An innovative investigative approach to characterize the effects observed in a combined fertility study in male and female rats

Publication date: Available online 7 April 2018 Source:Regulatory Toxicology and Pharmacology Author(s): Jianxun Xie, Juergen Funk, Martin Bopst, Giorgio Ottaviani, Noel Downes, Scott Hackford, Loris Villabruna, Georg Schmitt, Paul Barrow This paper describes the characterization of male- and female-mediated effects in a standard ICH rat fertility and early embryonic development study with a discontinued clinical small molecule. In the standard study, the test item had no effect on the number of treated females becoming pregnant, but litter sizes were reduced at the high dose level. In the treated male rats, increased incidences of abnormal sperm, decreases in average sperm path and straight line velocities, and minimal retention of mature sperm in the seminiferous tubules were observed at all dose-levels tested. These findings were unexpected in view of a lack of histopathological changes in the reproductive organs of either gender in 4-week repeat dose studies in rats and monkeys. A follow-up fertility study was conducted using an innovative flexible study design and a single high-dose level. In the first instance, treated male rats were mated with untreated females, followed by necropsy of a subset of males. The intention was then to re-mate the males after an 8-week wash-out period with either treated or untreated females depending on the outcome of the first mating. On this occasion, litter sizes were not affected, but the testicular effects were reproduced. A...
Source: Regulatory Toxicology and Pharmacology - Category: Toxicology Source Type: research