2017 Study Highlights
- Epidemiological and model system studies support an early origin of reproductive dysfunction.
- Estrogenic/anti-androgenic chemicals as endocrine disrupting chemicals (EDCs) have vast developmental influences on adult reproductive outcomes.
- Gestational, perinatal, neonatal, and pubertal periods are “windows of susceptibility” for epigenetic programming.
- EDCs induce exposure-specific epigenetic modifications in regulatory genes in organs of the reproductive system.
- Germline epigenetic disruption is a mechanism underlying transgenerational inheritance of reproductive disorders.
Sex-specific differentiation, development, and function of the reproductive system are largely dependent on steroid hormones.
For this reason, developmental exposure to estrogenic and anti-androgenic endocrine disrupting chemicals (EDCs) is associated with reproductive dysfunction in adulthood.
Human data in support of “Developmental Origins of Health and Disease” (DOHaD) comes from multigenerational studies on offspring of diethylstilbestrol-exposed mothers/grandmothers.
Animal data indicate that ovarian reserve, female cycling, adult uterine abnormalities, sperm quality, prostate disease, and mating behavior are susceptible to DOHaD effects induced by EDCs such as bisphenol A, genistein, diethylstilbestrol, p,p’-dichlorodiphenyl-dichloroethylene, phthalates, and polyaromatic hydrocarbons.
Mechanisms underlying these EDC effects include direct mimicry of sex steroids or morphogens and interference with epigenomic sculpting during cell and tissue differentiation.
Exposure to EDCs is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues.
Here we review the literature exploring the connections between developmental exposure to EDCs and adult reproductive dysfunction, and the mechanisms underlying these effects.
Several studies have demonstrated the impact of developmental exposure to EDCs on DNA methylation patterns in female reproductive tissues. A paper from almost two decades ago showed that neonatal exposure to DES results in hypomethylation of specific CpGs in the promoter region of the lactoferrin (Ltf) gene. Ltf is normally an estrogen responsive gene in the uterus, but DES induced hypomethylation was correlated with aberrant expression of Ltf in the absence of estrogen throughout life, suggesting that a permanent alteration in the hormone responsiveness of the gene had occurred. A subsequent study using the same model examined uterine DNA methylation pattern differences in a non-biased way. Several gene promoter regions were found to have differential methylation following neonatal DES or genistein exposure; one of these was Nsbp1 (now named Hmgn5), a protein that plays a role in chromatin compaction. The promoter region of this gene was hypomethylated later in life (6 months of age) following developmental exposure to either DES or genistein, and this was correlated with aberrant over-expression of uterine Nsbp1. Prenatal DES exposure results in hypermethylation of the Homeobox (Hox)a10 promoter that correlates with a decrease in gene expression.
Sources and more information
- Environmental factors, epigenetics, and developmental origin of reproductive disorders, Reproductive toxicology (Elmsford, N.Y.), NCBI PubMed PMID: 27421580, 2017 Mar.
- Freestyle (Non-parametric) featured image credit Daniel Friedman.