Editorial: Legacies of epigenetic perturbations (original) (raw)
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Transgenerational epigenetic actions of environmental compounds
Endocrine disrupting chemicals are known for their capacity to alter development and reproduction in mammals. One of the periods most sensitive to endocrine disruptor exposure is embryonic gonadal sex determination, when the germ line is undergoing epigenetic programming and DNA re-methylation. Epigenetic changes derived from exposure to endocrine disruptors have been described in several tissues and organisms. Endocrine disruptor induced epigenetic changes may have a wide range of phenotypic consequences, leading to disease conditions such as cancers, reproductive defects and obesity. Interestingly, the incidence of some diseases resulting from exposure to endocrine disruptors can be transgenerationally transmitted. In particular, exposure to the endocrine disruptor vinclozolin during early development is capable of inducing adult onset disease states that can be perpetuated across multiple generations. Environmental compounds such as endocrine disruptors can produce changes in the genome without altering DNA sequence. These changes are epigenetic in basis and can produce phenotypes that perpetuate transgenerationally. The suggestion that environmental factors can reprogram early development to induce epigenetic transgenerational phenotypes is a new paradigm in biology that will open new avenues for studies in disease etiology, reproduction and evolutionary biology.
PLoS ONE, 2012
Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease.
Epigenetic inheritance in mammals: Evidence for the impact of adverse environmental effects
Neurobiology of Disease, 2010
The epigenome is the overall epigenetic state of a cell and represents the ensemble of chromatin modifications. It is an essential mechanism for the regulation of the genome that depends on modifications of DNA and histones but does not involve any change of the DNA sequence. It was previously assumed that in order for appropriate cellular development and differentiation to occur in mammals, the epigenome was fully erased and reestablished between generations. However, several examples of incomplete erasure at specific genes have been reported, and this is suggested to be associated with the epigenetic inheritance of gene profiles. Although the existence of such a mode of inheritance has been controversial, there is increasing evidence that it does occur in rodents and humans. In this review, we discuss the evidence that adverse environmental factors can affect not only the individuals directly exposed to these factors but also their offspring. Because the epigenome is sensitive to environmental influence and, in some cases, can, in part, be transmitted across generations, it provides a potential mechanism for the transgenerational transmission of the impact of environmental factors. Environmental factors examined include exposure to toxicants, diet, and postnatal care, and DNA methylation is the main mechanism discussed in this review.
Environmentally induced epigenetic toxicity: potential public health concerns
Critical Reviews in Toxicology
Throughout our lives, epigenetic processes shape our development and enable us to adapt to a constantly changing environment. Identifying and understanding environmentally induced epigenetic change(s) that may lead to adverse outcomes is vital for protecting public health. This review, therefore, examines the present understanding of epigenetic mechanisms involved in the mammalian life cycle, evaluates the current evidence for environmentally induced epigenetic toxicity in human cohorts and rodent models and highlights the research considerations and implications of this emerging knowledge for public health and regulatory toxicology. Many hundreds of studies have investigated such toxicity, yet relatively few have demonstrated a mechanistic association among specific environmental exposures, epigenetic changes and adverse health outcomes in human epidemiological cohorts and/or rodent models. While this small body of evidence is largely composed of exploratory in vivo high-dose range studies, it does set a precedent for the existence of environmentally induced epigenetic toxicity. Consequently, there is worldwide recognition of this phenomenon, and discussion on how to both guide further scientific research towards a greater mechanistic understanding of environmentally induced epigenetic toxicity in humans, and translate relevant research outcomes into appropriate regulatory policies for effective public health protection.
2012
Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying V. K. Cortessis and D. C. Thomas contributed equally to this work.
Effect of Environmental Chemical Exposures on Epigenetics of Diseases: A Systematic Review
Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Out of all these environmental chemicals, effects of air pollution is responsible for death of 3.3 million people prematurely worldwide-a figure that could double by 2050 if emissions continue to rise at the current rate. Increasing number of evidences has linked environmental pollutants with epigenetic variations, including changes in DNA methylation status, histone modifications and other factors like incorporation of miRNAs, nucleosome remodeling, etc. These entire mechanisms are likely to play important roles in disease aetiology, and their modifications, thus providing further understanding of disease aetiology, as well as biomarkers for these exposures to environmental chemicals and/or prediction of the risk for the disease. In this, we had tried to summarize the different epigenetic alterations related to environmental chemical exposures, and propose the probable mechanisms of action behind such epigenetic changes. We will also focus onopportunities, challenges and further directions for future epidemiology research in environmental epigenomics. Further studies are needed in this regard to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. Moreover, there are several reports of epigenetic modifications arising from environmental chemical exposures, but most have not been directly linked to disease endpoints.
Environmentally induced epigenetic transgenerational inheritance of phenotype and disease
Molecular and Cellular Endocrinology, 2012
The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology.
Epigenetics and its implications for ecotoxicology
Ecotoxicology, 2011
Epigenetics is the study of mitotically or meiotically heritable changes in gene function that occur without a change in the DNA sequence. Interestingly, epigenetic changes can be triggered by environmental factors. Environmental exposure to e.g. metals, persistent organic pollutants or endocrine disrupting chemicals has been shown to modulate epigenetic marks, not only in mammalian cells or rodents, but also in environmentally relevant species such as fish or water fleas. The associated changes in gene expression often lead to modifications in the affected organism's phenotype. Epigenetic changes can in some cases be transferred to subsequent generations, even when these generations are no longer exposed to the external factor which induced the epigenetic change, as observed in a study with fungicide exposed rats. The possibility of this phenomenon in other species was demonstrated in water fleas exposed to the epigenetic drug 5-azacytidine. This way, populations can experience the effects of their ancestors' exposure to chemicals, which has implications for environmental risk assessment. More basic research is needed to assess the potential phenotypic and populationlevel effects of epigenetic modifications in different species and to evaluate the persistence of chemical exposureinduced epigenetic effects in multiple subsequent generations.
Environmental Deflection: The Impact of Toxicant Exposures on the Aging Epigenome
Toxicological Sciences
Epigenetic drift and age-related methylation have both been used in the literature to describe changes in DNA methylation that occurs with aging. However, ambiguity remains regarding the exact definition of both of these terms, and neither of these fields of study explicitly considers the impact of environmental factors on the aging epigenome. Recent twin studies have demonstrated longitudinal, pair-specific discordance in DNA methylation patterns, suggesting an effect of the environment on age-related methylation and/or epigenetic drift. Supporting this idea, other new reports have shown clear environment-and toxicant-mediated shifts away from the baseline rates of age-related methylation and epigenetic drift within an organism, a process we now term "environmental deflection." By defining and delineating environmental deflection, this contemporary review aims to highlight the effects of specific toxicological factors on the rate of DNA methylation changes that occur over the life course. In an effort to inform future epigenetics-based toxicology studies, a field of research now classified as toxicoepigenetics, we provide clear definitions and examples of "epigenetic drift" and "age-related methylation," summarize the recent evidence for environmental deflection of the aging epigenome, and discuss the potential functional effects of environmental deflection.