Collaborative work on evaluation of ovarian toxicity. 15) Two- or four-week repeated-dose studies and fertility study of bromocriptine in female rats

J Toxicol Sci. 2009:34 Suppl 1:SP157-65. doi: 10.2131/jts.34.s157.

Abstract

The main focus of this study is to determine the optimal administration period concerning toxic effects on ovarian morphological changes in a repeated-dose toxicity study. To assess morphological and functional changes induced in the ovary by bromocriptine, the compound was administered to female rats at dose levels of 0, 0.08, 0.4 and 2 mg/kg for the 2- or 4-week repeated-dose toxicity study, and for the female fertility study from 2 weeks prior to mating to day 7 of gestation. In the 2-week repeated-dose toxicity study, increase of ovarian weights was observed at 2 mg/kg. In the 4-week repeated-dose toxicity study, ovarian weights were increased at 0.4 and 2 mg/kg. The number of corpora luteum was increased in the 0.4 and 2 mg/kg groups of the 2- and 4-week repeated-dose toxicity studies by histopathological examination of the ovaries. Bromocriptine did not affect estrous cyclicity in 2- and 4-week repeated dosing. In the female fertility study, although animals in any groups mated successfully, no females in 0.4 and 2 mg/kg groups were pregnant. There were no adverse effects on reproductive performance in the 0.08 mg/kg group. Based on these findings, the histopathological changes in the ovary are considered important parameters for evaluation of drugs including ovarian damage. We conclude that a 2-week administration period is sufficient to detect ovarian toxicity of bromocriptine in a repeated-dose toxicity study.

MeSH terms

  • Animals
  • Antiparkinson Agents / administration & dosage
  • Antiparkinson Agents / toxicity*
  • Bromocriptine / administration & dosage
  • Bromocriptine / toxicity*
  • Corpus Luteum / drug effects
  • Corpus Luteum / pathology
  • Drug Administration Schedule
  • Estrous Cycle / drug effects
  • Female
  • Fertility / drug effects*
  • Infertility, Female / chemically induced*
  • Infertility, Female / pathology
  • Infertility, Female / physiopathology
  • Japan
  • Longevity / drug effects
  • Male
  • Organ Size / drug effects
  • Ovarian Diseases / chemically induced*
  • Ovarian Diseases / metabolism
  • Ovarian Diseases / pathology
  • Ovary / drug effects*
  • Ovary / metabolism
  • Ovary / pathology
  • Pituitary Gland / drug effects
  • Pituitary Gland / pathology
  • Pregnancy
  • Proliferating Cell Nuclear Antigen / metabolism
  • Public-Private Sector Partnerships
  • Rats
  • Rats, Sprague-Dawley
  • Societies, Scientific
  • Toxicity Tests / methods*

Substances

  • Antiparkinson Agents
  • Proliferating Cell Nuclear Antigen
  • Bromocriptine