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Updated: May 14, 2026
Contractility Measurements of Human Uterine Smooth Muscle to Aid Drug Development
Published on: January 26, 2018
The inhibin B response to a motilin receptor agonist in male rats
Mary K Ziejewski1, Justin D Vidal, Dinesh Stanislaus
1Department of Safety Assessment, Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, PA 19406, USA.
Background:
In a repeat oral dose toxicity study, all of 16 male rats given 100 mg/kg/day GSK1322888 sustained testicular injury after 4 weeks of treatment; the findings were not reversible after 12 weeks off-dose. The current study was conducted to further characterize testicular toxicity and to explore the possible relationship between onset of lesions, and changes in circulating hormone levels.
Methods:
Male Sprague Dawley rats were orally administered 30 or 100 mg/kg/day GSK1322888 for 2 weeks with a 4-week off-dose period. Blood was collected via tail vein twice during the treatment period (days 4 and 11) and three times during the off-dose period (days 28, 36, and 42) for measurement of serum testosterone, dihydrotestosterone, and Inhibin B, luteinizing hormone, and follicle stimulating hormone concentrations. A histopathologic examination of testes was performed at the end of the treatment and off-dose periods.
Results:
At 100 mg/kg/day, microscopic findings of the testis (degeneration of the germinal epithelium) were evident for 9 of 10 male rats on day 14 and all 10 rats at the end of the 4-week recovery period. There was no testicular toxicity observed at 30 mg/kg/day. During all stages of evaluation, there was no apparent difference among control and treated animals in hormone concentrations.
Conclusion:
There was poor correlation between changes in serum levels of Inhibin B and testis histopathology. Based on these observations, the utility of Inhibin B as a hormonal marker for germ cell toxicity is limited.
Insights
High doses of GSK1322888 caused irreversible testicular injury in male rats. Hormone levels, including Inhibin B, did not correlate with observed testicular toxicity, limiting their use as biomarkers.
Area of Science:
- Toxicology
- Reproductive toxicology
- Pharmacology
Background:
- A previous study indicated testicular injury in male rats following 4 weeks of 100 mg/kg/day GSK1322888, with no reversibility after 12 weeks.
- This study aimed to further characterize the testicular toxicity of GSK1322888 and investigate potential links between lesion development and hormonal changes.
Purpose of the Study:
- To evaluate the dose-dependent testicular toxicity of GSK1322888 in male Sprague Dawley rats.
- To assess the correlation between serum hormone levels (testosterone, dihydrotestosterone, Inhibin B, luteinizing hormone, follicle stimulating hormone) and testicular histopathology following GSK1322888 administration.
Main Methods:
- Male Sprague Dawley rats received oral doses of 30 or 100 mg/kg/day GSK1322888 for 2 weeks, followed by a 4-week off-dose period.
- Serum hormone concentrations were measured at multiple time points during treatment and recovery.
- Testicular histopathology was examined at the end of the treatment and recovery periods.
Main Results:
- Testicular degeneration of the germinal epithelium was observed in 90% of rats at 100 mg/kg/day by day 14 and in all rats after the 4-week recovery period.
- No testicular toxicity was evident at the 30 mg/kg/day dose.
- No significant differences in serum hormone concentrations were observed between control and GSK1322888-treated groups.
Conclusions:
- GSK1322888 at 100 mg/kg/day causes significant and persistent testicular germinal epithelium degeneration in male rats.
- Serum hormone levels, including Inhibin B, did not show a correlation with the observed testicular histopathology.
- The utility of Inhibin B as a predictive biomarker for GSK1322888-induced germ cell toxicity is limited.
