The Antidepressant Sertraline Inhibits CatSper Ca2+ Channels in Human Sperm

Rita Rahban; Anders Rehfeld; Christian Schiffer; Christoph Brenker; Dorte Louise Egeberg Palme; Tao Wang; Johannes Lorenz; Kristian Almstrup; Niels E. Skakkebaek; Timo Strünker; Serge Nef

Disclosures

Hum Reprod. 2021;36(10):2638-2648. 

In This Article

Abstract and Introduction

Abstract

Study Question: Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?

Summary Answer: The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.

What is Known Already: 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.

Main Results and the Role Of Chance: 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.

Wider Implications of the Findings: 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.

Trial Registration Number: NA.

Introduction

Infertility affects 10–15% of couples worldwide (Barratt et al., 2017). Causes can be of male or female origin or due to a combination of both; however, in 15–20% of the cases, infertility remains idiopathic (Nieschlag, 2010; Barratt et al., 2017; Cunningham, 2017). Among the etiological factors involved in infertility, adverse effects of common medications are often neglected in the clinical setting and rather understudied (Jarow et al., 2010; Samplaski and Nangia, 2015; Semet et al., 2017). It is however well known that a plethora of synthetic exogenous compounds affects the function of human sperm in vitro (Gore et al., 2015). Several studies have revealed that diverse endocrine disrupting chemicals (EDCs) activate the sperm-specific Ca2+ channel CatSper (Tavares et al., 2013; Schiffer et al., 2014; Rehfeld et al., 2016; Brenker et al., 2018; Majzoub et al., 2018; Yuan et al., 2020) that controls the intracellular Ca2+ concentration ([Ca2+]i) and, thereby, sperm function (reviewed by Kaupp and Strünker, 2017; Rahban and Nef, 2020; Wang et al., 2021). Physiological stimuli that activate CatSper are depolarization of the membrane potential (Vm), alkalization of the intracellular pH (pHi) as well as steroids and prostaglandins released in the oviduct (Kirichok and Lishko, 2011; Strünker et al., 2011). Activation of CatSper by steroids or prostaglandins has been shown to be implicated in critical sperm functions like capacitation (Sumigama et al., 2015), chemotaxis (Eisenbach and Giojalas, 2006; Publicover et al., 2008), hyperactivation (Alasmari et al., 2013; Williams et al., 2015), penetration into viscous media (Williams et al., 2015; Rennhack et al., 2018; Luo et al., 2019) and acrosomal exocytosis (Tamburrino et al., 2014; Luo et al., 2019). This suggests that exogenous compounds interfering with the activity of CatSper can impair the ability of sperm to reach and fertilize the egg.

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressants in the USA and in Europe (Preskorn, 2004; Dawson et al., 2016). Rates of depressive symptoms are twice as high among infertile couples, and almost 11% of women undergoing IVF are taking SSRIs during the procedure (Dawson et al., 2016; Sylvester et al., 2019). Treatment with SSRIs is usually prescribed for several months and can last up to years, or even a lifetime. Sperm might be exposed to SSRIs in the male reproductive tract, during their journey through the female genital tract, and/or during the fertilization process. SSRIs primarily target serotonin transporters, but off-target actions on voltage-gated Ca2+, Na+ and K+ channels in somatic cells have been described (Choi et al., 1999; Hahn et al., 1999; Lory et al., 2006; Lee et al., 2012, 2016; Kim et al., 2017). Whether SSRIs also affect CatSper is, however, unknown. Here, using kinetic Ca2+ fluorimetry and patch-clamp recordings, we studied the action of SSRIs on human sperm. We show that several SSRIs affect [Ca2+]i and/or suppress progesterone- and prostaglandin-evoked Ca2+ influx, indicating that SSRIs affect the activity of CatSper. In particular, the SSRI Sertraline inhibits in a concentration-dependent fashion ligand-, pHi-, and voltage-activation of human CatSper. Moreover, Sertraline attenuated progesterone- and prostaglandin E1-evoked acrosomal exocytosis and sperm penetration into viscous media. Altogether, we conclude that inhibition of CatSper by antidepressant treatment with SSRIs might impair human fertilization in vivo.

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