Developmental exposure to endocrine disrupting chemicals alters the epigenome

Identification of reprogrammed targets

2016 Study Abstract

Endocrine disruptions induced by environmental toxicants have placed an immense burden on society to properly diagnose, treat and attempt to alleviate symptoms and disease. Environmental exposures during critical periods of development can permanently reprogram normal physiological responses, thereby increasing susceptibility to disease later in life – a process known as developmental reprogrammingDuring development, organogenesis and tissue differentiation occur through a continuous series of tightly-regulated and precisely-timed molecular, biochemical and cellular events. Humans may encounter endocrine disrupting chemicals (EDCs) daily and during all stages of life, from conception and fetal development through adulthood and senescence. Though puberty and perimenopausal periods may be affected by endocrine disruption due to hormonal effects, prenatal and early postnatal windows are most critical for proper development due to rapid changes in system growth. Developmental reprogramming is shown to be caused by alterations in the epigenome. Development is the time when epigenetic programs are ‘installed’ on the genome by ‘writers’, such as histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), which add methyl groups to lysine and arginine residues on histone tails and to CpG sites in DNA, respectively. A number of environmental compounds, referred to as estrogenic endocrine disruptors (EEDs), are able to bind to estrogen receptors (ERs) and interfere with the normal cellular development in target tissues including the prostate and uterus. These EEDs, including diethylstilbestrol (DES), bisphenol A (BPA), and genistein (a phytoestrogen derived from soybeans), have been implicated in the malformation of reproductive organs and later development of disease. Due to the lack of fully understanding the underlying mechanisms of how environmental toxicants and their level of exposure affect the human genome, it can be challenging to create clear clinical guidance to address the potential health effects of lower-level exposures commonly experienced within the general population. In addition, human studies concerning environmental exposures are limited in feasibility by ethical concerns for human safety. Therefore, studies in animal models provide great opportunities to reveal links between early-life exposure to EDCs and related diseases. It has been shown that developmental exposure to EDCs, such as diethylstilbestrol (DES) and genistein, during reproductive tract development increases the incidence, multiplicity and overall size of uterine fibroids in the Eker rat model, concomitantly reprogramming estrogen-responsive gene expression. Importantly, EDC exposure represses enhancer of zeste 2 (EZH2) and reduces levels of the histone 3 lysine 27 trimethylation (H3K27me3) repressive mark through Estrogen receptor / Phosphatidylinositide 3-kinases / Protein kinase B non-genomic signaling in the developing uterus. More recent research identified a developmental reprogramming target, Scbg2a1 gene, whose epigenetic status can be altered by early exposure to BPA in the rat prostate. Molecular analyses revealed markedly increased expression (greater than 100 fold) of Scgb2a1, a secretaglobin gene in response to developmental exposure to BPA. This increase in Scgb2a1 expression is concomitantly associated with increased enrichment of acetylated H3K9 (H3K9Ac representing active chromatin status) and hypomethylation of DNA for a CpG island upstream of the transcription start site of Scgb2a1. These data suggest that expression of Scgb2a1 in the adult prostate could be epigenetically reprogrammed by BPA exposure during prostate development. Further studies are needed to create more targeted preventative interventions as well as specific, effective therapeutics to decrease the incidence of diseases.

DES exposure and estrogen signaling

Diethylstilbestrol (DES) is able to bind to estrogen receptors (ERs) and interfere with the normal cellular development in target tissues including the prostate and uterus.

Past mass-exposures to endocrine disrupting chemicals, like DES, during reproductive tract development have been linked with reprogramming of estrogen-responsive gene expression in the uterine myometrium. This leads to tissue hyper-responsiveness to ovarian sex hormones, specifically estrogen and progesterone, later in adult life, and predisposes women to the development of uterine leiomyoma. Animal studies have shown that early-life exposure to DES during uterine development (in rats, uterine development occurs post-natally) permanently alters the morphology of the reproductive tract via an “estrogen imprint” despite the readily-metabolized nature of DES and its efficient clearing from the body. These experiments have provided evidence of the long-term, permanent pathophysiological effects of even brief exposure to environmental endocrine disruptors, such as DES. The challenge remains, however, to connect exposure to other environmental toxicants which result in permanent epigenetic changes and disease-related outcomes.

Developmental exposures to EDCs increase uterine fibroid development

Due to the lack of fully understanding the underlying mechanisms of how environmental toxicants and their level of exposure affect the human genome, it can be challenging to create clear clinical guidance to address the potential health effects of lower-level exposures commonly experienced within the general population. In addition, human studies concerning environmental exposures are limited in feasibility by ethical concerns for human safety. Therefore, studies in animal models provide great opportunities to reveal links between early-life exposure to EDCs and related human diseases including uterine fibroids. For example, Eker (TscEk/+) rats, heterozygous for the tuberous sclerosis 2 (Tsc2) gene, i.e. carrying one Tsc2 mutant allele, have a 65% incidence of spontaneously developing uterine fibroids, generally around 12 months of age. Dr. Walker’s group described the long-term effects of postnatal exposure to EDCs (DES, and genistein) on the uteri of Eker rats after allowing them to develop to 16 months of age. Early-life exposure to EDCs including DES or genistein increased tumor penetrance (from 65% to >90%), tumor multiplicity, and overall size. While the molecular mechanisms are still being revealed, these experiments with genistein show that in the developing uterus, genistein induces epigenetic changes of non-genomic estrogen receptor (ER) signaling by way of activation of the PI3K/AKT pathway. This in turn phosphorylates histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2), a potent epigenetic regulator of gene expression and inactivates EZH2. This ultimately reduces levels of H3K27me3 found in chromatin, which are normally a mark of repressed gene expression. Thus, the overall expression of estrogen-responsive genes is, in turn, increased. Even 16 months following brief exposure to genistein during uterine development, their studies showed increased activity of EZH2 suggesting interference with epigenetic programming in the development of the uterus, leading to permanent alterations that persist into adult life. Further investigation is needed to identify the direct epigenetic link between developmental programming targets and EDC exposures during uteri development.

Sources and more information
  • Full study (free access) Developmental exposure to endocrine disrupting chemicals alters the epigenome: Identification of reprogrammed targets, Gynecology and obstetrics research : open journal, PMC4966680, 2016 Jul.
  • Early-life exposure to BPA featured image credit PMC4966680/figure/F1.
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