TGF-β signaling links early-life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells

Environmental exposure to endocrine-disrupting chemicals (EDCs) is associated with uterine fibroids (UFs) development, the most common benign tumors in women of reproductive age. It has been shown that UFs originate from abnormal myometrial stem cells (MMSCs) and there is evidence that defective DNA repair capacity could be involved in the emergence of mutations with implications for tumorigenesis. Moreover, the multifunctional cytokine TGF-β1 has been related to UF progress and some works revealed its connection with certain DNA damage repair pathways. Eker rats develop spontaneous uterine tumors in adulthood, which makes it a useful model for the study of UFs emergence The purpose of this study was to evaluate the impact of endocrine-disrupting chemicals (EDCs exposure on TGF-β1 pathway and nucleotide excision repair (NER) capacity, on Eker rat myometrial stem cells (MMSCs). MMSCs were isolated using Stro-1 and CD44 surface markers from 5-months old Eker rats exposed neonatally to Diethylstilbestrol (DES, an EDCs) or vehicle (VEH). After the in vitro treatment of VEH-MMSCs with TGF-β1 or EDC-MMSCs with TGF-β Receptor I inhibitor, we performed RNA-seq to determine global gene expression profiles and identified altered genes and pathways.