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Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats

1
Department of Pharmacology and Toxicology, National Organization for Drug Control and Research (NODCAR), Cairo 35521, Egypt
2
Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA
3
Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11591, Egypt
4
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
5
Department of Physiology, Reproductive Science Research Program, Morehouse School of Medicine, Atlanta, GA 30310, USA
6
Department of Clinical Pharmacy, Faculty of Pharmacy, British University in Egypt, Cairo 11837, Egypt
*
Author to whom correspondence should be addressed.
Cells 2020, 9(6), 1459; https://doi.org/10.3390/cells9061459
Received: 28 April 2020 / Revised: 8 June 2020 / Accepted: 9 June 2020 / Published: 12 June 2020
(This article belongs to the Section Stem Cells)
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. View Full-Text
Keywords: uterine fibroids; myometrial stem cells; endocrine-disrupting chemicals; DNA damage; vitamin D3 uterine fibroids; myometrial stem cells; endocrine-disrupting chemicals; DNA damage; vitamin D3
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MDPI and ACS Style

Elkafas, H.; Ali, M.; Elmorsy, E.; Kamel, R.; Thompson, W.E.; Badary, O.; Al-Hendy, A.; Yang, Q. Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats. Cells 2020, 9, 1459. https://doi.org/10.3390/cells9061459

AMA Style

Elkafas H, Ali M, Elmorsy E, Kamel R, Thompson WE, Badary O, Al-Hendy A, Yang Q. Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats. Cells. 2020; 9(6):1459. https://doi.org/10.3390/cells9061459

Chicago/Turabian Style

Elkafas, Hoda, Mohamed Ali, Engy Elmorsy, Rehab Kamel, Winston E. Thompson, Osama Badary, Ayman Al-Hendy, and Qiwei Yang. 2020. "Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats" Cells 9, no. 6: 1459. https://doi.org/10.3390/cells9061459

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