Thiopurines exert harmful effects on spermatogenesis in Nudt15R138C knock-in mice

Background: The association between thiopurine use and testicular reproductive functions remains unclear. In this study, we investigated whether thiopurines affect testicular functions based on the NUDT15 genotypes using Nudt15(R138C) knock-in mice.Methods: The male Nudt15(R138C) knock-in mice (9-12 weeks) were treated with mercaptopurine (MP: 0.5 mg/kg/day) for 4 or 12 weeks. To examine reversibility, some mice were maintained for a further 12 weeks under MP-free condition.Results: After MP treatment for 4 weeks, Nudt15(R138C/R138C) mice exhibited a significant reduction of testis weight compared to Nudt15(+/+) mice and Nudt15(+/R138C) mice. The epithelial height and diameter of seminiferous tubules were significantly reduced in Nudt15(R138C/R138C) mice compared to Nudt15(+/+) and Nudt15(+/R138C) mice. Apoptotic cells were significantly increased in Nudt15(R138C/R138C) mice, and most of apoptotic cells were spermatogonia. There were no significant changes in sperm counts and sperm morphology in MP-treated Nudt15(R138C/R138C) mice after 4-week MP treatment. On the other hand, after MP treatment for 12 weeks, the Nudt15(+/R138C) mice, but not Nudt15(+/+) mice, exhibited a significant reduction in the testis weight and atrophic changes of seminiferous tubules, but these changes disappeared after 12-week rearing under MP-free condition. Despite a significant increase in abnormal sperm rate, there were no changes in the ability to conceive. No differences in serum levels of follicle-stimulating hormone or testosterone were observed between MP-treated Nudt15(+/R138C) and Nudt15(+/+) mice after 12-week MP treatment.Conclusions: Thiopurines exert harmful effects on testicular reproductive function according to host NUDT15 genotypes.

Automated summary

Thiopurines have harmful effects on testicular reproductive function according to host NUDT15 genotypes.