Collaborative work on evaluation of ovarian toxicity 13) Two- or four-week repeated dose studies and fertility study of PPAR .ALPHA./.GAMMA. dual agonist in female rats

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  • Sato Norihiro
    Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation
  • Uchida Keisuke
    Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation
  • Nakajima Mikio
    Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation
  • Watanabe Atsushi
    Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation
  • Kohira Terutomo
    Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation

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  • Collaborative work on evaluation of ovarian toxicity (13) Two- or four-week repeated dose studies and fertility study of PPAR α/γ dual agonist in female rats
  • Collaborative work on evaluation of ovarian toxicity 13 Two or four week repeated dose studies and fertility study of PPAR a g dual agonist in female rats

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The main focus of this study was to determine the optimal dosing period in a repeated dose toxicity study based on toxic effects as assessed by ovarian morphological changes. To assess morphological and functional changes induced in the ovary by a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist, the compound was administered to female rats at dose levels of 0, 4, 20, and 100 mg/kg/day in a repeated dose toxicity study for 2 or 4 weeks, and from 2 weeks prior to mating to Day 7 of pregnancy in a female fertility study. In the repeated dose toxicity study, an increase in atresia of large follicles, a decrease in corpora lutea, and an increase in stromal cells were observed in the treated groups. In addition, the granulosa cell exfoliations into antrum of large follicles and corpora lutea with retained oocyte are morphological characteristics induced by this compound, and they might be related with abnormal condition of ovulation. In the female fertility study, the pregnancy rate tended to decrease in the 100 mg/kg/day group. At necropsy, decreases in the number of corpora lutea, implantations and live embryos were noted in the 20 and 100 mg/kg/day group. No changes were observed in animals given 4 mg/kg/day. These findings indicated that histopathological changes in the ovary are important endpoints for evaluation of drugs inducing ovarian damage. In conclusion, a 2-week administration period is sufficient to detect ovarian toxicity of this test compound in the repeated dose toxicity study.

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