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Objective: The aim of this study was to evaluate whether short sleep duration or later sleep timing is a risk factor for insulin resistance (IR) in late adolescence. Methods: Mexico City adolescents enrolled in a longitudinal birth cohort (ELEMENT) took part in two study visits during peri‐puberty that occurred approximately 2 years apart. IR was assessed with serum glucose and insulin. Four groups were defined using puberty‐specific cut points: no IR over the follow‐up period, transition from normal to IR, transition from IR to normal, and IR at both time points. Baseline sleep assessments were measured with 7‐day wrist actigraphy. Multinomial logistic regression models were used to evaluate associations between sleep duration and timing with homeostatic model assessment of insulin resistance categories, adjusting for age, sex, and baseline pubertal status. Results: Adolescents who were ≥ 1 hour below the sleep duration recommendations‐for‐age were 2.74 times more likely to develop IR (95% CI: 1.0‐7.4). Similarly, adolescents who were in the latest category of sleep midpoint (>4:33 a.m.) were more likely than those with earliest midpoints (1 a.m.–3 a.m.) to develop IR (odds ratio = 2.63, 95% CI: 1.0‐6.7). Changes in adiposity over follow‐up did not mediate sleep and IR. Conclusions: Insufficient sleep duration and late sleep timing were associated with development of IR over a 2‐year period in late adolescence. [ABSTRACT FROM AUTHOR]

The genetic material of every organism exists within the context of regulatory networks that govern gene expression, collectively called the epigenome. Epigenetics has taken center stage in the study of diseases such as cancer and diabetes, but its integration into the field of environmental health is still emerging. As the Environmental Mutagenesis and Genomics Society (EMGS) celebrates its 50th Anniversary this year, we have come together to review and summarize the seminal advances in the field of environmental epigenomics. Specifically, we focus on the role epigenetics may play in multigenerational and transgenerational transmission of environmentally induced health effects. We also summarize state of the art techniques for evaluating the epigenome, environmental epigenetic analysis, and the emerging field of epigenome editing. Finally, we evaluate transposon epigenetics as they relate to environmental exposures and explore the role of noncoding RNA as biomarkers of environmental exposures. Although the field has advanced over the past several decades, including being recognized by EMGS with its own Special Interest Group, recently renamed Epigenomics, we are excited about the opportunities for environmental epigenetic science in the next 50 years. Environ. Mol. Mutagen. 61:176–192, 2020. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Environmental factors early in life can have lasting influence on the development and phenotypes of animals, but the underlying molecular modifications remain poorly understood. We examined cross‐sectional associations among early life socioecological factors and global DNA methylation in 293 wild spotted hyenas (Crocuta crocuta) in the Masai Mara National Reserve, Kenya, grouped according to three age classes (cub, subadult and adult). Explanatory variables of interest included annual maternal rank based on outcomes of dyadic agonistic interactions, litter size, wild ungulate prey density and anthropogenic disturbance in the year each hyena was born based on counts of illegal livestock in the Reserve. The dependent variable of interest was global DNA methylation, assessed via the LUminometric Methylation Assay, which provides a percentage methylation value calculated at CCGG sites across the genome. Among cubs, we observed approximately 2.75% higher CCGG methylation in offspring born to high‐ than low‐ranking mothers. Among cubs and subadults, higher anthropogenic disturbance corresponded with greater %CCGG methylation. In both cubs and adults, we found an inverse association between prey density measured before a hyena was 3 months old and %CCGG methylation. Our results suggest that maternal rank, anthropogenic disturbance and prey availability early in life are associated with later life global DNA methylation. Future studies are required to understand the extent to which these DNA methylation patterns relate to adult phenotypes and fitness outcomes. [ABSTRACT FROM AUTHOR]

ABSTRACT: Developmental plasticity, a phenomenon of importance in both evolutionary biology and human studies of the developmental origins of health and disease (DOHaD), enables organisms to respond to their environment based on previous experience without changes to the underlying nucleotide sequence. Although such phenotypic responses should theoretically improve an organism's fitness and performance in its future environment, this is not always the case. Herein, we first discuss epigenetics as an adaptive mechanism of developmental plasticity and use signaling theory to provide an evolutionary context for DOHaD phenomena within a generation. Next, we utilize signalling theory to identify determinants of adaptive developmental plasticity, detect sources of random variability – also known as process errors that affect maintenance of an epigenetic signal (DNA methylation) over time, and discuss implications of these errors for an organism's health and fitness. Finally, we apply life‐course epidemiology conceptual models to inform study design and analytical strategies that are capable of parsing out the potential effects of process errors in the relationships among an organism's early environment, DNA methylation, and phenotype in a future environment. Ultimately, we hope to foster cross‐talk and interdisciplinary collaboration between evolutionary biology and DOHaD epidemiology, which have historically remained separate despite a shared interest in developmental plasticity. [ABSTRACT FROM AUTHOR]

Objectives Atypical antipsychotics ( AAPs) carry a significant risk of cardiometabolic side effects, including insulin resistance. It is thought that the insulin resistance resulting from the use of AAPs may be associated with changes in DNA methylation. We aimed to identify and validate a candidate gene associated with AAP-induced insulin resistance by using a multi-step approach that included an epigenome-wide association study ( EWAS) and validation with site-specific methylation and metabolomics data. Methods Subjects with bipolar disorder treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze peripheral blood DNA methylation and insulin resistance. Epigenome-wide DNA methylation was analyzed in a discovery sample ( n = 48) using the Illumina 450K BeadChip. Validation analyses of the epigenome-wide findings occurred in a separate sample ( n = 72) using site-specific methylation with pyrosequencing and untargeted metabolomics data. Regression analyses were conducted controlling for known confounders in all analyses and a mediation analysis was performed to investigate if AAP-induced insulin resistance occurs through changes in DNA methylation. Results A differentially methylated probe associated with insulin resistance was discovered and validated in the fatty acyl CoA reductase 2 ( FAR2) gene of chromosome 12. Functional associations of this DNA methylation site with untargeted phospholipid-related metabolites were also detected. Our results identified a mediating effect of this FAR2 methylation site on AAP-induced insulin resistance. Conclusions Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance. [ABSTRACT FROM AUTHOR]

Developmental exposure to the endocrine-active compound bisphenol A (BPA) has been linked to epigenotoxic and potential carcinogenic effects in rodent liver, prostate, and mammary glands. A dose-dependent increase in hepatic tumors in 10-month mice perinatally exposed to one of three doses of BPA (50 ng, 50 µg, or 50 mg BPA/kg chow) was previously reported. These tumors represent early-onset disease and lack classical sexual dimorphism in incidence. Here, adult epigenome-wide liver DNA methylation profiles to identify gene promoters associated with perinatal BPA exposure and disease in 10-month mice with and without liver tumors were investigated. Mice with hepatic tumors showed 12,822 (1.8%) probes with differential methylation as compared with non-tumor animals, of which 8,656 (67.5%) were hypomethylated. A significant enrichment of differential methylation in Gene Ontology (GO) terms and biological processes related to morphogenesis and development, and epigenomic alteration were observed. Pathway enrichment revealed a predominance of hypermethylated neuronal signaling pathways linked to energy regulation and metabolic function, supporting metabolic consequences in the liver via BPA-induced disruption of neuronal signaling pathways. Hypothesis-driven pathway analysis revealed mouse and human genes linked to BPA exposure related to intracellular Jak/STAT and MAPK signaling pathways. Taken together, these findings are indicators of the relevance of the hepatic tumor phenotype seen in BPA-exposed mice to human health. This work demonstrated that epigenome-wide discovery experiments in animal models were effective tools for identification and understanding of paralagous epimutations salient to human disease. Environ. Mol. Mutagen. 57:435-446, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Alterations in xenobiotic metabolizing enzyme (XME) expression across the life course, along with genetic, nutritional, and environmental regulation, can influence how organisms respond to toxic insults. In this study, we investigated the hypothesis that in utero exposure to the endocrine active compound, bisphenol A (BPA), influences expression and epigenetic regulation of phase I and II XME genes during development. Using healthy 1st to 2nd trimester human fetal liver specimens quantified for internal BPA levels, we examined XME gene expression using PCR Array ( n = 8) and RNA-sequencing ( n = 12) platforms. Of the greater than 160 XME genes assayed, 2 phase I and 12 phase II genes exhibited significantly reduced expression with higher BPA levels, including isoforms from the carboxylesterase, catechol O-methyltransferase, glutathione S-transferase, sulfotransferase, and UDP-glucuronosyltransferase families. When the promoters of these candidate genes were evaluated in silico, putative binding sites for the E-twenty-six (ETS) and activator protein1 (AP1) related transcription factor families were identified and unique to 97% of all candidate transcripts. Interestingly, many ETS binding sites contain cytosine-guanine dinucleotides (CpGs) within their consensus sequences. Thus, quantitative analysis of CpG methylation of three candidate genes was conducted across n = 50 samples. Higher BPA levels were associated with increased site-specific methylation at COMT ( P < 0.005) and increased average methylation at SULT2A1 ( P < 0.020) promoters. While toxicological studies have traditionally focused on high-dose effects and hormonal receptor mediated regulation, our findings suggest the importance of low-dose effects and nonclassical mechanisms of endocrine disruption during development. Environ. Mol. Mutagen. 55:184-195, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Modification of the epigenome may be a mechanism underlying toxicity and disease following chemical exposure. Animal and human data suggest that mercury (Hg) impacts DNA methylation. We hypothesize that methylmercury and inorganic Hg exposures from fish consumption and dental amalgams, respectively, may be associated with altered DNA methylation at global repetitive elements (long interspersed elements, LINE-1) and candidate genes related to epigenetic processes ( DNMT1) and protection against Hg toxicity ( SEPW1, SEPP1). Dental professionals were recruited at Michigan Dental Association (MDA) meetings in 2009 and 2010. Subjects ( n = 131) provided survey data (e.g. exposure sources, demographics) and biological samples for Hg measurement and epigenetic analysis. Total Hg was quantified via atomic absorption spectrophotometry in hair and urine, indicative of methylmercury and inorganic Hg exposures, respectively. Global repetitive and candidate gene methylation was quantified via pyrosequencing of bisulfite converted DNA isolated from buccal mucosa. Hair Hg (geometric mean (95% CI): 0.37 (0.31-0.44) µg/g) and urine Hg (0.70 (0.60-0.83) µg/L) were associated with sources of exposure (fish consumption and dental amalgams, respectively). Multivariable linear regression revealed a trend of SEPP1 hypomethylation with increasing hair Hg levels, and this was significant ( P < 0.05) among males. The trend remained when excluding non-dentists. No significant relationships between urine Hg and DNA methylation were observed. Thus, in a limited cohort, we identified an association between methylmercury exposure and hypomethylation of a potentially labile region of the genome ( SEPP1 promoter), and this relationship was gender specific. Environ. Mol. Mutagen. 54:195-203, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The development of adult-onset diseases is influenced by perinatal exposure to altered environmental conditions. One such exposure, bisphenol A (BPA), has been associated with obesity and diabetes, and consequently labeled an obesogen. Using an isogenic murine model, we examined the effects of perinatal exposure through maternal diet to 50 ng (n=20), 50 µg (n=21), or 50 mg (n=18) BPA/kg diet, as well as controls (n=20) on offspring energy expenditure, spontaneous activity, and body composition at 3, 6, and 9 mo of age, and hormone levels at 9 and 10 mo of age. Overall, exposed females and males exhibited increased energy expenditure (P<0.001 and 0.001, respectively) throughout the life course. In females, horizontal and vertical activity increased (P=0.07 and 0.06, respectively) throughout the life course. Generally, body composition measures were not different throughout the life course in exposed females or males (all P>0.44), although body fat and weight decreased in exposed females at particular ages (all P<0.08). Milligram-exposed females had improved glucose, insulin, adiponectin, and leptin profiles (all P<0.10). Thus, life-course analysis illustrates that BPA is associated with hyperactive and lean phenotypes. Variability across studies may be attributable to differential exposure duration and timing, dietary fat and phytoestrogen content, or lack of sophisticated phenotyping across the life course. [ABSTRACT FROM AUTHOR]

Humans are exposed to low-dose ionizing radiation (LDIR) from a number of environmental and medical sources. In addition to inducing genetic mutations, there is concern that LDIR may also alter the epigenome. Such heritable effects early in life can either be positively adaptive or result in the enhanced formation of diseases, including cancer, diabetes, and obesity. Herein, we show that LDIR significantly increased DNA methylation at the viable yellow agouti (Avy) locus in a sex-specific manner (P= 0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 and 7:6 cGy, with maximum effects at 1.4 and 3.0 cGy (P<0.01). Offspring coat color was concomitantly shifted toward pseudoagouti (P<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring. Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic Avy mouse model, epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful. [ABSTRACT FROM AUTHOR]

ABSTRACT Widespread exposure to the endocrine active compound, bisphenol A (BPA), is well documented in humans. A growing body of literature suggests adverse health outcomes associated with varying ranges of exposure to BPA. In the current study, we measured the internal dose of free BPA and conjugated BPA and evaluated gene expression of biotransformation enzymes specific for BPA metabolism in 50 first- and second-trimester human fetal liver samples. Both free BPA and conjugated BPA concentrations varied widely, with free BPA exhibiting three times higher concentrations than conjugated BPA concentrations. As compared to gender-matched adult liver controls, UDP-glucuronyltransferase, sulfotransferase, and steroid sulfatase genes exhibited reduced expression whereas β-glucuronidase mRNA expression remained unchanged in the fetal tissues. This study provides evidence that there is considerable exposure to BPA during human pregnancy and that the capacity for BPA metabolism is altered in the human fetal liver. © 2012 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:116-123, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21459 [ABSTRACT FROM AUTHOR]

Animal studies have linked perinatal bisphenol A (BPA) exposure to altered DNA methylation, but little attention is given to analyzing multiple physiologically relevant doses. Utilizing the viable yellow agouti ( A vy) mouse, we examine the effects of developmental exposure through maternal diet to 50 ng BPA/kg ( n = 14 litters), 50 μg BPA/kg ( n = 9 litters), or 50 mg BPA/kg ( n = 13 litters) on global and candidate gene methylation at postnatal day 22. Global methylation analysis reveals hypermethylation in tail tissue of a/a and Avy/a offspring across all dose groups compared with controls ( n = 11 litters; P < 0.02). Analysis of coat color phenotype replicates previous work showing that the distribution of 50 mg BPA/kg Avy/a offspring shifts toward yellow ( P = 0.006) by decreasing DNA methylation in the retrotransposon upstream of the Agouti gene ( P = 0.03). Maternal exposure to 50 μg or 50 ng BPA/kg, however, results in altered coat color distributions in comparison with control ( P = 0.04 and 0.02), but no DNA methylation effects at the Agouti gene are noted. DNA methylation at the CDK5 activator-binding protein ( Cabp IAP) metastable epiallele shows hypermethylation in the 50 μg BPA/kg offspring, compared with controls ( P = 0.02). Comparison of exposed mouse liver BPA levels to human fetal liver BPA levels indicates that the three experimental exposures are physiologically relevant. Thus, perinatal BPA exposure affects offspring phenotype and epigenetic regulation across multiple doses, indicating the need to evaluate dose effects in human clinical and population studies. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article focuses on the implications of epigenetics to ecotoxicology, from the basic science to international policy. It says that epigenetic marks are susceptible to environmental influences including diet, stress, and behavior, wherein chemicals are also a factor. It also mentions the beneficial impact of epigenetics which include the creation of temporal disconnect between chemical exposure and effect, biomonitoring and ecological risk assessment, and the field of biomarker research.

The article focuses on the study concerning environmental epigenomics in human health and disease. The epigenome is reproduced during mitosis and consists of the DNA methylation marks and histone modifications. The innate plasticity of the epigenome enables it to be reprogrammed by chemical, nutritional and physical factors. Emerging research has determined the mechanisms responsible for phenotypic differences in genetically identical individuals, specifically the basis of adult disease. The mechanisms of epigenetic includes chromatic folding, packaging of DNA around nucleosomes and DNA methylation.