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

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2017-01, Vol.67, p.65-78
• Main Authors: Madden, Jill A., Thomas, Porsha Q., Keating, Aileen F.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Antineoplastic Agents, Alkylating - toxicity; Autophagy - drug effects; Female; Golgi Apparatus - drug effects; Golgi Apparatus - ultrastructure; In Vitro Techniques; Mammalian target of rapamycin; Mitochondria - drug effects; Mitochondria - ultrastructure; Ovarian Follicle - drug effects; Ovarian Follicle - ultrastructure; Ovary - drug effects; Ovary - metabolism; Ovary - ultrastructure; Ovotoxicity; Phosphatidylinositol-3 kinase; Phosphoramide mustard; Phosphoramide Mustards - toxicity; Rats, Inbred F344; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2016.11.014

•Phosphoramide mustard histologically alters follicle structure prior to demise.•Rapamycin prevents phosphoramide mustard-induced follicle loss.•Phosphoramide mustard tended to reduce ovarian ABCB1 protein. 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 (60μM)±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