Prospects for studying epigenetic mediation of exposure–response relationships

2012 Study Abstracts

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 epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.

Epigenetic effects in neurological disorders

Historically, the field of epigenetics has focused on elucidating mechanisms for maintaining DNA methylation in dividing cells. However, recent work has discovered dynamic DNA methylation changes in non-dividing cells including neurons, motivating studies of effects of environmental exposures on epigenetic marks in relation to neurological disorders.

Alzheimer’s disease, schizophrenia, and autism spectrum disorders show a variety of epigenetic anomalies. An epigenetic mechanism has been proposed to explain the association between famine during the prenatal period and schizophrenia risk, as well as associations between expression of imprinted genes and both autism and schizophrenia. Recent studies, moreover, report associations of both conditions with DNA methylation in additional, non-imprinted genes.

Human studies – Diethylstilbestrol (DES)

Decades ago, human males exposed in utero to DES were found to have excess occurrence of urogenital malformations, including hypospadias, and elevated prevalence of hypospadias was subsequently reported among unexposed boys whose mothers had been exposed in utero to DES. More recently, in a study addressing potential competing effects of measured environmental and genotypic factors, a notable excess of hypospadias was reported among unexposed grandsons of women who had been exposed in utero to DES. One postulated mechanism for these observations is that epigenetic changes in the androgen receptor gene are induced in primordial germ cells of DES-exposed female fetuses at the time that the reproductive system is forming, and subsequently transmitted across generations to affected sons and grandsons. To our knowledge, this mechanism has not been examined at the molecular level.

Multigenerational studies – Diethylstilbestrol offspring

DES is regarded as a potential environmental endocrine disruptor by many researchers because this compound binds steroid hormone receptors and has only exogenous sources. Because exposure occurred only in relatively controlled clinic settings, cohorts of exposed individuals could in theory provide an opportunity to trace any epigenetic effects of exposure among themselves and their descendents to the restricted time periods of their pregnancies or gestation before administration to pregnant women ended in the 1970s. Exposure and comparison group data of varying quality are or could be made available from several sources, the highest quality in theory being participants in trials of DES efficacy conducted in the 1950s, although sample sizes were limited. Nonetheless, the numerous case–control sets, DES-exposed cohorts, and interest groups that subsequently enrolled large numbers of exposed men and women to monitor and investigate health effects of exposed individuals could prove to be valuable resources for investigation of potential epigenetic and transgenerational effects of DES among exposed individuals and their descendents. Initial proof-of-concept studies could include investigation of epigenetic marks postulated to have been disrupted by DES exposures.

  • Read and download the full study (free access) Environmental epigenetics: prospects for studying epigenetic mediation of exposure–response relationships, on the NCBI, PubMed, PMC3432200, 2012 Oct.
  • Image credit Daniel Friedman.
DES DIETHYLSTILBESTROL RESOURCES

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