Publication Date

9-9-2023

Journal

Cellular and Molecular Life Sciences

DOI

10.1007/s00018-023-04928-z

PMID

37689587

PMCID

PMC10492698

PubMedCentral® Posted Date

9-9-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Female, Animals, Rats, DNA Repair, DNA Damage, Transforming Growth Factor beta, Carcinogenesis, Endocrine Disruptors, Leiomyoma, Uterine leiomyoma risk, Environmental exposure, DNA damage, Developmental reprogramming, Transforming growth factor superfamily

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.

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