Environmental Epigenetics最新文献

Life experiences and environmental conditions in childhood can change the physiology and behaviour of exposed individuals and, in some cases, of their offspring. In rodent models, stress/trauma, poor diet, and endocrine disruptors in a parent have been shown to cause phenotypes in the direct progeny, suggesting intergenerational inheritance. A few models also examined transmission to further offspring and suggested transgenerational inheritance, but such multigenerational inheritance is not well characterized. Our previous work on a mouse model of early postnatal stress showed that behaviour and metabolism are altered in the offspring of exposed males up to the 4th generation in the patriline and up to the 2nd generation in the matriline. The present study examined if symptoms can be transmitted beyond the 4th generation in the patriline. Analyses of the 5th and 6th generations of mice revealed that altered risk-taking and glucose regulation caused by postnatal stress are still manifested in the 5th generation but are attenuated in the 6th generation. Some of the symptoms are expressed in both males and females, but some are sex-dependent and sometimes opposite. These results indicate that postnatal trauma can affect behaviour and metabolism over many generations, suggesting epigenetic mechanisms of transmission.

Acute environmental stressors such as short-term exposure to pollutants can have lasting effects on organisms, potentially impacting future generations. Parental exposure to toxicants can result in changes to the epigenome (e.g., DNA methylation) that are passed down to subsequent, unexposed generations. However, it is difficult to gauge the cumulative population-scale impacts of epigenetic effects from laboratory experiments alone. Here, we developed a size- and age-structured delay-coordinate population model to evaluate the long-term consequences of epigenetic modifications on population sustainability. The model emulated changes in growth, mortality, and fecundity in the F0, F1, and F2 generations observed in experiments in which larval Menidia beryllina were exposed to environmentally relevant concentrations of bifenthrin (Bif), ethinylestradiol (EE2), levonorgestrel (LV), or trenbolone (TB) in the parent generation (F0) and reared in clean water up to the F2 generation. Our analysis suggests potentially dramatic population-level effects of repeated, chronic exposures of early-life stage fish that are not captured by models not accounting for those effects. Simulated exposures led to substantial declines in population abundance (LV and Bif) or near-extinction (EE2 and TB) with the exact trajectory and timeline of population decline dependent on the combination of F0, F1, and F2 effects produced by each compound. Even acute one-time exposures of each compound led to declines and recovery over multiple years due to lagged epigenetic effects. These results demonstrate the potential for environmentally relevant concentrations of commonly used compounds to impact the population dynamics and sustainability of an ecologically relevant species and model organism.

Although the effects of lead, mercury, manganese, and copper on individual disease processes are well understood, estimating the health effects of long-term exposure to these metals at the low concentrations often observed in the general population is difficult. In addition, the health effects of joint exposure to multiple metals are difficult to estimate. Biological aging refers to the integrative progression of multiple physiologic and molecular changes that make individuals more at risk of disease. Biomarkers of biological aging may be useful to estimate the population-level effects of metal exposure prior to the development of disease in the population. We used data from 290 participants in the Detroit Neighborhood Health Study to estimate the effect of serum lead, mercury, manganese, and copper on three DNA methylation-based biomarkers of biological aging (Horvath Age, PhenoAge, and GrimAge). We used mixed models and Bayesian kernel machine regression and controlled for participant sex, race, ethnicity, cigarette use, income, educational attainment, and block group poverty. We observed consistently positive estimates of the effects between lead and GrimAge acceleration and mercury and PhenoAge acceleration. In contrast, we observed consistently negative associations between manganese and PhenoAge acceleration and mercury and Horvath Age acceleration. We also observed curvilinear relationships between copper and both PhenoAge and GrimAge acceleration. Increasing total exposure to the observed mixture of metals was associated with increased PhenoAge and GrimAge acceleration and decreased Horvath Age acceleration. These findings indicate that an increase in serum lead or mercury from the 25th to 75th percentile is associated with a ∼0.25-year increase in two epigenetic markers of all-cause mortality in a population of adults in Detroit, Michigan. While few of the findings were statistically significant, their consistency and novelty warrant interest.

4,4'-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,p'-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,p'-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.

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.

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.

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.

Phthalates are used in many consumer products, leading to daily human exposure. Although many studies focus on single phthalates, humans are exposed to mixtures of phthalates. Our laboratory created a phthalate mixture consisting of six different phthalates and found that it negatively affected female reproduction and accelerated some biomarkers of reproductive aging. However, it was unknown if prenatal exposure to the mixture accelerates the natural decline in reproductive capacity and ovarian aging in mice. Therefore, we tested the hypothesis that prenatal exposure to a phthalate mixture accelerates the age-related decline in reproductive capacity and biomarkers of ovarian aging in the F1 generation of mice. Pregnant CD-1 dams were orally dosed with control or phthalate mixture (20 µg/kg/day-200 mg/kg/day) daily from gestational day 10-birth. The F1 female pups were aged to 11-13 months, and then estrous cyclicity and breeding trials were conducted at 11 and 13 months. Ovaries were collected from the F1 females at 13 months to examine biomarkers of ovarian aging. Prenatal exposure to the phthalate mixture decreased the time the F1 females spent in proestrus and the ability of the F1 females to give birth at 11 and 13 months of age compared to control. In contrast, prenatal exposure to the mixture did not affect biomarkers of direct aging of the ovary in the F1 generation. Collectively, our data show that prenatal phthalate mixture exposure accelerates the natural age-related decline in reproductive capacity but may not affect some biomarkers of ovarian aging in the F1 generation.

Accumulating evidence suggests that exposure to unfavorable conditions early in life can substantially contribute to the risk of chronic disorders later in life ('developmental programming' phenomenon). The mechanistic basis for this phenomenon remains poorly understood so far, although epigenetic mechanisms such as DNA methylation, histone modifications and microRNA-mediated gene regulation apparently play a crucial role. The key role of epigenetic modifications triggered by unfavorable environmental cues during sensitive developmental periods in linking adverse early-life events to later-life health outcomes is evident from a large body of studies, including methylome-wide association studies and research of candidate genes. Toxic metals (TMs), such as heavy metals, including lead, chromium, cadmium, arsenic, mercury, etc., are among environmental contaminants currently most significantly impacting human health status. Since TMs can cross the placental barrier and accumulate in fetal tissues, exposure to high doses of these xenobiotics early in development is considered to be among important factors contributing to the developmental programming of adult-life diseases in modern societies. In this mini-review, we summarize epidemiological findings indicating that prenatal TM exposure can induce epigenetic dysregulation, thereby potentially affecting adult health outcomes.

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.