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

作者：Madden Jill A; Thomas Porsha Q; Keating Aileen F

来源：Reproductive Toxicology, 2017, 67: 65-78.

DOI：10.1016/jseprotox.2016.11.014

• Ovotoxicity
• Phosphoramide mustard
• Mammalian target of rapamycin
• Phosphatidylinositol-3 kinase

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.

• 出版日期2017-1