Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity

Madden, Jill A; Hoyer, Patricia B; Devine, Patrick J. et Keating, Aileen F (2014). Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity Toxicology and Applied Pharmacology , vol. 277 , nº 1. pp. 1-7. DOI: 10.1016/j.taap.2014.03.006.

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Résumé

The finite ovarian follicle reserve can be negatively impacted by exposure to chemicals including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4 days before being exposed once to PM (10 or 30 muM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P<0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60 muM) exposure destroyed all stage follicles after 4 days (P<0.05). VC from nearby wells depleted primordial follicles after 4 days (P<0.05), temporarily reduced secondary follicle number after 2 days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.

Type de document:	Article
Mots-clés libres:	Animals; Antineoplastic Agents/pharmacokinetics`Aziridines/pharmacology/ toxicity; Cyclophosphamide/pharmacokinetics; Dose-Response Relationship; Drug; Female; Ovarian Follicle/drug effects; Ovary/ drug effects; Phosphoramide Mustards/pharmacokinetics/ toxicity; Rats
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	23 juin 2017 00:15
Dernière modification:	04 nov. 2022 19:41
URI:	https://espace.inrs.ca/id/eprint/3081

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