Endocrine-disrupting chemicals and epigenetic reprogramming in developmental origin of uterine fibroids

Abstract

Endocrine-disrupting chemicals (EDCs) are a class of exogenous substances that mimic the effects of hormones in the body, inducing hormonal dysregulation and contributing to various disorders. Epigenome regulation has emerged as an important mechanism for maintaining organ function in health and disease. Dissecting epigenomic and resultant gene expression changes provides unprecedented insight into the chromatin state, which underlines disease development and shapes risk and phenotypic plasticity in response to the environment and internal cues. The cutting-edge, high throughput technologies provide new routes to understanding the etiology of disease and new footholds on the promising path to better treatment and disease prevention. We have recently revealed that myometrial stem cells (MMSCs), the cell origin of UFs, are the target of developmental EDC exposure. The EDC-induced epigenetic changes in MMSCs identified by multi-omics approaches include DNA methylation and histone modification modulated by DNA methyltransferases and MLL1, which characterized the molecular mechanism underlying EDC-related risk in hormone-dependent UFs. Future studies are needed to determine the link between real-life exposures to EDCs and their impact on the development of human diseases and transgenerational epigenetic inheritance, which can help explore strategies that may prevent adverse outcomes linked to EDC exposure.

Keywords: Leiomyoma; developmental reprogramming; endocrine-disrupting chemicals; hormone-dependent tumor; myometrial stem cells.

Figure 1.

EDCs: a promoter of diseases targeting multiple tissues. Growing evidence reveals that EDC exposures significantly impact on human health, targeting numerous tissues, including prostate, breast, liver, thyroid, adipose tissue, brain, ovary, testis, and uterus. Developmental exposures to EDCs have more negative impacts than adult exposure since organs during development are susceptible to adverse environmental exposures. EDCs can disrupt normal development patterns and alter disease susceptibility via various hormone axes and relevant pathways. Remarkably, developmental exposures to EDCs have been shown to have lifelong ramifications and even cause transgenerational effects on male and female reproduction and other diseases.

Figure 2.

Developmental exposure to EDCs can lead to an increased risk of UF development. MMSCs in the myometrium of the uterus are the cellular target for EDC. Epigenetic reprogramming can alter the MMSC characteristics. EDC-induced adverse effects on MMSCs include increased cell number, inflammation activation, DNA repair dysfunction, and hyper-estrogenic phenotype. Ac: acetylation modification on histones; EDCs: endocrine-disrupting chemicals; ERGs: estrogen-responsive genes; IRGs: inflammatory responsive genes; Me: methylation modification on histones; MMSCs: myometrial stem cells; UF: uterine fibroids.