Associations between CD70 methylation of T cell DNA and age in adults with systemic lupus erythematosus and population controls: The Michigan Lupus Epidemiology & Surveillance (MILES) Program.

BACKGROUND: Environmental factors can influence epigenetic regulation, including DNA methylation, potentially contributing to systemic lupus erythematosus (SLE) development and progression. We compared methylation of the B cell costimulatory CD70 gene, in persons with lupus and controls, and characterized associations with age. RESULTS: In 297 adults with SLE and 92 controls from the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort, average CD70 methylation of CD4+ T cell DNA across 10 CpG sites based on pyrosequencing of the promoter region was higher for persons with SLE compared to controls, accounting for covariates [ß = 2.3, p = 0.011]. Using Infinium MethylationEPIC array data at 18 CD70-annoted loci (CD4+ and CD8+ T cell DNA), sites within the promoter region tended to be hypomethylated in SLE, while those within the gene region were hypermethylated. In SLE but not controls, age was significantly associated with pyrosequencing-based CD70 methylation: for every year increase in age, methylation increased by 0.14 percentage points in SLE, accounting for covariates. Also within SLE, CD70 methylation approached a significantly higher level in Black persons compared to White persons (ß = 1.8, p = 0.051). CONCLUSIONS: We describe altered CD70 methylation patterns in T lymphocyte subsets in adults with SLE relative to controls, and report associations particular to SLE between methylation of this immune-relevant gene and both age and race, possibly a consequence of "weathering" or accelerated aging which may have implications for SLE pathogenesis and potential intervention strategies.

Associations between mercury exposure with blood pressure and lipid levels: A cross-sectional study of dental professionals.

Mercury (Hg) exposure is a public health problem worldwide that is now being addressed through the Minamata Convention on Mercury. Fish containing methylmercury and dental amalgam containing elemental Hg are the major sources of exposure for most populations. There is some evidence that methylmercury impacts cardiovascular and metabolic health, primarily in populations with high exposure levels. Studies of elemental Hg and these outcomes are relatively rare. We aimed to examine associations between Hg exposure (both elemental and methylmercury) and blood pressure, as well as cholesterol and triglyceride levels. In 2012, we recruited dental professionals attending the Health Screening Program at the American Dental Association (ADA) Annual Session in California. Total Hg levels in hair and blood samples were analyzed as indicators of methylmercury exposure and in urine as an indicator of primarily elemental Hg exposure (n = 386; mean ± sd age 55 ± 11 years). We measured blood pressure (systolic and diastolic) and lipid profiles (total cholesterol, high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL] and triglycerides). The geometric means (geometric standard deviations) for blood, hair, and urine Hg were 3.64 (2.39) µg/L, 0.60 (2.91) µg/g, and 1.30 (2.44) µg/L, respectively. For every one µg/L increase in specific gravity-adjusted urine Hg, LDL increased by 2.31 mg/dL (95% CI = 0.09, 4.54), in linear regression adjusting for BMI, race, sex, polyunsaturated fatty acid intake from fish consumption, smoking status, and use of cholesterol-lowering medication. No significant associations between Hg biomarkers and blood pressure or hair or blood Hg with lipid levels were observed. Results suggest that elemental Hg exposure may influence LDL concentrations in adults with low-level exposure, and this relationship merits further study in other populations.

Cross-sectional associations between phthalates, phenols, and parabens with metabolic syndrome risk during early-to-mid adolescence among a cohort of Mexican youth.

BACKGROUND: Epidemiological studies on children and adults have linked toxicants from plastics and personal care products to metabolic disruption. Yet, the impact of endocrine-disrupting chemicals (EDCs) on adolescent metabolic syndrome (MetS) risk during early and mid-adolescence is unclear. METHODS: To examine the links between exposure to EDCs and MetS risk and its components, cross-sectional data from 344 Mexican youth in early-to-mid adolescence (10-17 years) were analyzed. Urinary biomarker concentrations of phthalates, phenol, and paraben analytes were measured from a single spot urine sample collected in 2015; study personnel obtained anthropometric and metabolic measures. We examined associations between summary phthalates and metabolites, phenol, and paraben analytes with MetS risk z-scores using linear regression, adjusted for specific gravity, sex, age, pubertal status, smoking, alcohol intake, physical activity level, and screen time. As a secondary aim, mediation analysis was conducted to evaluate the role of hormones in the association between summary phthalates with lipids and MetS risk z-scores. RESULTS: The mean (SD) age was 13.2 (1.9) years, and 50.9% were female. Sex-stratified analyses revealed associations between summary phthalates and lipids ratio z-scores, including Σ DEHP [ß = 0.21 (95% CI: 0.04, 0.37; p < 0.01)], phthalates from plastic sources (Σ Plastic) [ß = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], anti-androgenic phthalates (Σ AA) [ß = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], and individual phthalate metabolites (MEHHP, MEOHP, and MECPP) among males. Among females, BPA [ß = 0.24 (95% CI: 0.03, 0.44; p < 0.05)] was positively associated with lipids ratio z-score and one phenol (2,5 DCP) [ß = 0.09 (95% CI: 0.01, 0.18); p < 0.05)] was associated with increased waist circumference z-score. Results showed no evidence of mediation by hormone concentrations in the association between summary phthalates with lipids ratio or MetS risk z-scores. CONCLUSION: Higher EDC exposure was positively associated with serum lipids during adolescence, particularly among males.

Repeat measures of DNA methylation in an inception cohort of firefighters.

OBJECTIVES: Firefighters face exposures associated with adverse health outcomes including risk for multiple cancers. DNA methylation, one type of epigenetic regulation, provides a potential mechanism linking occupational hazards to adverse health outcomes. We hypothesised that DNA methylation profiles would change in firefighters after starting their service and that these patterns would be associated with occupational exposures (cumulative fire-hours and fire-runs). METHODS: We profiled DNA methylation with the Infinium MethylationEPIC in blood leucocytes at two time points in non-smoking new recruits: prior to live fire training and 20-37 months later. Linear mixed effects models adjusted for potential confounders were used to identify differentially methylated CpG sites over time using data from 50 individuals passing all quality control. RESULTS: We report 680 CpG sites with altered methylation (q value <0.05) including 60 with at least a 5% methylation difference at follow-up. Genes with differentially methylated CpG sites were enriched in biological pathways related to cancers, neurological function, cell signalling and transcription regulation. Next, linear mixed effects models were used to determine associations between occupational exposures with methylation at the 680 loci. Of these, more CpG sites were associated with fire-runs (108 for all and 78 for structure-fires only, q<0.05) than with fire-hours (27 for all fires and 1 for structure fires). These associations were independent of time since most recent fire, suggesting an impact of cumulative exposures. CONCLUSIONS: Overall, this study provides evidence that DNA methylation may be altered by fireground exposures, and the impact of this change on disease development should be evaluated.

Considering environmental exposures to per- and polyfluoroalkyl substances (PFAS) as risk factors for hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, lead to significant maternal morbidity and in some cases, maternal mortality. Environmental toxicants, especially those that disrupt normal placental and endothelial function, are emerging as potential risk factors for HDP. Per- and polyfluoroalkyl substances (PFAS) are a large group of ubiquitous chemicals found in consumer products, the environment, and increasingly in drinking water. PFAS have been associated with a multitude of adverse health effects, including dyslipidemia, hypertension, and more recently, HDP. In this review, we present epidemiological and mechanistic evidence for the link between PFAS and HDP and recommend next steps for research and prevention efforts. To date, epidemiological studies have assessed associations between only ten of the thousands of PFAS and HDP. Positive associations between six PFAS (PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonic acid; PFHxS, perfluorohexane sulfonic acid; PFHpA, perfluoroheptanoic acid; PFBS, perfluorobutanesulfonic acid; and PFNA, perfluoronanoic acid) and risk for HDP have been reported in some, but not all, studies. PFAS disrupt placental and immune function, cause oxidative stress, and disrupt lipid metabolism. These physiological disruptions may be mechanisms through which PFAS can lead to HDP. Overall, limited epidemiological evidence and plausible mechanisms support PFAS as risk factors for HDP. More research is needed in diverse, well-powered cohorts that assess exposures to as many PFAS as possible. Such research should consider not only individual PFAS but also the totality of exposures to PFAS and other environmental chemicals. Pregnant women may be a group that is vulnerable to PFAS exposure, and as such HDP risk should be considered by policymakers setting PFAS exposure limits. In the interim, medical and public health professionals in regions with PFAS contamination could provide short-term solutions in the form of patient-level prevention, increased monitoring, and early intervention for HDP.

Variation in biomarker levels of metals, persistent organic pollutants, and omega-3 fatty acids in association with genetic polymorphisms among Inuit in Nunavik, Canada.

BACKGROUND: Biomarker measures of contaminant exposure and nutrient status can help increase understanding of the risks and benefits associated with the consumption of traditional foods by Inuit. While gene-environment and gene-nutrient interactions may help explain variations in biomarker measures, the role of genetic polymorphisms is largely understudied especially for vulnerable sub-populations. OBJECTIVE: The aim of this study was to characterize the relationship between single nucleotide polymorphisms (SNPs) in key genes and blood concentrations of environmental chemicals and nutrients among Inuit. METHODS: Blood samples from 665 individuals who participated in the Qanuippitaa Survey (Nunavik, Canada) in 2004 were analyzed for toxicants and nutrients. DNA was extracted and 140 SNPs in classes relevant to the toxicokinetics and/or toxicodynamics of the target contaminants and nutrients, and/or are involved in cardiovascular health and lipid metabolism were genotyped using the Sequenom iPLEX Gold platform. RESULTS: Geometric means (µg/L) of mercury (Hg), cadmium (Cd), lead (Pb), DDE, PCB-153, and selenium (Se) were 11.1, 2.8, 39.9, 2.9, 1.1 and 301.2, respectively. Red blood cell membrane levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were 5.1%/total fatty acid (TFA) and 1.3%/TFA respectively. Out of 106 SNPs which met our inclusion criteria, biomarker levels for Hg, Cd, Pb, DDE, PCB-153, DHA, and EPA differed (p < 0.05) by genotype for 20, 13, 12, 19, 21, 9 and 8 SNPs, respectively. Following Bonferroni correction (p < 0.0005), only 9 SNPs remained significant (rs2274976 in MTHFR, rs174602 in FADS2, rs7115739 and rs74771917 in FADS3, rs713041 in GPX4, rs2306283 and rs4149056 in SLCO1B1, rs1885301 in ABCC2/MRP2, and rs4244285 in CYP2C19; 5 associated with Hg, 2 with Pb, 2 with DDE, 4 with PCB-153, 1 with DHA). CONCLUSIONS: The findings suggest that polymorphisms in environmentally-responsive genes can influence biomarker levels of key toxicants and nutrients. While there are no immediate clinical or public health implications of these findings, we believe that such gene-environment and gene-nutrient studies provide a foundation that will inform and provide direction to future studies.

Mercury exposure in relation to sleep duration, timing, and fragmentation among adolescents in Mexico City.

INTRODUCTION: Mercury intoxication is known to be associated with adverse symptoms of fatigue and sleep disturbances, but whether low-level mercury exposure could affect sleep remains unclear. In particular, children may be especially vulnerable to both mercury exposures and to poor sleep. We sought to examine associations between mercury levels and sleep disturbances in Mexican youth. METHODS: The study sample comprised 372 youth from the Early Life Exposures to Environmental Toxicants (ELEMENT) cohort, a birth cohort from Mexico City. Sleep (via 7-day actigraphy) and concurrent urine mercury were assessed during a 2015 follow-up visit. Mercury was also assessed in mid-childhood hair, blood, and urine during an earlier study visit, and was considered a secondary analysis. We used linear regression and varying coefficient models to examine non-linear associations between Hg exposure biomarkers and sleep duration, timing, and fragmentation. Unstratified and sex-stratified analyses were adjusted for age and maternal education. RESULTS: During the 2015 visit, participants were 13.3 ± 1.9 years, and 48% were male. There was not a cross-sectional association between urine Hg and sleep characteristics. In secondary analysis using earlier biomarkers of Hg, lower and higher blood Hg exposure was associated with longer sleep duration among girls only. In both boys and girls, Hg biomarker levels in 2008 were associated with later adolescent sleep midpoint (for Hg urine in girls, and for blood Hg in boys). For girls, each unit log Hg was associated with 0.2 h later midpoint (95% CI 0 to 0.4), and for boys each unit log Hg was associated with a 0.4 h later sleep midpoint (95% CI 0.1 to 0.8). CONCLUSIONS: There were mostly null associations between Hg exposure and sleep characteristics among Mexican children. Yet, in both boys and girls, higher Hg exposure in mid-childhood (measured in urine and blood, respectively) was related to later sleep timing in adolescence.

Neonatal bloodspot DNA methylation patterns are associated with childhood weight status in the Healthy Families Project.

BACKGROUND: This study measured longitudinal DNA methylation dynamics at growth-related genes during childhood, and then tested whether DNA methylation at various stages of childhood was associated with obesity status. METHODS: Using neonatal bloodspot (n = 132) and matched childhood blood samples (n = 65), DNA methylation was quantified at a repetitive element (long interspersed nuclear element-1 (LINE-1)), two imprinted genes (IGF2, H19), and four non-imprinted genes (LEP, PPARA, ESR1, SREBF1) related to growth and adiposity. Logistic regression was used to test whether neonatal bloodspot DNA methylation at target genes was associated with log odds of obesity (Y/N) in children recruited from three age groups-12-24 months old (n = 40), 3-5 years of age (n = 40), and 10-12 years of age (n = 52). RESULTS: In 3-5 year olds, neonatal bloodspot LINE-1 methylation was negatively associated with obesity (log odds = -0.40, p = 0.04). Across childhood age group in matched blood samples, DNA methylation levels in blood decreased (p < 0.05) at LINE-1, PPARA, ESR1, SREBF1, IGF2, and H19, and increased (p < 0.05) at LEP. CONCLUSIONS: Our results suggest that age-related epigenetic changes occur at growth-related genes in the first decade of life, and that gene-specific neonatal bloodspot DNA methylation may be a useful biomarker of obesity likelihood during childhood.

Bioaccessibility and bioavailability of methylmercury from seafood commonly consumed in North America: In vitro and epidemiological studies.

Methylmercury (MeHg) is a global contaminant of concern and human exposures are largely realized via seafood consumption. While it is assumed that 95-100% of the ingested MeHg from seafood reaches systemic circulation, recent in vitro studies have yielded results to suggest otherwise. Of the published studies to have characterized the bioaccessibility or bioavailability of MeHg from seafood, only a handful of seafood species have been characterized, there exists tremendous variability in data within and across species, few species of relevance to North America have been studied, and none of the in vitro studies have adapted results to an epidemiology study. The objective of the current study was two-fold: (a) to characterize in vitro MeHg bioaccessibility and bioavailability from ten commonly consumed types of seafood in North America; and (b) to apply the bioaccessibility and bioavailability data from the in vitro study to an existing human MeHg exposure assessment study. Raw seafood samples (cod, crab, halibut, salmon, scallop, shrimp, tilapia, and three tuna types: canned light, canned white, fresh) were purchased in Montreal and their MeHg concentrations generally overlapped with values reported elsewhere. The bioaccessibility of MeHg from these samples ranged from 50.1±19.2 (canned white tuna) to 100% (shrimp and scallop) of the amount measured in the raw undigested sample. The bioavailability of MeHg from these samples ranged from 29.3±10.4 (crab) to 67.4±9.7% (salmon) of the value measured in the raw undigested sample. There were significant correlations between the initial MeHg concentration in seafood with the percent of that Hg that was bioaccessible (r=-0.476) and bioavailable (r=-0.294). When the in vitro data were applied to an existing MeHg exposure assessment study, the estimated amount of MeHg absorbed into systemic circulation decreased by 25% and 42% when considering bioaccessibility and bioavailability, respectively. When the in vitro data were integrated into a regression model relating dietary MeHg intake from seafood with hair and blood Hg biomarkers, there were no differences in key model parameters when comparing the default model (that assumes 100% bioavailability) with models adjusted for the in vitro bioaccessibility and bioavailability data. In conclusion this work adds to a growing number of studies that together suggest that MeHg bioavailability from seafood may be less than 100%, but also documents the challenges when integrating such in vitro data into human exposure and risk assessments.

Genetic polymorphisms are associated with hair, blood, and urine mercury levels in the American Dental Association (ADA) study participants.

BACKGROUND/AIMS: Mercury (Hg) is a potent toxicant of concern to the general public. Recent studies suggest that several genes that mediate Hg metabolism are polymorphic. We hypothesize that single nucleotide polymorphisms (SNPs) in such genes may underline inter-individual differences in exposure biomarker concentrations. METHODS: Dental professionals were recruited during the American Dental Association (ADA) 2012 Annual Meeting. Samples of hair, blood, and urine were collected for quantifying Hg levels and genotyping (88 SNPs in classes relevant to Hg toxicokinetics including glutathione metabolism, selenoproteins, metallothioneins, and xenobiotic transporters). Questionnaires were administrated to obtain information on demographics and sources of Hg exposure (e.g., fish consumption and use of dental amalgam). Here, we report results for 380 participants with complete genotype and Hg biomarker datasets. ANOVA and linear regressions were used for statistical analysis. RESULTS: Mean (geometric) Hg levels in hair (hHg), blood (bHg), urine (uHg), and the average estimated Hg intake from fish were 0.62µg/g, 3.75µg/L, 1.32µg/L, and 0.12µg/kg body weight/day, respectively. Out of 88 SNPs successfully genotyped, Hg biomarker levels differed by genotype for 25 SNPs, one of which remained significant following Bonferroni correction in ANOVA. When the associations between sources of Hg exposure and SNPs were analyzed with respect to Hg biomarker concentrations, 38 SNPs had significant main effects and/or gene-Hg exposure source interactions. Twenty-five, 23, and four SNPs showed significant main effects and/or interactions for hHg, bHg, and uHg levels, respectively (p<0.05), and six SNPs (in GCLC, MT1M, MT4, ATP7B, and BDNF) remained significant following Bonferroni correction. CONCLUSION: The findings suggest that polymorphisms in environmentally-responsive genes can influence Hg biomarker levels. Hence, consideration of such gene-environment factors may improve the ability to assess the health risks of Hg more precisely.

Mercury levels in pregnant women, children, and seafood from Mexico City.

BACKGROUND: Mercury is a global contaminant of concern though little is known about exposures in México. OBJECTIVES: To characterize mercury levels in pregnant women, children, and commonly consumed seafood samples. METHODS: Use resources of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohorts to measure total mercury levels in archived samples from 348 pregnant women (blood from three trimesters and cord blood), 825 offspring (blood, hair, and urine) and their mothers (hair), and 91 seafood and canned tuna samples from Mexico City. RESULTS: Maternal blood mercury levels correlated across three trimesters and averaged 3.4 µg/L. Cord blood mercury averaged 4.7 µg/L and correlated with maternal blood from trimester 3 (but not trimesters 1 and 2). In children, blood, hair and urine mercury levels correlated and averaged 1.8 µg/L, 0.6 µg/g, and 0.9 µg/L, respectively. Hair mercury was 0.5 µg/g in mothers and correlated with child's hair. Mean consumption of canned tuna, fresh fish, canned sardine, and shellfish was 3.1, 2.2, 0.5, and 1.0 times per month respectively in pregnant women. Mean mercury content in 7 of 23 seafood species and 5 of 9 canned tuna brands purchased exceeded the U.S. EPA guidance value of 0.3 µg/g. CONCLUSIONS: Mercury exposures in pregnant women and children from Mexico City, via biomarker studies, are generally 3-5 times greater than values reported in population surveys from the U.S., Canada, and elsewhere. In particular, mercury levels in 29-39% of the maternal participants exceeded the biomonitoring guideline associated with the U.S. EPA reference dose for mercury.

Comparison of Serum Per- and Polyfluoroalkyl Substances Concentrations in Incumbent and Recruit Firefighters and Longitudinal Assessment in Recruits.

OBJECTIVE: Firefighters are occupationally exposed to per- and polyfluoroalkyl substances (PFAS). This study objective was to compare serum PFAS concentrations in incumbent and recruit firefighters and evaluate temporal trends among recruits. METHODS: Serum PFAS concentrations were measured in 99 incumbent and 55 recruit firefighters at enrollment in 2015-2016, with follow-up 20 to 37 months later for recruits. Linear and logistic regression and linear mixed-effects models were used for analyses. Fireground exposure impact on PFAS concentrations was investigated using adjusted linear and logistic regression models. RESULTS: Incumbents had lower n-PFOA and PFNA than recruits and most PFAS significantly decreased over time among male recruits. No significant links were found between cumulative fireground exposures and PFAS concentrations. CONCLUSIONS: Serum PFAS concentrations were not increased in incumbent firefighters compared with recruits and were not associated with cumulative fireground exposures.

Associations between Sleep and Physical Activity Behavior Clusters and Epigenetic Age Acceleration in Mexican Adolescents.

INTRODUCTION: Epigenetic aging, a marker of biological aging measured by DNA methylation, may be affected by behaviors, including sleep and physical activity. However, investigations of physical activity and sleep with epigenetic aging among pediatric populations are scant and have not accounted for correlated behaviors. METHODS: The study population included 472 Mexico City adolescents (52% female). Blood collection and 7-day wrist actigraphy (Actigraph GTX-BT) occurred during a follow-up visit when participants were 14.5 (2.09) years. Leukocyte DNA methylation was measured with the Infinium MethylationEPIC array after bisulfite conversion, and 9 epigenetic clocks were calculated. Sleep vs wake time was identified through a pruned dynamic programing algorithm, and physical activity was processed with Chandler cut-offs. Kmeans clustering was used to select actigraphy-assessed physical activity and sleep behavior clusters. Linear regression analyses were used to evaluate adjusted associations between the clusters and epigenetic aging. RESULTS: There were 3 unique clusters: "Short sleep/high sedentary behavior", "Adequate sleep duration and late timing/low moderate or vigorous physical activity (MVPA)", and "Adequate sleep duration/high MVPA". Compared to the "Adequate duration/high MVPA", adolescents with "Adequate duration and late sleep timing/low MVPA" had more accelerated aging for the GrimAge clock (ß = 0.63;95% CI 0.07, 1.19). In pubertal-stratified analyses, more mature adolescents in the "Adequate duration and late sleep timing/low MVPA group" had accelerated epigenetic aging. In contrast, females in the "Short sleep/high sedentary" group had decelerated epigenetic aging for the Wu pediatric clock. CONCLUSIONS: Associations between behavior clusters and epigenetic aging varied by pubertal status and sex. Contrary results in the Wu clock suggest the need for future research on pediatric-specific clocks.

Translational toxicoepigenetic Meta-Analyses identify homologous gene DNA methylation reprogramming following developmental phthalate and lead exposure in mouse and human offspring.

Although toxicology uses animal models to represent real-world human health scenarios, a critical translational gap between laboratory-based studies and epidemiology remains. In this study, we aimed to understand the toxicoepigenetic effects on DNA methylation after developmental exposure to two common toxicants, the phthalate di(2-ethylhexyl) phthalate (DEHP) and the metal lead (Pb), using a translational paradigm that selected candidate genes from a mouse study and assessed them in four human birth cohorts. Data from mouse offspring developmentally exposed to DEHP, Pb, or control were used to identify genes with sex-specific sites with differential DNA methylation at postnatal day 21. Associations of human infant DNA methylation in homologous mouse genes with prenatal DEHP or Pb were examined with a meta-analysis. Differential methylation was observed on 6 cytosines (adjusted-p < 0.05) and 90 regions (adjusted-p < 0.001). This translational approach offers a unique method that can detect conserved epigenetic differences that are developmentally susceptible to environmental toxicants.

Firefighting, per- and polyfluoroalkyl substances, and DNA methylation of genes associated with prostate cancer risk.

Prostate cancer is the leading incident cancer among men in the United States. Firefighters are diagnosed with this disease at a rate 1.21 times higher than the average population. This increased risk may result from occupational exposures to many toxicants, including per- and polyfluoroalkyl substances (PFAS). This study assessed the association between firefighting as an occupation in general or PFAS serum levels, with DNA methylation. Only genomic regions previously linked to prostate cancer risk were selected for analysis: GSTP1, Alu repetitive elements, and the 8q24 chromosomal region. There were 444 male firefighters included in this study, with some analyses being conducted on fewer participants due to missingness. Statistical models were used to test associations between exposures and DNA methylation at CpG sites in the selected genomic regions. Exposure variables included proxies of cumulative firefighting exposures (incumbent versus academy status and years of firefighting experience) and biomarkers of PFAS exposures (serum concentrations of 9 PFAS). Proxies of cumulative exposures were associated with DNA methylation at 15 CpG sites and one region located within FAM83A (q-value <0.1). SbPFOA was associated with 19 CpG sites (q < 0.1), but due to low detection rates, this PFAS was modeled as detected versus not detected in serum. Overall, there is evidence that firefighting experience is associated with differential DNA methylation in prostate cancer risk loci, but this study did not find evidence that these differences are due to PFAS exposures specifically.

What Happens In Utero Does Not Stay In Utero: a Review of Evidence for Prenatal Epigenetic Programming by Per- and Polyfluoroalkyl Substances (PFAS) in Infants, Children, and Adolescents.

PURPOSE OF REVIEW: Review human literature on the relationship between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and epigenetic modifications in infants, children, and adolescents < 18 years of age. RECENT FINDINGS: Eleven studies were identified, with study populations located in the U.S., Taiwan, Japan, and the Kingdom of Denmark. Many studies (n = 5) were cross-sectional, with PFAS exposure and epigenetic outcomes measured in the same tissue collected at delivery via cord blood or dried newborn blood spots. The other six studies were prospective, with prenatal PFAS measured on maternal blood during pregnancy and DNA methylation (DNAm) assessed in cord blood and childhood peripheral leukocytes (n = 1 study). Epigenetic marks of interest included global DNAm measures (LINE-1, Alu, and an ELISA-based method), candidate genes (IFG2, H19, and MEST), and epigenome-wide DNA methylation via array-based methods (Infinium 450 K and EPIC). Two studies using array-based methods employed discovery and validation paradigms, in which a small subset of loci (n = 6 and n = 4) were replicated in the discovery population. One site (TNXB) was a hit in two independent studies. Collectively, loci associated with PFAS were in regions involved in growth and development, lipid metabolism, and nutrient metabolism. There is moderate human evidence supporting associations of prenatal PFAS exposure on DNAm at birth, with one study suggesting sustained effects into childhood. Future studies are warranted to link PFAS-associated DNAm to health outcomes, as well as to investigate the role of other epigenetic marks such as hydroxymethylation, miRNA expression, and histone modifications.

The potential role of environmental factors in modulating mitochondrial DNA epigenetic marks.

Many studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases. Mitochondria are responsible for most cellular energy production, and unlike other cytoplasmic organelles, mitochondria contain their own genome. Most research to date, through investigating mitochondrial DNA copy number, has focused on larger structural changes or alterations to the entire mitochondrial genome and their role in human disease. Using these methods, mitochondrial dysfunction has been linked to cancers, cardiovascular disease, and metabolic health. However, like the nuclear genome, the mitochondrial genome may experience epigenetic alterations, including DNA methylation that may partially explain some of the health effects of various exposures. Recently, there has been a movement to understand human health and disease within the context of the exposome, which aims to describe and quantify the entirety of all exposures people encounter throughout their lives. These include, among others, environmental pollutants, occupational exposures, heavy metals, and lifestyle and behavioral factors. In this chapter, we summarize the current research on mitochondria and human health, provide an overview of the current knowledge on mitochondrial epigenetics, and describe the experimental and epidemiologic studies that have investigated particular exposures and their relationships with mitochondrial epigenetic modifications. We conclude the chapter with suggestions for future directions in epidemiologic and experimental research that is needed to advance the growing field of mitochondrial epigenetics.

Prenatal exposures to endocrine disrupting chemicals: The role of multi-omics in understanding toxicity.

Endocrine disrupting chemicals (EDCs) are a diverse group of toxicants detected in populations globally. Prenatal EDC exposures impact birth and childhood outcomes. EDCs work through persistent changes at the molecular, cellular, and organ level. Molecular and biochemical signals or 'omics' can be measured at various functional levels - including the epigenome, transcriptome, proteome, metabolome, and the microbiome. In this narrative review, we introduce each omics and give examples of associations with prenatal EDC exposures. There is substantial research on epigenomic modifications in offspring exposed to EDCs during gestation, and a growing number of studies evaluating the transcriptome, proteome, metabolome, or microbiome in response to these exposures. Multi-omics, integrating data across omics layers, may improve understanding of disrupted function pathways related to early life exposures. We highlight several data integration methods to consider in multi-omics studies. Information from multi-omics can improve understanding of the biological processes and mechanisms underlying prenatal EDC toxicity.