Phosphoramide mustard induces autophagy markers and mTOR inhibition prevents follicle loss due to phosphoramide mustard exposure

被引：15

作者：

Madden, Jill A. ^{[1
]}

Thomas, Porsha Q. ^{[1
]}

Keating, Aileen F. ^{[1
]}

机构：

[1] Iowa State Univ, Dept Anim Sci, 2356J Kildee Hall, Ames, IA 50011 USA

来源：

REPRODUCTIVE TOXICOLOGY | 2017年 / 67卷

关键词：

Ovotoxicity; Phosphoramide mustard; Mammalian target of rapamycin; Phosphatidylinositol-3; kinase; NECROSIS-FACTOR-ALPHA; DAMAGE REPAIR RESPONSE; BOVINE GRANULOSA-CELLS; GENE-EXPRESSION; CYCLOPHOSPHAMIDE METABOLITES; SIGNALING PATHWAYS; OVARIAN TOXICITY; MAMMALIAN TARGET; P-GLYCOPROTEIN; EX-VIVO;

D O I：

10.1016/j.reprotox.2016.11.014

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Phosphoramide mustard (PM) is an ovotoxic metabolite of cyclophosphamide. Postnatal day 4 Fisher 344 rat ovaries were exposed to vehicle control (1% DMSO) or PM (60 mu M)+/- LY294002 or rapamycin for 2 or 4 d. Transmission election microscopy revealed abnormally large golgi apparatus and electron dense mitochondria in PM-exposed ovaries prior to and at the time of follicle depletion. PM exposure increased (P< 0.05) mRNA abundance of Bbc3, Cdknla, Ctfr, Edn1, Gstp1, Nqol, TIr4, Tnfrsfla, Txnrdl and decreased (P<0.05) Caspl and Ill b after 4d. PM exposure increased (P<0.1) BECN1 and LAMP, decreased (P<0.1) ABCB1 and did not alter ABCC1 protein. LY294002 did not impact PM-induced ovotoxicity, but decreased ABCC1 and ABCB1 protein. Rapamycin prevented PM-induced follicle loss. These data suggest that the mammalian target of rapamycin, mTOR, may be a gatekeeper of PM-induced follicle loss. (C) 2016 Elsevier Inc. All rights reserved.

引用

页码：65 / 78

页数：14

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