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

  • Original Article—Alimentary Tract
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Abstract

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 Nudt15R138C knock-in mice.

Methods

The male Nudt15R138C 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, Nudt15R138C/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 Nudt15R138C/R138C mice compared to Nudt15+/+ and Nudt15+/R138C mice. Apoptotic cells were significantly increased in Nudt15R138C/R138C mice, and most of apoptotic cells were spermatogonia. There were no significant changes in sperm counts and sperm morphology in MP-treated Nudt15R138C/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.

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Acknowledgements

The authors wish to thank DR. Keiji Tomita, Prof. Susumu Kageyama and Prof. Akihiro Kawauchi (Department of Urology, Shiga University of Medical Science) for professional opinions and helpful discussion.

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant number JP23ek0410091 (YK), and in part by a Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan under grant number 22K08054 (AA), and in part by Grants from the Japan Sciences Research Grant for Research on Intractable Diseases (Japanese Inflammatory Bowel Disease Research Group) affiliated with the Japan Ministry of Health, Labour and Welfare under grant number 20FC1027.

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Authors and Affiliations

  1. Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, 520-2192, Japan

    Yoshihiro Yokota, Takayuki Imai, Masahiro Kawahara, Osamu Inatomi, Atsushi Nishida & Akira Andoh

  2. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan

    Yoichi Kakuta & Atsushi Masamune

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  1. Yoshihiro Yokota
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  2. Takayuki Imai
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  8. Akira Andoh
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Contributions

All authors contributed to the study conception and design. Material preparation, performing experiments, data collection and analysis were performed by YY and TI. The first draft of the manuscript was written by YY and AA, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Akira Andoh.

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Conflict of interest

AA receiving lecture fee from Takeda Pharmaceutical Co. Ltd., AbbVie GK, and Miyarisan Pharmaceutical Co. Ltd. YK received patent royalties from Medical & Biological Laboratories Co., Ltd, and lecture fee from Takeda Pharmaceutical Co. Ltd., AbbVie　GK, and Janssen Pharmaceutical K.K. All other authors declare that they have no conflict of interest in this study.

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Yokota, Y., Imai, T., Kawahara, M. et al. Thiopurines exert harmful effects on spermatogenesis in Nudt15R138C knock-in mice. J Gastroenterol 59, 109–118 (2024). https://doi.org/10.1007/s00535-023-02059-7

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  • DOI: https://doi.org/10.1007/s00535-023-02059-7

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