycyclic aromatic hydrocarbons (PAH) increases the risk of cancer and is common particularly for workers in occupations such as chimney sweeping. In exposed workers, screening of early cancer-related markers provides important information to identify individuals at risk. Here, we aimed to elucidate the associations between PAH exposure and serum levels of cancer-related proteins in 118 chimney sweeps and 126 occupationally unexposed controls, all non-smoking males from Sweden. Monoydroxylated metabolites of pyrene, phenanthrene, benzo[a]pyrene and benzo[a]anthracene were measured in urine using liquid chromatography coupled to tandem mass spectrometry and 90 cancer-related proteins were measured in serum using a proximity extension assay. Linear regression analysis adjusted for age and body mass index, and false discovery rate (FDR) identified 17 serum proteins that were differentially expressed (16 upregulated and 1 downregulated) in chimney sweeps compared with controls (FDR < 0.05). Concentrations of the peptidase kallikrein 13 (KLK13) showed significant positive associations with urinary concentrations of the PAH metabolites 3-hydroxybenzo[a]pyrene (3-OH-BaP) [B, 95% confidence interval (CI): 0.042, 0.008–0.076] and 3-hydroxybenzo[a]anthracene (3-OH-BaA) (B, 95% CI: 0.068, 0.002–0.134). Moreover, dose–response relationships were observed between KLK13 and 3-OH-BaP (trend test P = 0.027) and 3-OH-BaA (P = 0.035). Pathway and gene ontology analyses showed that cell movement, cell adhesion and cell migration were the predominant molecular functions associated with the top differentially expressed proteins. In conclusion, we found a number of putative cancer-related proteins differentially expressed in workers exposed to PAH. This warrants effective measure to reduce PAH exposure among workers as well as further investigation to confirm these findings. [ABSTRACT FROM AUTHOR]

Some polycyclic aromatic hydrocarbons (PAH) are known carcinogens and workplace PAH exposure may increase the risk of cancer. Monitoring early cancer-related changes can indicate whether the exposure is carcinogenic. Here, we enrolled 151 chimney sweeps, 152 controls and 19 creosote-exposed male workers from Sweden. We measured urinary PAH metabolites using LC/MS/MS, the cancer-related markers telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) using qPCR, and DNA methylation of lung cancer-related genes F2RL3 and AHRR using pyrosequencing. The median 1-hydroxypyrene (PAH metabolite) concentrations were highest in creosote-exposed workers (8.0 μg/g creatinine) followed by chimney sweeps (0.34 μg/g creatinine) and controls (0.05 μg/g creatinine). TL and mtDNAcn did not differ between study groups. Chimney sweeps and creosote-exposed workers had significantly lower methylation of AHRR CpG site cg05575921 (88.1 and 84.9%, respectively) than controls (90%). Creosote-exposed workers (73.3%), but not chimney sweeps (76.6%) had lower methylation of F2RL3 cg03636183 than controls (76.7%). Linear regression analyses showed that chimney sweeps had lower AHRR cg05575921 methylation (B = –2.04; P < 0.057, adjusted for smoking and age) and lower average AHRR methylation (B = –2.05; P < 0.035), and non-smoking chimney sweeps had lower average F2RL3 methylation (B = –0.81; P < 0.042, adjusted for age) compared with controls. These cancer-related markers were not associated with urinary concentrations of PAH metabolites. In conclusion, although we found no associations with PAH metabolites in urine (short-term exposure), our results suggest dose–response relationship between PAH exposure and DNA hypomethylation of lung cancer-related loci. These findings indicate that further protective measures should be taken to reduce PAH exposure. [ABSTRACT FROM AUTHOR]

Objectives: To explore chimney sweeping work tasks, chimney sweeps' use of protective equipment, and type of fuel used by clients, over time. Further, to assess work-relatedness of current eye and airway symptoms. Methods: In a cross-sectional study in 2011, male Swedish chimney sweeps ( n = 483; age 21-69 years) answered a questionnaire about their occupational history and eye and airway symptoms. Results: Between 1960 and 2010, black-soot-sweeping in private homes was the major task, although it decreased during the time period, for chimney sweeps. Between 1975 and 2010, the use of petroleum oil decreased, whereas the use of pellets and wood increased. Also, the use of gloves and masks increased significantly. Black-soot-sweeping in industry was associated with work-related eye symptoms (prevalence odds ratio POR = 3.76, 95% CI: 1.72-8.24, for every 10% increment of working time, adjusted for age and tobacco smoking). Chimney sweeps also had slightly higher prevalence of cough with increasing black-soot-sweeping (POR = 1.06, 95% CI: 0.99-1.13 for every 10% increment, further adjusted for the use of mask), and the association was more pronounced, although nonsignificant, for black-soot-sweeping in industry (adjusted POR = 1.26, 95% CI: 0.98-1.61). Conclusions: Chimney sweeping tasks and use of protective equipment as well as type of fuel used by the clients changed significantly over the last 35 years, which may have changed chimney sweeps' exposure to soot. Still, chimney sweeps in Sweden have black-soot-sweeping-related eye and airway symptoms. [ABSTRACT FROM AUTHOR]

Working as hairdressers has been associated with increased risk for cancer, particularly bladder cancer. To evaluate if current hairdressers have elevated risks of adverse health effects, we measured several biomarkers related to cancer-related DNA alterations. We enrolled 295 hairdressers and 92 non-hairdressers (all female non-smokers) from Stockholm and southern Sweden. Questionnaire data were collected for each participant, including work tasks for the hairdressers. We measured telomere length in peripheral blood leucocytes using quantitative PCR and DNA methylation status of genes relevant for bladder cancer using methylation sensitive high resolution melting analysis. The hairdressers had shorter telomeres ( β = −0.069, P = 0.019) compared with non-hairdressers. Shorter telomeres were found in hairdressers up to 32 years old performing hair waving more than once per week as compared with hairdressers in the same age group performing hair waving less often ( β = −0.12, P = 0.037). Hair waving was associated with less frequent CDKN2A methylation (odds ratio, OR = 0.19, P = 0.033). Shorter telomeres in hairdressers may indicate a genotoxic effect. Performing hair waving was associated with short telomere length, although the effect was only observed in young hairdressers. No clear patterns were discerned with regard to DNA methylation of bladder cancer-related genes. The observed changes of methylation were not all in the expected direction and warrant further investigation. Environ. Mol. Mutagen. 57:159-167, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common singlenucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N=406), the Argentinean Andes (N=198), and Italy (N=238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N=101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P=.027) and Italy (10.6%, P=.012), but not as clear in Bangladesh (3.4%, P=.21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P=.033; adjusted for age and sex) and reduced SLC30A10 expression (-24.6%, P=.029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (-18.4%, P=.04), and increased finger-tapping speed (8.7%, P=.025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels. [ABSTRACT FROM AUTHOR]

Background: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans. Objective: This study aimed to elucidate the human metabolism of selenium to TMSe. Design: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y-old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 µg/L in mothers, 14 µg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 µg/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. Results: TMSe "producers" were prevalent (approximately one-third) among the Bangladeshi women and their children, in whom TMSe constituted ~ 10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-µg U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6-15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine N-methyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P < 0.001, false-discovery rate corrected) in both cohorts. Conclusions: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health. The MINIMat trial was registered at isrctn.org as ISRCTN16581394. [ABSTRACT FROM AUTHOR]

Background: The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes. Objective: To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg. Methods: The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts. Results: ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = −0.29, 95%CI −0.47, −0.12) and TT (β = −0.49, 95%CI −0.71, −0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = −0.12, 95%CI −0.33, 0.09), and TT (β = −0.28, 95%CI −0.51, −0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32) versus GG. Conclusion: The ABC transporters appear to play a role in accumulation of MeHg during early development. [ABSTRACT FROM AUTHOR]