环境暴露于内分泌干扰物（EDCs）与女性子宫肌瘤（UFs）的发生有关。UFs是非癌性肿瘤，据信起源于异常的子宫肌干细胞（MMSCs）。缺陷的DNA修复能力可能导致促进肿瘤生长的突变的出现。多功能细胞因子TGFβ1与UF进展和DNA损伤修复途径相关。为了研究EDC暴露对TGFβ1和核苷酸切除修复（NER）途径的影响，我们从新生期接受二乙基雌酚（DES），一种EDC，或接受载体（VEH）的5个月大Eker大鼠中分离了MMSCs。与VEH-MMSCs相比，EDC-MMSCs表现出超活化的TGFβ1信号传导和NER途径成分的mRNA和蛋白水平降低。EDC-MMSCs还表现出受损的NER能力。将VEH-MMSCs暴露于TGFβ1会降低其NER能力，而抑制EDC-MMSCs中的TGFβ信号传导则恢复了NER能力。RNA-seq分析和进一步验证发现，TGFβ1处理的VEH-MMSCs中抑制素UVrag（一种参与DNA损伤识别的肿瘤抑制基因）表达下降，而TGFβ信号传导抑制后EDC-MMSCs中的表达增加。总体而言，我们证明了TGFβ途径超活化将早期暴露于EDCs与受损的NER能力联系起来，这将导致增加的遗传不稳定性、突变的出现和肌瘤发生。我们证明了TGFβ途径的超活化将早期暴露于EDCs与增加的肌瘤发生率联系起来。©2023. 作者。

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.© 2023. The Author(s).