3.7. CatSper and Neurotransmitters
In mammals, receptors for many neurotransmitters and neuromodulators (such as acetylcholine, adenosine, adenosine triphosphate, γ-aminobutyric acid, serotonin, norepinephrine, and dopamine) are found in sperm. Therefore, a sperm is regarded as a neuron with a tail
[53,54][53][54]. Interestingly, P4 activates CatSper in human sperm via an unconventional endocannabinoid signaling pathway (P4/ABHD2/2-AG/CatSper)
[31]. In addition, serotonergic signals enhance hamster sperm hyperactivation via CatSper
[55].
3.8. CatSper and Odorant Attractants
Sperm chemotaxis guides sperm toward the oocyte and is closely related to sperm capacitation, hyperactivation, the acrosome reaction, and male fertility. In humans, bourgeonal is a typical odorant and chemoattractant that is proposed to activate olfactory receptors (OR1D2) and to open CatSper to increase [Ca
2+]
i via a G-protein-coupled receptor/olfactory G-protein/cAMP/PKA pathway
[9,56,57][9][56][57]. Moreover, men with idiopathic infertility and low sensitivity to bourgeonal have decreased OR1D2 protein expression and bourgeonal-activated CatSper current in their sperm
[58]. These findings link odor perception to CatSper and male infertility. This sperm odorant attractant may provide a feasible screening method for CatSper-related male infertility.
4. CatSper and Medicines
4.1. CatSper and Traditional Medicine
CatSper is regarded as a primary target for the pharmacological treatment of male infertility and a novel non-hormone target for male contraception. Some traditional medicine has shown promise for improving male infertility through CatSper. Sheng Jing Shan (SJS), a traditional Chinese medicine, has shown efficacy in treating asthenozoospermia. Notably, SJS effectively improved the sperm motility of a rat model of cyclophosphamide (CP)-induced asthenozoospermia by upregulating
Catsper1 expression
[59]. Trigonelline semen (TS), also known as fenugreek, is a natural herbal substance recognized for its ability to improve sperm count and motility in infertile men
[60]. In a rat model of CP-induced male infertility, TS effectively restored sperm count, motility, testosterone levels, and the expression of
Catsper1,
Catsper2,
Catsper3, and
Catsper4 [61].
Panax ginseng, a well-known traditional medicine with multiple pharmacological activities, is beneficial in treating various diseases
[62]. Regarding male fertility, studies have noted that mice treated with
P. ginseng exhibit increased sperm motility and Ca
2+ levels
[63].
P. ginseng significantly increases the expression of
Catsper1,
Catsper2,
Catsper3, and
Catsper4 in mouse sperm
[63]. A recent investigation reported that a natural herb called
Putranjiva roxburghii could effectively upregulate the expression of CatSper genes in bull sperm and markedly boost sperm motility
[64]. In addition, escanbil is a traditional medicine applied to treat abnormal menstruation and menstrual cramps in folk medicine
[65]. It improves sperm motility and alters the expression of CatSper genes in aging mice
[66]. These results suggest that CatSper may be a potential therapeutic agent for natural medicine treatment of male infertility.
4.2. CatSper and Anti-Depressants
Selective serotonin reuptake inhibitors are the most widely used antidepressants in the United States and Europe, but recent research has highlighted their potential to impair male fertility
[71][67]. Researchers have demonstrated that sertraline inhibits CatSper currents induced by intracellular alkalinization, voltage changes, P4, and PGs in human sperm
[72][68]. Sertraline has a significant inhibitory effect on the acrosome reaction and viscous-medium penetration induced by P4 and PGs
[72][68]. These findings suggest that the therapeutic administration of sertraline for depression may impair human reproduction.
4.3. CatSper and 5-Alpha Reductase Inhibitors
Finasteride (FS) and dutasteride (DS), two 5-alpha reductase inhibitors, are widely used to treat benign prostate hyperplasia. However, their prolonged use has been shown to adversely affect male semen quality
[73][69]. FS activates CatSper, at least partially, via PG binding sites, whereas DS activates CatSper, at least partially, through P4 binding sites in human sperm
[74][70]. Thus, they interfere with Ca
2+ signaling mediated by PGs and P4. In addition, the exposure of mice to DS affected sperm count and motility and the expression of CatSper genes in caput and caudal epididymal sperm
[75][71].
4.4. CatSper and Analgesics
Paracetamol is widely used as a mild analgesic to alleviate fever and pain. However, rodent studies have shown that paracetamol may have negative effects on sperm count and motility due to its endocrine effects. Additionally, high concentrations of paracetamol in male urine have been linked to lower sperm motility
[76][72]. In human sperm, paracetamol is metabolized to N-arachidonoylphenolamine via fatty acid amide hydrolase expressed in the sperm neck region. N-arachidonoylphenolamine directly activates human CatSper, reduces sperm motility, and affects viscous-medium penetration
[77][73].
4.5. CatSper and Ca
2+
Channel Blockers
Nifedipine is a Ca
2+ channel blocker and is used as an antihypertensive medicine. It exhibits anti-fertility effects in male rats, resulting in a significant reduction in sperm motility and count
[78][74]. Nifedipine treatment reduces sperm motility and count and substantially downregulates the expression of CatSper genes in mouse epididymal sperm
[75][71]. In addition, RU1968, a steroid-based selective and potent cross-species inhibitor of CatSper, has been demonstrated to suppress the activation of CatSper in human, mouse, and sea urchin sperm
[79][75]. Therefore, nifedipine serves as a powerful tool for the investigation of the physiological function of CatSper in human sperm and for the promotion of the development of non-hormonal male contraceptives.
4.6. CatSper and Phosphodiesterase (PDE)-Inhibitors
Trequinsin hydrochloride, a PDE-3 inhibitor, has emerged as a promising CatSper agonist. In human sperm, trequinsin hydrochloride exhibits a P4-like agonist profile and significantly potentiates the CatSper current, effectively increasing sperm hyperactivation and viscous-medium penetration
[80][76]. Additionally, this CatSper agonist induces a concentration-dependent elevation in Ca
2+ levels through cross-desensitization with PGE1
[80][76].
4.7. CatSper and Anti-Inflammatory Drugs
Cisplatin is the most widely used drug in oncology treatment. However, cisplatin-based treatment of testicular cancer disrupts spermatogenesis and reduces the sperm motility of patients
[81][77]. The indole derivative N′-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide (MMINA) has significant anti-inflammatory and antioxidant effects and can protect against the testicular toxicity induced by cisplatin
[82][78]. Most importantly, MMINA activates CatSper by upregulating the expression of CatSper genes in rat sperm
[83][79]. Moreover, MMINA is capable of forming hydrogen bonds with CatSper
[83][79].
5. CatSper and EDCs
5.1. CatSper and Environmental Estrogens
Initially, EDCs were called xenoestrogens due to their estrogenic, antiestrogenic, androgenic, and antiandrogenic effects
[85][80]. Steviol, a natural non-caloric sweetener metabolite, exerts endocrine effects on human sperm by antagonizing P4 and agonizing CatSper, resulting in a rapid influx of Ca
2+ [86][81]. Bisphenol A (BPA), a ubiquitous EDC and synthetic organic compound, has been significantly and negatively associated with male fertility
[87][82]. BPA binds to estrogen receptors α and β and exhibits estrogenic activity
[88][83]. Animal studies have revealed that BPA impairs sperm function by reducing the expression of CatSper genes and the CatSper current
[89][84]. In GC-2 cells, a mouse spermatogonia cell line, BPA decreased the growth rate and [Ca
2+]
i, and downregulated the expression of
Catsper1,
Catsper2,
Catsper3, and
Catsper4 through Ten-eleven translocation 1
[90][85]. In humans, bisphenol A diglycidyl ether and bisphenol analogs—but not BPA—activate CatSper
[91][86]. Diethylstilbestrol, a well-known, synthetic, non-steroidal estrogen, potentiates CatSper currents, increases the [Ca
2+]
i, and inhibits P4-induced Ca
2+ influx and sperm functions in humans
[92][87]. Perfluorooctane acid, an organic pollutant, activates CatSper to elevate the [Ca
2+]
i in human sperm
[93][88]. Like diethylstilbestrol, perfluorooctane acid suppresses the P4-induced CatSper current, Ca
2+ influx, and sperm functions
[93][88]. In addition, the diversity of EDCs implies that even heavy metals may possess estrogenic activity. Cadmium is considered an EDC with significant toxicity to the reproductive system; it acts as an estrogen mimic and has the ability to bind ERs
[94][89]. Cadmium impairs sperm function via a CatSper-mediated mechanism by affecting the expression of CatSper genes in mice
[95][90].
5.2. CatSper and Pesticides
p,p′-Dichlorodiphenyldichloroethylene, a metabolite of dichloro-diphenyl-trichloroethane commonly found in human reproductive fluids, activates CatSper to induce Ca
2+ entry into sperm and disrupts acrosome reaction
[96][91]. Pentachlorophenol, a widely used pesticide, suppresses the P4-induced CatSper current, Ca
2+ influx, and sperm functions in humans
[97][92]. Recently, a study investigated the effect of 53 pesticides and pesticide metabolites on human sperm. The results demonstrated that, although 26 pesticides activated CatSper and interfered with signaling triggered by P4 and PGs, they may interact with the unique binding sites or the P4 and PG binding sites of CatSper
[98][93]. Thus, pesticides, either alone or in low-dose mixtures, have the potential to negatively affect sperm function by interfering with normal Ca
2+ signaling in human sperm via CatSper.
5.3. CatSper and Chemical Ultraviolet (UV) Filters
Chemical UV filters, commonly present in daily-use sunscreens, are among the most potent triggers of Ca
2+ signaling. They directly activate CatSper in human sperm and elevate [Ca
2+]
i [84][94]. A recent study investigated the effect of 31 chemical UV filters approved in the European Union and the United States on human sperm. Although 29 of the 31 chemical UV filters induced Ca
2+ signaling in human sperm, only nine of these chemicals could activate CatSper, including 4-Methylbenzylidene camphor, 3-Benzylidene camphor, meradimate, amiloxate, octisalate, benzylidene camphor sulfonic acid, homosalate, benzophenone-3, and octinoxate
[99][95]. Of these chemicals, 3-Benzylidene camphor, benzylidene camphor sulfonic acid, and 4-Methylbenzylidene camphor have been found to competitively inhibit P4-induced Ca
2+ signaling and target its binding sites in CatSper
[84,99][94][95]. These results suggest that some chemical UV filters have the potential to interfere with P4-induced Ca
2+ signaling and negatively affect sperm functions.
6. CatSper and Drugs of Abuse
Interestingly, some addictive drugs affect sperm functions through CatSper. Methamphetamine (METH) is a highly addictive central nervous system stimulant that has detrimental effects on male reproductive health, including impaired spermatogenesis, testicular damage, and abnormal sperm quality
[100][96]. In particular, a novel investigation showed that rats receiving METH resulted in a decrease in testis and epididymis weight
[101][97]. Meanwhile, the relative expression levels of
Catsper1,
Catsper2,
Catsper3, and
Catsper4, as well as the sperm motility associated gene
Mvh, were decreased significantly
[101][97]. In addition, the exclusive expression of
Catsper1–4 in testes is required for sperm motility and fertility
[21,102][21][98]. As a result, the downregulation of these genes induced by METH increases the possibility of male infertility. Therefore, men addicted to METH may encounter potential reproductive problems.
Ketamine, a dissociative anesthetic widely used in human and animal medicine, has become a popular recreational drug because it can induce hallucinatory effects. ketamine affects sperm motility, viscous-medium penetration, and the P4-induced acrosome reaction by inhibiting CatSper in human sperm, thus decreasing [Ca
2+]
i [103][99]. In addition, ketamine is an antagonist of the N-Methyl-D-aspartic acid (NMDA) receptor. The NMDA receptor is expressed in human sperm and involved in the inhibitory effect of ketamine on human sperm functions
[104][100]. Specifically, NMDA, the physiological ligand of NMDA, could partly alleviate the motility of human sperm and significantly recover the capacitation and acrosome reaction, as well as [Ca
2+]
i [104][100]. Therefore, the competitive receptor binding between ketamine and NMDA may provide novel insight for clinical diagnoses of ketamine abusers. Collectively, CatSper-related drugs of abuse have been implicated in impaired sperm function and/or male infertility.
7. CatSper and Antioxidants
Oxidative stress occurs when the generation of reactive oxygen species (ROS) exceeds the natural antioxidant defenses of bodies. Thus, the precise balance of ROS and antioxidants within sperm are necessary for capacitation and fertilization. The major effect of oxidative stress compromising sperm function is caused by two principal mechanisms, DNA damage and lipid peroxidation
[105][101]. In human sperm, ROS damages DNA directly by the production of 1,N
6-ethenoadenosine and 1,N
2-ethenoguanosine, resulting in DNA structure instability and leading to single-strand breaks
[106][102]. Once the transcription and translation of post-spermiogenesis stop, the DNA repair during developing sperm is terminated
[107][103]. Hence, sperm function and pregnancy outcome are strongly impacted.
To counteract ROS damage, the human body has developed a variety of antioxidant strategies. For instance, non-enzymatic antioxidants contained within the seminal fluid, like vitamin E and selenium
[108][104]. Interestingly, treatment with these two antioxidants upregulates the expression of
Catsper in the testes of young adult and aged male mice, which are the genes responsible for sperm motility
[109,110][105][106]. Meanwhile, sperm parameters such as viability rate and morphology also show an improvement after treatment
[109,110][105][106]. Consequently, these two essential components play a crucial role in the maintenance of male reproduction.