The Inhibin B Response to a Motilin Receptor Agonist in Male Rats

Authors

  • Mary K. Ziejewski,

    1. Department of Safety Assessment, Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
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  • Justin D. Vidal,

    1. Department of Safety Assessment, Pathology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
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  • Dinesh Stanislaus,

    1. Department of Safety Assessment, Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
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  • April Apostoli,

    1. Department of Safety Assessment, Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
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  • Probash Chowdhury,

    1. Department of Safety Assessment, Toxicology, GlaxoSmithKline Research & Development, Ware, United Kingdom
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  • Susan Laffan

    Corresponding author
    • Department of Safety Assessment, Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
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Correspondence to: Susan Laffan, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406. E-mail: susan.b.laffan@gsk.com

Abstract

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.

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