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Background: Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles., Objective: Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb ( HCN2 , NINJ2 , RAB5A , TPPP) in whole blood leukocytes of children ages 11-18 years of age., Methods: Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected ( n = 144 ) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation ( 5 mC + 5 hmC ) and 5mC only; 5hmC is estimated by subtraction., Results: Participants were 51% male, and mean maternal blood lead levels (BLL) were 6.43 ± 5.16 μ g / dL in Trimester 1 (T1), 5.66 ± 5.21 μ g / dL in Trimester 2 (T2), and 5.86 ± 4.34 μ g / dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 ( mean ± standard deviation ( SD ) , 2.08 ± 4.18 % ), NINJ2 (G/C: 2.01 ± 5.95 ; GG: 0.90 ± 3.97 ), RAB5A ( 0.66 ± 0.80 % ), and TPPP ( 1.11 ± 6.67 % ). Furthermore, 5mC levels were measured in HCN2 ( 81.3 ± 9.63 % ), NINJ2 (heterozygotes: 38.6 ± 7.39 % ; GG homozygotes: 67.3 ± 9.83 % ), RAB5A ( 1.41 ± 1.21 % ), and TPPP ( 92.5 ± 8.03 % ). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 ( β = - 0.37 , p = 0.03 ) and 5hmC in NINJ2 ( β = 0.49 , p = 0.003 ); T2 BLLs with 5mC in HCN2 ( β = 0.37 , p = 0.03 ) and 5hmC in NINJ2 ( β = 0.27 , p = 0.008 ); and T3 BLLs with 5mC in HCN2 ( β = 0.50 , p = 0.01 ) and NINJ2 ( β = - 0.35 , p = 0.004 ) and 5hmC in NINJ2 ( β = 0.45 , p < 0.001 ). NINJ2 5mC was negatively correlated with gene expression (Pearson r = - 0.5 , p -value = 0.005 ), whereas 5hmC was positively correlated ( r = 0.4 , p -value = 0.04 )., Discussion: These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507.

Background: Exposure to chemicals during critical windows of development may re-program liver for increased risk of nonalcoholic fatty liver disease (NAFLD). Bisphenol A (BPA), a plastics component, has been described to impart adverse effects during gestational and lactational exposure. Our work has pointed to nuclear factor E2-related factor 2 (Nrf2) being a modulator of hepatic lipid accumulation in models of NAFLD., Objectives: To determine if chemical exposure can prime liver for steatosis via modulation of NRF2 and epigenetic mechanisms., Methods: Utilizing BPA as a model exposure, pregnant CD-1 mice were administered 25μg/kg/day BPA via osmotic minipumps from gestational day 8 through postnatal day (PND)16. The offspring were weaned on PND21 and exposed to same dose of BPA via their drinking water through PND35. Tissues were collected from pups at week 5 (W5), and their littermates at week 39 (W39)., Results: BPA increased hepatic lipid content concomitant with increased Nrf2 and pro-lipogenic enzyme expression at W5 and W39 in female offspring. BPA exposure increased Nrf2 binding to a putative antioxidant response element consensus sequence in the sterol regulatory-element binding protein-1c ( Srebp-1c ) promoter. Known Nrf2 activators increased SREBP-1C promoter reporter activity in HepG2 cells. Methylated DNA immunoprecipitation-PCR and pyrosequencing revealed that developmental BPA exposure induced hypomethylation of the Nrf2 and Srebp-1c promoters in livers of W5 mice, which was more prominent in W39 mice than in others., Conclusion: Exposure to a xenobiotic during early development induced persistent fat accumulation via hypomethylation of lipogenic genes. Moreover, increased Nrf2 recruitment to the Srebp-1c promoter in livers of BPA-exposed mice was observed. Overall, the underlying mechanisms described a broader impact beyond BPA exposure and can be applied to understand other models of NAFLD. https://doi.org/10.1289/EHP664.

Background: Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes., Objectives: Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis., Methods: We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research., Discussion: A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health., Conclusion: The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.

Background: Recent studies have suggested that several genes that mediate mercury metabolism are polymorphic in humans., Objective: We hypothesized that single-nucleotide polymorphisms (SNPs) in metallothionein (MT) genes may underlie interindividual differences in mercury biomarker levels. We studied the potential modifying effects of MT SNPs on mercury exposure-biomarker relationships., Methods: We measured total mercury in urine and hair samples of 515 dental professionals. We also surveyed occupational and personal exposures to dental amalgam and dietary fish consumption, from which daily methylmercury (MeHg) intake was estimated. Log-transformed urine and hair levels were modeled in multivariable linear regression separately against respective exposure surrogates, and the effect modification of 13 MT SNPs on exposure was investigated., Results: The mean mercury levels in urine (1.06 μg/L) and hair (0.51 μg/g) were not significantly different from the U.S. general population (0.95 μg/L and 0.47 μg/g, respectively). The mean estimated daily MeHg intake was 0.084 μg/kg/day (range, 0-0.98 μg/kg/day), with 25% of study population intakes exceeding the current U.S. Environmental Protection Agency reference dose of 0.1 μg/kg/day. Multivariate regression analysis showed that subjects with the MT1M (rs2270837) [corrected] AA genotype (n = 10) or the MT2A (rs10636) CC genotype (n = 42) had lower urinary mercury levels than did those with the MT1M or MT2A GG genotype (n = 329 and 251, respectively) after controlling for exposure and potential confounders. After controlling for MeHg intake, subjects with MT1A (rs8052394) GA and GG genotypes (n = 24) or the MT1M (rs9936741) TT genotype (n = 459) had lower hair mercury levels than did subjects with MT1A AA (n = 113) or MT1M TC and CC genotypes (n = 15), respectively., Conclusion: Our findings suggest that some MT genetic polymorphisms may influence mercury biomarker concentrations at levels of exposure relevant to the general population.