Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
Swiss Centre for Applied Human Toxicology, Basel, Switzerland.
Hum Reprod. 2021 Sep 18;36(10):2638-2648. doi: 10.1093/humrep/deab190.
Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?
The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.
In human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown.
STUDY DESIGN, SIZE, DURATION: We studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test.
Several SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media.
LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study. Future studies have to assess the physiological relevance in vivo.
The off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l'Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.
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选择性 5-羟色胺再摄取抑制剂（SSRIs）类抗抑郁药是否会影响人类精子的功能？
SSRIs 类抗抑郁药舍曲林（如左洛复）抑制人精子特异性 Ca2+ 通道 CatSper，并影响体外人类精子功能。
在人类精子中，CatSper 将化学微环境的变化转化为细胞内 Ca2+ 浓度 ([Ca2+]i) 的变化和游动行为的变化。CatSper 被输卵管配体非特异地激活，但也被可能干扰受精过程的合成化学物质激活。众所周知，SSRIs 对体细胞中的 Ca2+、Na+ 和 K+ 通道具有非靶向作用。然而，SSRIs 是否影响 CatSper 的活性尚不清楚。
研究设计、规模、持续时间：我们研究了属于最常开处方的抗抑郁药类别的七种药物对人精子中 CatSper 的静息 [Ca2+]i 和 CatSper 介导的 Ca2+ 内流的作用。选择 SSRIs 舍曲林进行深入分析，研究其对甾体、前列腺素、pH 值和电压激活的人 CatSper 的作用。此外，还评估了舍曲林对精子顶体反应和穿透粘性介质的作用。
参与者/材料、设置、方法：使用动力学 Ca2+ 荧光法和膜片钳记录技术研究健康志愿者精子中的 CatSper 活性。使用豌豆凝集素和图像细胞术研究顶体反应。使用 Kremer 试验评估精子在粘性介质中的穿透能力。
几种 SSRIs 影响 [Ca2+]i 并减弱配体诱导的 CatSper 介导的 Ca2+ 内流。特别是，SSRIs 舍曲林几乎完全抑制 CatSper 介导的 Ca2+ 内流。值得注意的是，该药物对前列腺素诱导的 Ca2+ 内流的抑制作用比甾体诱导的 Ca2+ 内流强约四倍。舍曲林还抑制碱性和电压激活的 CatSper，表明该药物直接抑制该通道。最后，舍曲林损害配体诱导的顶体反应和精子穿透粘性介质。
局限性、谨慎的原因：这是一项体外研究。未来的研究必须评估体内的生理相关性。
舍曲林对人精子中 CatSper 的非靶向作用可能会损害受精过程。在研究环境中，舍曲林可用于选择性抑制前列腺素诱导的 Ca2+ 内流。
研究资金/竞争利益：这项工作得到了瑞士应用人类毒理学中心 (SCAHT)、日内瓦州教育部、德国研究基金会 (CRU326)、明斯特多学科临床研究中心 (IZKF; Str/014/21)、丹麦创新基金 (14-2013-4 号) 和 Kirsten 和 Freddy Johansen 基金会的 EDMaRC 研究赠款的支持。作者声明，没有任何利益冲突会被视为损害研究报告的公正性。
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