Abstract
Early-life exposure of the myometrium to endocrine-disrupting chemicals (EDCs) has been shown to increase the risk of uterine fibroid (UF) prevalence in adulthood. Vitamin D3 (VitD3) is an unique, natural compound that may reduce the risk of developing UFs. However, little is known about the role and molecular mechanism of VitD3 on exposed myometrial stem cells (MMSCs). We investigated the role and molecular mechanism underlying VitD3 action on DNA damage response (DDR) defects in rat MMSCs due to developmental exposure to diethylstilbestrol (DES), with the additional goal of understanding how VitD3 decreases the incidence of UFs later in life. Female newborn Eker rats were exposed to DES or a vehicle early in life; they were then sacrificed at 5 months of age (pro-fibroid stage) and subjected to myometrial Stro1+/CD44+ stem cell isolation. Several techniques were performed to determine the effect of VitD3 treatment on the DNA repair pathway in DES-exposed MMSCs (DES-MMSCs). Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01). VitD3 treatment significantly decreased the DNA damage levels in DES-MMSCs. Concomitantly, the levels of key DNA damage repair members, including the MRN complex, increased in DES-MMSCs following treatment with VitD3 (p < 0.01). VitD3 acts on DNA repair via the MRN complex/ATM axis, restores the DNA repair signaling network, and enhances DDR. This study demonstrates, for the first time, that VitD3 treatment attenuated the DNA damage load in MMSCs exposed to DES and classic DNA damage inducers. Moreover, VitD3 targets primed MMSCs, suggesting a novel therapeutic approach for the prevention of UF development.
Highlights
Uterine fibroids (UFs) are the most common benign monoclonal tumors of the reproductive tract
African American women, the group with the highest risk for these tumors, exhibited the highest number of myometrial stem cells (MMSCs). These findings indicate that Stro1+/CD44+ MMSCs as myometrial stem/progenitor cells are markers for environmental factors that contribute to the increased risk for UFs [20]
We investigated whether Vitamin D3 (VitD3) treatment restores the suppressed expression levels of DNA repair proteins in DES-MMSCs caused by early-life exposure to DES
Summary
Uterine fibroids (UFs) are the most common benign monoclonal tumors of the reproductive tract. They originate from myometrial stem cells and serve as one of the most frequent reasons for myomectomies and hysterectomies [1,2]. UFs can cause profound gynecologic and reproduction conditions ranging from prolonged bleeding, anemia, and pelvic pain to recurrent abortion, subfertility, and preterm labor [3]. These complications impart an economic burden, and it is estimated that upwards of $34.4 billion is spent annually in the United States alone on treating the condition and the complications arising from it [4]. Surgery remains the standard treatment, with the condition negatively affecting the quality of life for women and especially affecting women of color, who experience a higher prevalence of UFs [5]
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