Epigenetics and transgenerational effects of DES

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals

2015 Paper Abstract

The mechanisms of action of EDCs are varied and not entirely understood, but recent evidence suggests that some EDCs may cause epigenetic changes, which in turn may lead to transgenerational effects of EDCs on numerous organ systems. Epigenetic changes are described as heritable changes in gene expression that are not due to changes in DNA sequence (ie, not due to mutation). Several possible mechanisms of epigenetic change exist, including methylation of cytosine residues on DNA, post-translational modification of histones, and altered microRNA expression. To date, most studies on the effects of EDCs on epigenetic changes have focused on DNA methylation, but recent studies have also addressed the effects of EDCs on histone modifications and microRNA expression.

DNA methylation is a process in which methyl groups are attached to cytosine residues by DNA methyltransferase enzymes (DNMTs), usually in cytosine-guanosine dinucleotide pairs (CpG sites), although DNA methylation can occur on non-CpG residues. DNA methylation is important for several normal developmental and reproductive processes such as gametogenesis and embryogenesis. Hypermethylation in a promoter region is thought to repress gene transcription because the methylated promoter region has a decreased affinity for transcription factors and an increased affinity for methylated DNA-binding proteins, methyltransferases, histone deacetylases (HDACs), and/or corepressors.

Histone modification is a process in which specific amino acids in the N-terminal ends of histones undergo post-translational modification, including acetylation, methylation, phosphorylation, sumoylation, and ubiquitination by enzymes such as histone acetyltransferases, deacetylases, methyltransferases, and demethylases. These modifications determine whether the DNA wrapped around histones is available for transcription and play roles in determining the rate of transcription. Histone modifications also help regulate replication, recombination, and higher-order organization of the chromosomes. Changes to these modifications are often found in diseases such as cancer and are best studied for those diseases.

The molecular mechanisms by which microRNAs and other noncoding RNAs affect gene expression are not entirely understood, but it is likely that microRNAs play a role in gene regulation and chromatin organization. MicroRNAs often bind to the 3′ end of gene transcripts and initiate mRNA degradation or suppression of protein translation. Studies also suggest that microRNAs can affect the expression of other epigenetic regulators such as DNMTs and histone-modification enzymes.

Both hormones and EDCs cause DNA methylation, histone modifications, and altered microRNA expression. These epigenetic changes often cause phenotypic changes in organisms, which may appear immediately or long after EDC exposure. These properties are dictated by the timing of exposure. When EDCs introduce epigenetic changes during early development, they permanently alter the epigenome in the germline, and the changes can be transmitted to subsequent generations. When an EDC introduces epigenetic changes during adulthood, the changes within an individual occur in somatic cells and are not permanent or transmitted to subsequent generations. For an EDC to have truly transgenerational effects, exposure must occur during development, and the effects need to be observed in the F3 generation. This is because when a pregnant F0 female is exposed to an EDC, germ line cells in her F1 fetus are directly exposed to the EDC. These exposed F1 germ line cells are then used to produce the F2 generation, and thus, the F2 generation was directly exposed to the EDC via the germ cells. This exposure scenario makes the F3 generation the first generation that was not directly exposed to the EDC.

EDC-induced epigenetic changes are also influenced by dose of exposure, and they are tissue specific. Thus, it is important to consider both dose of EDC and the tissue before making firm conclusions about the epigenetic effects of EDCs. DNA methylation changes are the best-studied mechanism in this regard. For example, prenatal exposure to DES caused hypermethylation of the Hoxa10 gene in the uterus of mice and was linked to uterine hyperplasia and neoplasia later in life. Beyond the effects of prenatal exposure to DES on the daughters exposed in utero are suggestions that this leads to transgenerational effects of the chemical on the reproductive system, although whether this is linked to DNA methylation changes in humans is unknown.

Little is known about the ability of EDCs to cause histone modifications and whether this leads to transgenerational effects in animals or humans. DES caused histone deacetylation in the promoter region of the cytochrome P450 side chain cleavage (P450scc) gene. Further studies, however, need to be conducted to identify other EDCs causing histone modifications in animals and humans and to determine whether such modifications lead to transgenerational effects.

Synthetic estrogens are well known disruptors of uterine structure and function in humans and animals. Consistent with previous studies, recent data indicate that neonatal DES exposure caused endometrial hyperplasia/dysplasia in hamsters and increased uterine adenocarcinoma and uterine abnormalities in Donryu rats. Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members, caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells and increased the incidence of cystic glands in rats.

EDC exposures to pregnant animals have been shown to cause multigenerational or transgenerational effects on a number of disease endpoints, particularly reproduction, neurobehavior, and adiposity. This work needs much more follow-up to better determine the underlying mechanisms, which are likely to include epigenetic molecular programming changes. Moreover, research is needed in human populations. Some work has been conducted in grandchildren of DES-exposed women who took this estrogenic pharmaceutical during pregnancy. The consequences on the offspring (F1 generation) are well-studied, and research is beginning to be published on the grandchildren (F2 generation).

In summary, a prominent mechanism for increased disease risk in adulthood as a function of early-life EDC exposure is attributed to epigenomic reprogramming, a result of high plasticity as the epigenetic code is installed during development. Furthermore, the environment-gene interface must be considered as a basis for individual disease susceptibility whereby EDC-induced modifications of the epigenetic code early in life permit cryptic genetic variants or low-penetrant mutations to emerge and to manifest a phenotype at later life stages, long after the initial EDC exposure.

Sources

  • Full study (free access) : EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, Endocrine Reviews, NCBI PubMed PMC4702494, 2015 Dec.
  • Featured image by archive.transgenderuniverse.
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