Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive

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Science  01 Oct 2015:
DOI: 10.1126/science.aad0836

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Calcineurin inhibitors, 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 Ppp3cc and Ppp3r2 knockout male mice are infertile with reduced sperm motility due to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 phenocopies the sperm motility and morphological defects. These defects appear within 4-5 days of treatment indicating that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Mouse male fertility recovered a week after discontinuing treatment. Since human spermatozoa contain PPP3CC/PPP3R2 as a functional calcineurin, inhibition of sperm-specific calcineurin may lead to the development of a reversible male contraceptive targeting spermatozoa in the epididymis.

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