Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive
Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive
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DOI：
10.1126/science.aad0836
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发表时间：
2015-10-23
期刊：
影响因子：
56.9
通讯作者：
Ikawa, Masahito
中科院分区：
文献类型：
--
作者：
Miyata, Haruhiko;Satouh, Yuhkoh;Ikawa, Masahito
钙调神经磷酸酶抑制剂，如环孢素A和FK506，被用作免疫抑制剂，但其对男性生殖功能的不良影响仍不清楚。睾丸表达体细胞钙调神经磷酸酶和精子特异性亚型，其中包含催化亚基 (PPP3CC) 和调节亚基 (PPP3R2)。我们在此证明，缺乏 Ppp3cc 或 Ppp3r2 基因的雄性小鼠（基因敲除小鼠）是不育的，由于中段不灵活，精子活力降低。用环孢素 A 或 FK506 治疗小鼠会产生精子活力和形态缺陷的表型。这些缺陷在治疗后 4 至 5 天内出现，这表明精子特异性钙调神经磷酸酶在附睾运输过程中赋予中段灵活性。停止治疗一周后，雄性小鼠的生育能力恢复。由于人类精子含有 PPP3CC 和 PPP3R2 作为一种钙调神经磷酸酶，因此抑制这种精子特异性的钙调神经磷酸酶可能会导致开发出一种可逆的男性避孕药，该避孕药将靶向附睾中的精子。
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.