title: Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive.
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.
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Miyata
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yuhkoh
authors.initials: Y
authors.lastname: Satouh
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan. Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mashiko
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan. School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masanaga
authors.initials: M
authors.lastname: Muto
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan. Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Nozawa
authors.affiliation: Shimoda Marine Research Center, University of Tsukuba, 5-10-1 Shimoda, Shizuoka 415-0025, Japan.
authors.forename: Kogiku
authors.initials: K
authors.lastname: Shiba
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujihara
authors.affiliation: Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Isotani
authors.affiliation: Shimoda Marine Research Center, University of Tsukuba, 5-10-1 Shimoda, Shizuoka 415-0025, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Inaba
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan. Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan. Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan. ikawa@biken.osaka-u.ac.jp.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004822:Epididymis / Q000166:cytology / Q000187:drug effects; D005298:Fertility / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007248:Infertility, Male / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013081:Sperm Motility / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*; D013737:Testis / Q000187:drug effects / Q000201:enzymology
chemical_list: D065095:Calcineurin Inhibitors; D003272:Contraceptive Agents, Male; C000602830:PPP3R2 protein, mouse; D016572:Cyclosporine; D019703:Calcineurin; C000602854:PPP3CC protein, mouse; D016559:Tacrolimus