Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective

Abstract

The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed.

Figure 1. Techniques available to examine epigenetic mechanisms

Bisulfite treatment and conventional sequencing is the most common approach to obtain gene-specific CpG methylation status. Genome-wide analyses are necessary for identification of networks/pathways that are potentially altered. Combinations of restriction enzyme (RE) digestions at methylation sensitive sites or the immunoprecipitation of methyl cytosine residues followed by genomic arrays or high throughput sequencing alongside chromatin immunoprecipitation (ChIP) assays have given rise to a wide range of choices. See Supplemental Material online for details. Abbreviations: RLGS, restriction landmark genomic scanning; MSRF, methylation sensitive restriction fingerprinting; AP-PCR, methylation sensitive arbitrarily-primed PCR; HELP, HpaII tiny fragment enrichment by ligation-mediated PCR; DMH, differential methylation hybridization; MedIP, methylated DNA immunoprecipitation; MAP, methyl binding domain affinity purification, and QPCR, quantitative real-time PCR. * See [357] for details of techniques used in microRNA analysis. Validation methods: broken lines; Optional steps: dotted line.

Figure 2. Timeline of ovarian development in mice

The main stages of ovary development and function are shown. See text for details. After early embryonic lineage specification, germ cells proliferate and become sexually differentiated in mid-gestation. During these stages, the germ cell genome is methylated (thick line), with demethylation (dotted line) occuring after migration. Epigenetic reprogramming is sex-specific and remethylation events (thick line) occur postnatally in the ovary. The expression of estrogen and androgen receptors is at low levels or absent (dotted line) embryonically and increases (thick line) from early postnatal stages. ? - further studies are needed. Timeline is not to scale.