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ToxSci Advance Access published online on December 28, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj086
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 25, 2005
Accepted December 20, 2005

Reproductive and Developmental Toxicology

Characterizing the Ovotoxicity of Cyclophosphamide Metabolites on Cultured Mouse Ovaries

Patrice Desmeules 1 and Patrick J. Devine 1 *

1 Université du Québec, Institut national de la recherche scientifique - Institut Armand-Frappier, Pointe Claire, QC, Canada

* To whom correspondence should be addressed.
Patrick J. Devine, E-mail: patrick.devine{at}iaf.inrs.ca


  Abstract

Cyclophosphamide (CPA) is reported to target dormant primordial ovarian follicles in rodents and humans. However, mechanistic studies are complicated due to the complex ovarian structure. We present here the characterization of the sensitivity of ovaries to CPA metabolites and the timing of morphological alterations induced by phosphoramide mustard (PM) in an in vitro system. Intact mouse ovaries (postnatal-day-4) were cultured in vitro and exposed to multiple breakdown products of CPA on day 0 (d0). Tissues were cultured for up to d8, and then follicle counts and immunohistochemistry were performed. 4-hydroperoxy-CPA (4-HC), a precursor of an activated form of CPA, and PM depleted primordial and primary follicles (≥1µM and ≥3µM, respectively p<0.05); acrolein had effects on follicle numbers only under continuous exposure (≥60µM); carboxycyclophosphamide and 4-ketocyclophosphamide reduced primordial and small primary follicles only at high concentrations (100µM). PM-induced follicle loss became significant (p<0.05) by d1 or d2 following exposures to 10µM or 3µM PM, respectively, as determined by the numbers of pyknotic or TUNEL-positive follicles. Cellular targets were oocytes in the smallest follicles but granulosa cells in large primary follicles. TUNEL staining was observed in both cell types, but Caspase-3, a marker of apoptosis, was absent from primordial follicles. In addition, a pan-caspase inhibitor could not prevent follicle losses when administered prior to PM. Thus, brief exposures to 4-HC or PM are sufficient to induce permanent follicle loss in ovaries, and PM is likely the ultimate ovotoxicant. Furthermore, the cell death pathway is likely Caspase-independent.

Keywords: cyclophosphamide; chemotherapy; phosphoramide mustard; ovarian toxicity; in vitro; mouse; follicle.
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