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

Abstract

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFβ1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFβ1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFβ1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFβ1 decreased NER capacity while inhibiting TGFβ signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFβ1, but increased expression in EDC-MMSCs after TGFβ signaling inhibition. Overall, we demonstrated that the overactivation of the TGFβ pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFβ pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

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

“…Therefore, we incorporated the unique biology of reprogrammed MMSCs into our understanding of UF pathogenesis linked to EDC exposure. Notably, our previous and recent studies also demonstrated that single EDC exposure can increase the number of MMSCs, 9 decrease the DNA repair capacity, 10–12 and activate the pro-inflammatory pathway, 13 indicating that developmental EDC exposure altered the MMSC characteristics in an orchestrated manner (Figure 2).…”

The adverse role of endocrine disrupting chemicals in the reproductive system

“…Female Eker rats exposed to DES 11μg/d on days 10, 11, and 12 after birth reprogramed the methylome and found an augmenting estrogen activity of myometrial stem cells, leading to a “hyper-inflammatory phenotype” and an increased hormone-dependent risk of UFs ( 45 , 46 ). Further investigation into the molecular mechanisms implicated that early life exposure to DES suppressed nucleotide excision repair in rat myometrial stem cells through TGF-β signaling ( 47 ). Moreover, studies demonstrated that Vitamin D3 could mitigate the DNA damage caused by developmental DES exposure in uterine myometrial stem cells, effectively reducing the incidence of UF development ( 48 ).…”