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.
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) alpha/gamma 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.
Sato
Norihiro
N
Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni-shi, Shizuoka, Japan. sato.nc@om.asahi-kasei.co.jp
Uchida
Keisuke
K
Nakajima
Mikio
M
Watanabe
Atsushi
A
Kohira
Terutomo
T
D000818:Animals; D003338:Corpus Luteum / Q000187:drug effects / Q000473:pathology; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D020964:Embryo Loss / Q000139:chemically induced; D004622:Embryo, Mammalian / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007564:Japan; D008297:Male; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D047493:PPAR alpha / Q000819:agonists* / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D011247:Pregnancy; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests / Q000379:methods*; D015430:Weight Gain / Q000187:drug effects
D047493:PPAR alpha; D047495:PPAR gamma; D004364:Pharmaceutical Preparations