•MiRNA expression in a cohort highly exposed to perfluoroalkyl substances (PFAS)•MiR-101-3p, miR-144-3p and miR-19a-3p were downregulated with increased serum PFAS.•In silico analyses showed 7 target ...genes for these 3 miRNAs to be annotated to PFAS.•Ingenuity pathway analyses suggest these miRNAs associated to several health effects.•This study propose epigenetic mechanisms as a mode of action of PFAS toxicity.
Perfluoroalkyl substances (PFAS) are widespread synthetic substances with various adverse health effects. Not much is known about the modes of action of PFAS toxicity, but one likely mechanism is alteration of microRNA expression.
To investigate whether PFAS exposure is associated with altered microRNA expression in serum.
We selected women from the Ronneby cohort, with high exposure to perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS), emanating from drinking water contaminated by firefighting foam, and a control group of women from a neighbouring municipality without drinking water contamination. Serum levels of PFAS were analysed using LC/MS/MS. High coverage microRNA expression was analysed by next generation sequencing (NGS) in 53 individuals to screen for microRNAs associated with PFAS exposure. After verification by qPCR, associations between PFAS exposure and expression of 18 selected microRNAs were validated by qPCR in 232 individuals. In silico functional analyses were performed using Ingenuity pathway analysis (IPA).
Three microRNAs were consistently associated with PFAS exposure in the different steps of the study: miR-101-3p, miR-144-3p and miR-19a-3p (all downregulated with increasing exposure). In silico functional analyses suggested that these PFAS-associated microRNAs were annotated to e.g. cardiovascular function and disease, Alzheimer’s disease, growth of cancer cell lines and cancer. Seven predicted target genes for the downregulated microRNAs were annotated to PFAS in IPA knowledge database: DNA methyltransferase 3 alpha (DNMT3a), epidermal growth factor receptor (EGFR), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), nuclear receptor subfamily 1, group H, member 3 (NR1H3), peroxisome proliferator-activated receptor alpha (PPARα), prostaglandin-endoperoxide synthase 2 (PTGS2), and tumour growth factor alpha (TGFα).
PFAS exposure was associated with downregulation of specific microRNAs. Further, in silico functional analyses suggest potential links between the specific PFAS-associated microRNAs, specific microRNA target genes and possibly also health effects.
Objective This study investigated whether low-to-moderate exposure to welding fumes is associated with adverse effects on the cardiovascular system. Methods To test this, we performed a longitudinal ...analysis of 78 mild steel welders and 96 controls; these subjects were examined twice, six years apart (ie, timepoints 1 and 2). All subjects (male and non-smoking at recruitment) completed questionnaires describing their health, work history, and lifestyle. We measured their blood pressure, endothelial function (by EndoPAT), and risk markers for cardiovascular disease low-density lioprotein (LDL), homocysteine, C-reactive protein. Exposure to welding fumes was assessed from the responses to questionnaires and measurements of respirable dust in their breathing zones adjusted for use of respiratory protection equipment. Linear mixed-effect regression models were used for the longitudinal analysis. Results Median respirable dust concentrations, adjusted for respirable protection, of the welders were 0.7 (5-95 percentile range 0.2-4.2) and 0.5 (0.1-1.9) mg/m
at timepoints 1 and 2, respectively. Over the six-year period, welders showed a statistically significant increase in systolic 5.11 mm Hg, 95% confidence interval (CI) 1.92-8.31 and diastolic (3.12 mm Hg, 95% CI 0.74-5.5) blood pressure compared with controls (multi-variable adjusted mixed effect models). Diastolic blood pressure increased non-significantly by 0.22 mm Hg (95% CI -0.02-0.45) with every additional year of welding work. No consistent significant associations were found between exposure and endothelial function, LDL, homocysteine, or C-reactive protein. Conclusion Exposure to welding fumes at low-to-moderate levels is associated with increased blood pressure, suggesting that reducing the occupational exposure limit (2.5 mg/m
for inorganic respirable dust in Sweden) is needed to protect cardiovascular health of workers.
There is increasing evidence that environmental manganese (Mn) exposure early in life can have negative effects on children's neurodevelopment and increase the risk of behavioral problems, including ...attention deficit hyperactivity disorder (ADHD). Factors that may contribute to differences in sensitivity to Mn exposure are sex and genetic variation of proteins involved in the regulation of Mn concentrations. Here we investigate if sex and polymorphisms in Mn transporter genes SLC30A10 and SLC39A8 influence the association between Mn exposure and ADHD-related behavioral problems in children.
The SNPs rs1776029 and rs12064812 in SLC30A10, and rs13107325 in SLC39A8 were genotyped by TaqMan PCR or pyrosequencing in a population of Italian children (aged 11–14 years; n = 645) with a wide range of environmental Mn exposure. Mn in surface soil was measured in situ using XRF technology or modeled by geospatial analysis. Linear regression models or generalized additive models (GAM) were used for analyzing associations between soil Mn and neurobehavioral problems assessed by the Conners' behavior rating scales (self-, and parent-reported). Gene-environment interactions (Mn transporter genotype x soil Mn) were evaluated using a genetic score in which genotypes for the three SNPs were combined based on their association with blood Mn, as an indication of their influence on Mn regulation.
We observed differences in associations between soil Mn and neurobehavior between sexes. For several self-reported Conners' scales, girls showed U-shaped relationships with higher (worse) Conners' scoring at higher soil Mn levels, and several parent-reported scales showed positive linear relationships between increasing soil Mn and higher Conner's scores. For boys, we observed a positive linear relationship with soil Mn for one Conner's outcome only (hyperactivity, parent-reported). We also observed some interactions between soil Mn and the genetic score on Conner's scales in girls and girls with genotypes linked to high blood Mn showed particularly strong positive associations between soil Mn and parent-reported Conners' scales.
Our results indicate that sex and polymorphisms in Mn transporter genes contribute to differences in sensitivity to Mn exposure from the environment and that girls that are genetically less efficient at regulating Mn, may be a particularly vulnerable group.
•Influence of sex and genetics on Mn exposure vs neurobehavior was evaluated.•Stronger associations between soil Mn and behavioral problems in girls than boys•SNPs in Mn transporter genes influenced sensitivity to Mn exposure in girls.•Girls with inefficient Mn regulation may be particularly sensitive to Mn exposure.
Organisms have evolved the ability to tolerate toxic substances in their environments, often by producing metabolic enzymes that efficiently detoxify the toxicant. Inorganic arsenic is one of the ...most toxic and carcinogenic substances in the environment, but many organisms, including humans, metabolise inorganic arsenic to less toxic metabolites. This multistep process produces mono-, di-, and trimethylated arsenic metabolites, which the organism excretes. In humans, arsenite methyltransferase (AS3MT) appears to be the main metabolic enzyme that methylates arsenic. In this study, we examined the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic during evolution. These findings are supported by the observation that genetic variation in AS3MT correlates with the capacity to methylate arsenic. Adaptation to arsenic thus serves as a model for how organisms evolve to survive under toxic conditions.
Background:
Manganese (Mn) is an essential element but at excessive levels, it is neurotoxic. Even a moderate increase in Mn has been suggested to interfere with neurodevelopment in children. ...Genetics influencing Mn concentrations and toxicity is unclear.
Objective:
We assessed, in a cross-sectional study, whether common single-nucleotide polymorphisms in the Mn transporters SLC39A8 (influx) and SLC30A10 (efflux) are associated with neurodevelopment in children.
Design:
We genotyped
SLC39A8
(rs13107325 C/T) and
SLC30A10
(rs1776029 G/A and rs12064812 T/C) in Italian children (
n
= 686, ages 11–14). We then used linear regression models to analyze associations between genotype, blood Mn concentrations, and neurodevelopmental outcomes including intelligence, behavior, motor function, and sway. Inferred causal relationships were evaluated using instrumental variables (IV) analysis.
Results:
For
SLC30A10
rs1776029, the minor allele (A) was associated with increased average blood Mn of 41% (
p
< 0.001), whereas minor alleles for rs12064812 (C) and rs13107325 (T) were associated with reduced blood Mn of 7% (
p
= 0.002) and 15% (
p
< 0.001), respectively. For children carrying genotypes associated with high blood Mn, we observed lower performance for certain IQ subtests, increased sway, and increased scores for behavioral problems. High Mn genotypes showed odds ratios of 2–4
(p
≤ 0.01) for high scores in tests assessing ADHD-related behavior. IV analyses suggested that several of the associations were mediated by blood Mn.
Conclusions:
Our results suggest that common polymorphisms in
SLC39A8
and
SLC30A10
influence neurodevelopmental outcomes in children via differences in Mn homeostasis.
Glutathione (GSH) pathways play a key role the metabolism and elimination of the neurotoxicant methylmercury (MeHg). We hypothesized that maternal genetic variation linked to GSH pathways could ...influence MeHg concentrations in pregnant mothers and children and thereby also affect early life development.
The GCLM (rs41303970, C/T), GCLC (rs761142, T/G) and GSTP1 (rs1695, A/G) polymorphisms were genotyped in 1449 mothers in a prospective study of the Seychellois population with a diet rich in fish. Genotypes were analyzed in association with maternal hair and blood Hg, fetal blood Hg (cord blood Hg), as well as children's mental (MDI) and motor development (PDI; MDI and PDI assessed by Bayley Scales of Infant Development at 20 months). We also examined whether genotypes modified the association between Hg exposure and developmental outcomes.
GCLC rs761142 TT homozygotes showed statistically higher mean maternal hair Hg (4.12 ppm) than G carriers (AG 3.73 and GG 3.52 ppm) (p = 0.037). For the combination of GCLC rs761142 and GCLM rs41303970, double homozygotes TT + CC showed higher hair Hg (4.40 ppm) than G + T carriers (3.44 ppm; p = 0.018). No associations were observed between GSTP1 rs1695 and maternal hair Hg or between any genotypes and maternal blood Hg or cord blood Hg. The maternal GSTP1 rs1695 rare allele (G) was associated with a lower MDI among children (β = −1.48, p = 0.048). We also observed some interactions: increasing Hg in maternal and cord blood was associated with lower PDI among GCLC rs761142 TT carriers; and increasing Hg in hair was associated with lower MDI among GSTP1 rs1695 GG carriers.
Maternal genetic variation in genes involved in GSH synthesis is statistically associated with Hg concentrations in maternal hair, but not in maternal or fetal blood. We observed interactions that suggest maternal GSH genetics may modify associations between MeHg exposure and neurodevelopmental outcomes.
•Glutathione (GSH) is important for metabolism of the neurotoxicant methylmercury (MeHg).•Maternal GSH synthesis-related genotypes were associated with Hg in maternal hair.•Interactions were found between genotypes and Hg on children's neurodevelopment.•Maternal GSH genetics may influence fetal sensitivity to MeHg exposure.
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 single-nucleotide 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.
Fish contains methylmercury (MeHg) which can cause oxidative stress and neurodevelopmental toxicity at sufficiently high doses. Fish also contains polyunsaturated fatty acids (PUFA) which have both ...antioxidant (n-3) and oxidant (n-6) properties. Mitochondrial DNA (mtDNA) is sensitive to oxidative stress but has not been previously studied in relation to MeHg exposure or PUFA status.
To investigate the associations between MeHg exposure and PUFA status during pregnancy with relative mitochondrial DNA copy number (RmtDNAcn) in mothers and their newborns.
In total, 1488 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2 were included in this study. Total Hg was measured in maternal blood collected at 28 weeks' gestation, maternal hair at delivery, and in fetal cord blood. PUFA (n-3 and n-6) were measured only in maternal blood. RmtDNAcn was measured by qPCR in both maternal and cord blood.
Increasing maternal blood Hg (β = 0.001, 95%CI: 0.000, 0.002) and n-3 PUFA concentrations (β = 0.183, 95%CI: 0.048, 0.317) were associated with higher maternal RmtDNAcn. Increasing maternal n-6 PUFA (β = −0.103, 95%CI: −0.145, −0.062) and n-6/n-3 ratio (β = −0.011, 95%CI: −0.017, −0.004) were associated with lower maternal RmtDNAcn. Increasing fetal cord blood Hg was associated with lower fetal RmtDNAcn (β = −0.002, 95%CI: −0.004, −0.000). Neither maternal blood Hg nor PUFA status was associated with fetal RmtDNAcn.
Our findings suggest that MeHg and PUFA may influence mitochondrial homeostasis although the magnitude of these associations are small. Future studies should confirm the findings and explore the underlying mechanisms.
•We investigated, the associations between MeHg exposure, PUFA status and mtDNA copy number in a large mother-child cohort•Maternal blood Hg and n-3 PUFA were positively associated with maternal mtDNA copy number•Maternal blood n-6 PUFA and n-6/n-3 ratio were negatively associated with maternal mtDNA copy number•Fetal cord blood Hg was negatively associated with fetal mtDNA copy number•MeHg and PUFA seem to influence mitochondrial homeostasis
Individual variation in fetal hemoglobin (HbF, α₂γ₂) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and β thalassemia. HbF levels and HbF-associated ...quantitative traits (e.g., F cell levels) are highly heritable. We have previously mapped a major quantitative trait locus (QTL) controlling F cell levels in an extended Asian-Indian kindred with β thalassemia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBS1L, a member of the GTP-binding protein family that is expressed in erythroid progenitor cells. In this high-resolution association study, we have identified multiple genetic variants within and 5' to HBS1L at 6q23 that are strongly associated with F cell levels in families of Northern European ancestry (P = 10⁻⁷⁵). The region accounts for 17.6% of the F cell variance in northern Europeans. Although mRNA levels of HBS1L and MYB in erythroid precursors grown in vitro are positively correlated, only HBS1L expression correlates with high F cell alleles. The results support a key role for the HBS1L-related genetic variants in HbF control and illustrate the biological complexity of the mechanism of 6q QTL as a modifier of fetal hemoglobin levels in the β hemoglobinopathies.
ATP-binding cassette (ABC) transporters have been associated with methylmercury (MeHg) toxicity in experimental animal models.
To evaluate the association of single nucleotide polymorphisms (SNPs) in ...maternal ABC transporter genes with 1) maternal hair MeHg concentrations during pregnancy and 2) child neurodevelopmental outcomes.
Nutrition Cohort 2 (NC2) is an observational mother-child cohort recruited in the Republic of Seychelles from 2008–2011. Total mercury (Hg) was measured in maternal hair growing during pregnancy as a biomarker for prenatal MeHg exposure (N=1313) (mean 3.9ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20months of age (N=1331). Genotyping for fifteen SNPs in ABCC1, ABCC2 and ABCB1 was performed for the mothers.
Seven of fifteen ABC SNPs (ABCC1 rs11075290, rs212093, and rs215088; ABCC2 rs717620; ABCB1 rs10276499, rs1202169, and rs2032582) were associated with concentrations of maternal hair Hg (p<0.001 to 0.013). One SNP (ABCC1 rs11075290) was also significantly associated with neurodevelopment; children born to mothers with rs11075290 CC genotype (mean hair Hg 3.6ppm) scored on average 2 points lower on the Mental Development Index (MDI) and 3 points lower on the Psychomotor Development Index (PDI) than children born to mothers with TT genotype (mean hair Hg 4.7ppm) while children with the CT genotype (mean hair Hg 4.0ppm) had intermediate BSID scores.
Genetic variation in ABC transporter genes was associated with maternal hair Hg concentrations. The implications for MeHg dose in the developing child and neurodevelopmental outcomes need to be further investigated.
•SNPs in three ABC transporter genes were associated with hair mercury in mothers.•Maternal ABCC1 SNP rs11075290 was associated with child neurodevelopment.•Genetics of ABC may determine prenatal methylmercury concentrations.
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