Environmental Epigenetics
Latest Publications

Abstract Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects the competence of academic performance and social wellness in children and adults. The causes of ADHD are unclear. Both genetic and environmental factors contribute to the development of ADHD. The behavioral impairments in ADHD are associated with epigenetic changes in genes that are important for neurodevelopment. Among environmental causes of ADHD, the neurotoxin methylmercury (MeHg) is associated with an increased risk for ADHD. Developing children are susceptible to neurotoxic effects of prenatal MeHg exposure. Human epidemiology studies have shown that prenatal MeHg exposure could invoke epigenetic changes in genes that are involved in ADHD. In addition, the pathogenesis of ADHD involves dopaminergic system, which is a target of developmental MeHg exposure. MeHg-induced alterations in the dopaminergic system have a profound impact on behavioral functions in adults. As a trace level of MeHg (around nM) can induce long-lasting behavioral alterations, potential mechanisms of MeHg-induced functional changes in the dopaminergic system may involve epigenetic mechanisms. Here, we review the relevant evidence on developmental MeHg exposures and the risk for ADHD. We also point out research gaps in understanding environmental causes of ADHD.

Abstract Numerous human chronic pathological conditions depend on epigenetic modifications induced by environmental triggers throughout sensitive stages early in development. Developmental malnutrition is regarded as one of the most important risk factors in these processes. We present an overview of studies that the initiation and progression of many diseases are largely dependent on persisting epigenetic dysregulation caused by environmental insults early in life. For particular disorders, candidate genes were identified that underlie these associations. The current study assessed the most convincing evidence for the epigenetic link between developmental malnutrition and adult-life disease in the human population. These findings were obtained from quasi-experimental studies (so-called ‘natural experiments’), i.e. naturally occurring environmental conditions in which certain subsets of the population have differing levels of exposure to a supposed causal factor. Most of this evidence was derived on the DNA methylation level. We discussed DNA methylation as a key player in epigenetic modifications that can be inherited through multiple cell divisions. In this Perspective article, an overview of the quasi-experimental epidemiological evidence for the role of epigenetic mechanisms in the developmental programming by early-life undernutrition is provided.

Abstract 4,4ʹ-Isopropylidenediphenol (bisphenol A, BPA), a chemical substance that is widely used mainly as a monomer in the production of polycarbonates, in epoxy resins, and in thermal papers, is suspected to cause epigenetic modifications with potentially toxic consequences. Due to its negative health effects, BPA is banned in several products and is replaced by other bisphenols such as bisphenol S and bisphenol F. The present study examined the effects of BPA, bisphenol S, bisphenol F, p,pʹ-oxybisphenol, and the BPA metabolite BPA β-d-glucuronide on the expression of a set of microRNAs (miRNAs) as well as long interspersed nuclear element-1 methylation in human lung fibroblast and Caco-2 cells. The results demonstrated a significant modulation of the expression of different miRNAs in both cell lines including miR-24, miR-155, miR-21, and miR-146a, known for their regulatory functions of cell cycle, metabolism, and inflammation. At concentrations between 0.001 and 10 µg/ml, especially the data of miR-155 and miR-24 displayed non-monotonous and often significant dose–response curves that were U- or bell-shaped for different substances. Additionally, BPA β-d-glucuronide also exerted significant changes in the miRNA expression. miRNA prediction analysis indicated effects on multiple molecular pathways with relevance for toxicity. Besides, long interspersed nuclear element-1 methylation, a marker for the global DNA methylation status, was significantly modulated by two concentrations of BPA and p,pʹ-oxybisphenol. This pilot study suggests that various bisphenols, including BPA β-d-glucuronide, affect epigenetic mechanisms, especially miRNAs. These results should stimulate extended toxicological studies of multiple bisphenols and a potential use of miRNAs as markers.

Abstract The current evolutionary biology theory primarily involves genetic alterations and random DNA sequence mutations to generate the phenotypic variation required for Darwinian natural selection to act. This neo-Darwinian evolution is termed the Modern Evolution Synthesis and has been the primary paradigm for nearly 100 years. Although environmental factors have a role in neo-Darwinian natural selection, Modern Evolution Synthesis does not consider environment to impact the basic molecular processes involved in evolution. An Extended Evolutionary Synthesis has recently developed that extends the modern synthesis to consider non-genetic processes. Over the past few decades, environmental epigenetics research has been demonstrated to regulate genetic processes and directly generate phenotypic variation independent of genetic sequence alterations. Therefore, the environment can on a molecular level through non-genetic (i.e. epigenetic) mechanisms directly influence phenotypic variation, genetic variation, inheritance and adaptation. This direct action of the environment to alter phenotype that is heritable is a neo-Lamarckian concept that can facilitate neo-Darwinian (i.e. Modern Synthesis) evolution. The integration of genetics, epigenetics, Darwinian theory, Lamarckian concepts, environment, and epigenetic inheritance provides a paradigm shift in evolution theory. The role of environmental-induced epigenetic transgenerational inheritance in evolution is presented to describe a more unified theory of evolutionary biology.

Abstract Cannabis use alters sperm DNA methylation, but the potential reversibility of these changes is unknown. Semen samples from cannabis users and non-user controls were collected at baseline and again following a 77-day period of cannabis abstinence (one spermatogenic cycle). Users and controls did not significantly differ by demographics or semen analyses. Whole-genome bisulfite sequencing identified 163 CpG sites with significantly different DNA methylation in sperm between groups (P < 2.94 × 10−9). Genes associated with altered CpG sites were enriched with those involved in development, including cardiogenesis and neurodevelopment. Many of the differences in sperm DNA methylation between groups were diminished after cannabis abstinence. These results indicate that sustained cannabis abstinence significantly reduces the number of sperm showing cannabis-associated alterations at genes important for early development.

Abstract Environmental factors such as nutrition, stress, and toxicants can influence epigenetic programming and phenotypes of a wide variety of species from plants to humans. The current study was designed to investigate the impacts of hatchery spawning and rearing on steelhead trout (Oncorhynchus mykiss) vs the wild fish on a molecular level. Additionally, epigenetic differences between feeding practices that allow slow growth (2 years) and fast growth (1 year) hatchery trout were investigated. The sperm and red blood cells (RBC) from adult male slow growth/maturation hatchery steelhead, fast growth/maturation hatchery steelhead, and wild (natural-origin) steelhead were collected for DNA preparation to investigate potential alterations in differential DNA methylation regions (DMRs) and genetic mutations, involving copy number variations (CNVs). The sperm and RBC DNA both had a large number of DMRs when comparing the hatchery vs wild steelhead trout populations. The DMRs were cell type specific with negligible overlap. Slow growth/maturation compared to fast growth/maturation steelhead also had a larger number of DMRs in the RBC samples. A number of the DMRs had associated genes that were correlated to various biological processes and pathologies. Observations demonstrate a major epigenetic programming difference between the hatchery and wild natural-origin fish populations, but negligible genetic differences. Therefore, hatchery conditions and growth/maturation rate can alter the epigenetic developmental programming of the steelhead trout. Interestingly, epigenetic alterations in the sperm allow for potential epigenetic transgenerational inheritance of phenotypic variation to future generations. The impacts of hatchery exposures are not only important to consider on the fish exposed, but also on future generations and evolutionary trajectory of fish in the river populations.

Abstract Plastic-derived compounds are one of the most frequent daily worldwide exposures. Previously a mixture of plastic-derived toxicants composed of bisphenol A, bis(2-ethylhexyl) phthalate, and dibutyl phthalate at low-dose exposures of a gestating female rats was found to promote the epigenetic transgenerational inheritance of disease to the offspring (F1 generation), grand-offspring (F2 generation), and great-grand-offspring (F3 generation). Epigenetic analysis of the male sperm was found to result in differential DNA methylation regions (DMRs) in the transgenerational F3 generation male sperm. The current study is distinct and was designed to use an epigenome-wide association study to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Observations indicate disease-specific DMRs called epimutations in the transgenerational F3 generation great-grand-offspring of rats ancestrally exposed to plastics. The epigenetic DMR biomarkers were identified for testis disease, kidney disease, and multiple (≥2) diseases. These disease sperm epimutation biomarkers were found to be predominantly disease-specific. The genomic locations and features of these DMRs were identified. Interestingly, the disease-specific DMR-associated genes were previously shown to be linked with each of the specific diseases. Therefore, the germline has ancestrally derived epimutations that potentially transmit transgenerational disease susceptibilities. Epigenetic biomarkers for specific diseases could be used as diagnostics to facilitate clinical management of disease and preventative medicine.

Abstract Di(2-ethylhexyl) phthalate (DEHP) is a type of phthalate plasticizer found in a variety of consumer products and poses a public health concern due to its metabolic and endocrine disruption activities. Dysregulation of epigenetic modifications, including DNA methylation, has been shown to be an important mechanism for the pathogenic effects of prenatal exposures, including phthalates. In this study, we used an established mouse model to study the effect of perinatal DEHP exposure on the DNA methylation profile in liver (a primary target tissue of DEHP) and blood (a common surrogate tissue) of both juvenile and adult mice. Despite exposure ceasing at 3 weeks of age (PND21), we identified thousands of sex-specific differential DNA methylation events in 5-month old mice, more than identified at PND21, both in blood and liver. Only a small number of these differentially methylated cytosines (DMCs) overlapped between the time points, or between tissues (i.e. liver and blood), indicating blood may not be an appropriate surrogate tissue to estimate the effects of DEHP exposure on liver DNA methylation. We detected sex-specific DMCs common between 3-week and 5-month samples, pointing to specific DNA methylation alterations that are consistent between weanling and adult mice. In summary, this is the first study to assess the genome-wide DNA methylation profiles in liver and blood at two different aged cohorts in response to perinatal DEHP exposure. Our findings cast light on the implications of using surrogate tissue instead of target tissue in human population-based studies and identify epigenetic biomarkers for DEHP exposure.