Effect of metronidazole on fertility and testicular function in male rats

The reproductive toxicology of metronidazole was studied in rats. Male Charles River Crl:CD(SD)BR rats (10/group) were treated with metronidazole as a dietary admixture at doses of 0 (control), 25, 100, and 400 mg/kg/day for 8 weeks. The reversibility of effects after a 3 1/2-month recovery period was determined in separate groups of 10 control and 10 rats treated with 400 mg/kg/day of metronidazole. After 2 and 4 weeks of metronidazole treatment, mating performance and fertility in treated and control animals were comparable. After 6 weeks of treatment, all high-dose rats were infertile; however, fertility in low- and middose rats was not affected. High-dose male rats killed after 8 weeks of treatment showed markedly decreased testicular and epididymal weights, and markedly decreased testicular spermatid counts and epididymal sperm counts. Most of the few epididymal sperm present in high-dose rats were viable, but morphologically abnormal. Histologically, severe degeneration of the seminiferous epithelium was observed in the testes of high-dose rats; the tubules were generally devoid of primary or secondary spermatocytes and spermatids. Rats treated with the low and middle doses of metronidazole exhibited normal testicular and epididymal weights, and normal testicular spermatid counts and epididymal sperm reserves. Epididymal sperm viability and morphology of treated and control animals were comparable. Minimal histologic changes were observed in the testes of middose rats, including degenerative fragmentation of spermatozoa and spermatids. In high-dose recovery rats, fertility was restored in most rats by 8 weeks after the cessation of treatment; however, the testicular and epididymal weights and sperm counts of rats killed after 3 1/2 months of recovery had increased but were still significantly decreased in treated rats as compared with controls. Histologically, spermatogenesis was observed in most tubules; however, a portion of atrophic tubules persisted. It is concluded that high doses of metronidazole produce infertility in the male rat through inhibition of spermatogenesis as early as the stage of the primary spermatocyte. This effect is partially reversible.