The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Collaborative work on evaluation of ovarian toxicity
5) Two- or four-week repeated-dose studies and fertility study of busulfan in female rats
Yosuke SakuradaSatoshi KudoShogo IwasakiYuki MiyataMiyuki NishiYoshihiro Masumoto
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2009 Volume 34 Issue Special Pages SP65-SP72

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Abstract

Busulfan, an antineoplastic agent that targets small follicles (primordial and primary follicles), was given orally to female Sprague-Dawley rats (0, 0.1, 0.5, or 1.5 mg/kg/day; n = 10 in each group) for 2 or 4 weeks to assess the optimal administration period for detection of the toxic effects on ovarian morphology. Isolated ovaries were used for histopathological analysis and follicle counts. In addition, a female fertility study was conducted by giving the same dose levels of busulfan from 2 weeks before mating to day 7 of pregnancy to determine the non-observed-adverse-effect-level (NOAEL) for female reproduction. In the 2-week study, all rats treated with busulfan showed normal estrous cyclicity and no toxicological changes in weight or histopathology of the ovaries. In the 4-week study, a decrease in small follicles was found histopathologically in 1 rat, even at 0.5 mg/kg, and in 4 rats at 1.5 mg/kg. Proliferating cell nuclear antigen immunohistochemistry of the follicles confirmed the above decrease in number of small follicles at 1.5 mg/kg. In the female fertility study, increases in dead embryos and post-implantation loss were found in rats at 1.5 mg/kg. Taken together, the NOAELs were 1.5 mg/kg for reproductive performance and 0.5 mg/kg for early embryonic development. In conclusion, the present study indicates that a 4-week administration period and appropriate assessment, including careful histopathological analysis of stage-based follicles are needed to detect small follicle depletion in a general toxicity study used as a first-titer screen.

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© 2009 The Japanese Society of Toxicology
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