Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive
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Updated: Apr 1, 2026
A Seminiferous Tubule Squash Technique for the Cytological Analysis of Spermatogenesis Using the Mouse Model
Published on: February 6, 2018
Haruhiko Miyata1, Yuhkoh Satouh1, Daisuke Mashiko2
1Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Abstract:
Calcineurin inhibitors, such as cyclosporine A and FK506, are used as immunosuppressant drugs, but their adverse effects on male reproductive function remain unclear. The testis expresses somatic calcineurin and a sperm-specific isoform that contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We demonstrate herein that male mice lacking Ppp3cc or Ppp3r2 genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 creates phenocopies of the sperm motility and morphological defects. These defects appear within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after we discontinued treatment. Because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis.
Insights
Male mice lacking sperm calcineurin genes are infertile. Immunosuppressant drugs cause similar sperm defects, suggesting a reversible male contraceptive targeting sperm calcineurin.
Area of Science:
- Reproductive Biology
- Molecular Biology
- Pharmacology
Background:
- Calcineurin inhibitors like cyclosporine A and FK506 are immunosuppressants.
- Their adverse effects on male reproductive function are not fully understood.
- The testis has somatic calcineurin and a sperm-specific isoform (PPP3CC/PPP3R2).
Purpose of the Study:
- To investigate the role of sperm-specific calcineurin in male fertility.
- To determine the effects of calcineurin inhibitors on sperm function.
- To explore the potential for a reversible male contraceptive.
Main Methods:
- Generation and analysis of mice lacking Ppp3cc or Ppp3r2 genes (knockout mice).
- Treatment of mice with cyclosporine A or FK506.
- Assessment of sperm motility and midpiece morphology.
- Evaluation of fertility recovery after drug withdrawal.
Main Results:
- Ppp3cc or Ppp3r2 knockout mice are infertile with reduced sperm motility and inflexible midpieces.
- Cyclosporine A and FK506 treatment induce similar sperm defects within 4-5 days.
- Sperm midpiece flexibility during epididymal transit depends on sperm-specific calcineurin.
- Male fertility recovered within a week after discontinuing drug treatment.
Conclusions:
- Sperm-specific calcineurin (PPP3CC/PPP3R2) is crucial for sperm motility and midpiece flexibility.
- Calcineurin inhibitors phenocopy the infertility observed in knockout mice.
- Targeting sperm-specific calcineurin offers a potential strategy for a reversible male contraceptive.
