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首页> 外文期刊>The Journal of toxicological sciences >Collaborative work on evaluation of ovarian toxicity5) Two- or four-week repeated-dose studies and fertilitystudy of busulfan in female rats
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Collaborative work on evaluation of ovarian toxicity5) Two- or four-week repeated-dose studies and fertilitystudy of busulfan in female rats

机译：评价卵巢毒性的合作工作5）雌性大鼠中白消安的两到四周重复剂量研究和生育力研究

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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 imrmmohistochemistry 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.
机译：向雌性Sprague-Dawley大鼠（0、0.1、0.5或1.5 mg / kg /天;每组n = 10）口服给予以小卵泡（原始和初级卵泡）为目标的抗肿瘤药白消安，持续2或3天。 4周以评估最佳给药期，以检测对卵巢形态的毒性作用。分离的卵巢用于组织病理学分析和卵泡计数。此外，通过从交配前两周到怀孕第7天给予相同剂量的白消安，进行了女性生育力研究，以确定女性生殖的未观察到的不良反应水平（NOAEL）。在为期2周的研究中，所有接受白消安治疗的大鼠均表现出正常的发情周期，并且卵巢重量或组织病理学无毒理学变化。在为期4周的研究中，组织病理学上发现1只大鼠小卵泡减少，甚至在0.5 mg / kg时，在4只大鼠在1.5 mg / kg时也是如此。卵泡的增殖细胞核抗原免疫组织化学证实了在1.5mg / kg时小卵泡数目的上述减少。在雌性生育力研究中，以1.5 mg / kg的剂量发现老鼠体内死胚的增加和植入后的损失。两者合计，NOAELs的生殖性能为1.5 mg / kg，早期胚胎发育的为0.5 mg / kg。总之，本研究表明，在一般的毒性研究（用作第一个抗体筛查）中，需要进行4周的给药期和适当的评估，包括对基于阶段的卵泡进行仔细的组织病理学分析，以检测小卵泡的消耗。

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