Brayboy Lynae M, Oulhen Nathalie, Long Sokunvichet, Voigt Niesha, Raker Christina, Wessel Gary M
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA.
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Reprod Toxicol. 2017 Apr;69:121-131. doi: 10.1016/j.reprotox.2017.02.002. Epub 2017 Feb 12.
Ovarian protection from chemotoxicity is essential for reproductive health. Our objective is to determine the role of ATP-dependent, Multidrug Resistance Transporters (MDRs) in this protection. Previously we identified MDR-dependent cytoprotection from cyclophosphamide in mouse and human oocytes by use of MDR inhibitors. Here we use genetic deletions in MDR1a/b/BCRP of mice to test MDR function in ovarian somatic cells and find that mdr1a/b/bcrp-/- mice had significantly increased sensitivity to cyclophosphamide. Further, estrus cyclicity and follicle distribution in mdr1a/b/bcrp-/- mice also differed from age-matched wildtype ovaries. We found that MDR gene activity cycles through estrus and that MDR-1b cyclicity correlated with 17β-estradiol surges. We also examined the metabolite composition of the ovary and learned that the mdr1a/b/bcrp-/- mice have increased accumulation of metabolites indicative of oxidative stress and inflammation. We conclude that MDRs are essential to ovarian protection from chemotoxicity and may have an important physiological role in the ovary.
卵巢免受化学毒性侵害对生殖健康至关重要。我们的目标是确定ATP依赖的多药耐药转运蛋白（MDRs）在这种保护中的作用。此前，我们通过使用MDR抑制剂，在小鼠和人类卵母细胞中确定了MDR依赖的对环磷酰胺的细胞保护作用。在此，我们利用小鼠MDR1a/b/BCRP基因缺失来测试MDR在卵巢体细胞中的功能，发现mdr1a/b/bcrp-/-小鼠对环磷酰胺的敏感性显著增加。此外，mdr1a/b/bcrp-/-小鼠的发情周期和卵泡分布也与年龄匹配的野生型卵巢不同。我们发现MDR基因活性在发情周期中循环，且MDR-1b的循环与17β-雌二醇的激增相关。我们还检测了卵巢的代谢物组成，发现mdr1a/b/bcrp-/-小鼠中指示氧化应激和炎症的代谢物积累增加。我们得出结论，MDRs对卵巢免受化学毒性侵害至关重要，并且可能在卵巢中具有重要的生理作用。
