Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive

Science. 2015 Oct 23;350(6259):442-5. doi: 10.1126/science.aad0836. Epub 2015 Oct 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / genetics
  • Calcineurin / physiology*
  • Calcineurin Inhibitors / pharmacology*
  • Contraceptive Agents, Male / pharmacology*
  • Cyclosporine / pharmacology*
  • Epididymis / cytology
  • Epididymis / drug effects
  • Fertility / drug effects*
  • Fertility / genetics
  • HEK293 Cells
  • Humans
  • Infertility, Male / chemically induced*
  • Infertility, Male / enzymology
  • Infertility, Male / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Sperm Motility / drug effects
  • Sperm Motility / genetics
  • Sperm Motility / physiology
  • Spermatozoa / drug effects
  • Spermatozoa / physiology
  • Tacrolimus / pharmacology*
  • Testis / drug effects
  • Testis / enzymology


  • Calcineurin Inhibitors
  • Contraceptive Agents, Male
  • PPP3R2 protein, mouse
  • Cyclosporine
  • Calcineurin
  • PPP3CC protein, mouse
  • Tacrolimus