The Role of Zinc in Male Fertility

Abstract

Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn2+ in spermatozoa, focusing on its involvement in sperm motility, capacitation and acrosomal exocytosis, three functions that are crucial for successful fertilization. The impact of zinc supplementation on assisted fertilization techniques is also described. The impact of zinc on sperm motility has been investigated in many vertebrate and invertebrate species. It has been reported that Zn2+ in human seminal plasma decreases sperm motility and that Zn2+ removal enhances motility. Reduction in the intracellular concentration of Zn2+ during epididymal transit allows the development of progressive motility and the subsequent hyper activated motility during sperm capacitation. Extracellular Zn2+ affects intracellular signaling pathways through its interaction with the Zn2+ sensing receptor (ZnR), also named GPR39. This receptor was found in the sperm tail and the acrosome, suggesting the possible involvement of Zn2+ in sperm motility and acrosomal exocytosis. Our studies showed that Zn2+ stimulates bovine sperm acrosomal exocytosis, as well as human sperm hyper-activated motility, were both mediated by GPR39. Zn2+ binds and activates GPR39, which activates the trans-membrane-adenylyl-cyclase (tmAC) to catalyze cAMP production. The NHE (Na+/H+-exchanger) is activated by cAMP, leading in increased pHi and activation of the sperm-specific Ca2+ channel CatSper, resulting in an increase in [Ca2+]i, which, together with HCO3−, activates the soluble adenylyl-cyclase (sAC). The increase in [cAMP]i activates protein kinase A (PKA), followed by activation of the Src-epidermal growth factor receptor-Pphospholipase C (Src-EGFR-PLC) cascade, resulting in inositol-triphosphate (IP3) production, which mobilizes Ca2+ from the acrosome, causing a further increase in [Ca2+]i and the development of hyper-activated motility. PKA also activates phospholipase D1 (PLD1), leading to F-actin formation during capacitation. Prior to the acrosomal exocytosis, PLC induces phosphadidylinositol-4,5-bisphosphate (PIP2) hydrolysis, leading to the release of the actin-severing protein gelsolin to the cytosol, which is activated by Ca2+, resulting in F-actin breakdown and the occurrence of acrosomal exocytosis.

The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm

“…The Zn 2+ inhibition of prostaglandin activation of CatSper tapers off upon dilution of the seminal fluid, which might ensure that CatSper is activated only when sperm start escaping from the ejaculate into the female genital tract. In fact, the action of Zn 2+ in sperm and its role during fertilization are complex and only ill-defined ( Allouche-Fitoussi and Breitbart, 2020 ). It has been reported that seminal Zn 2+ decreases sperm motility and that the motility is stimulated only upon its removal ( Allouche-Fitoussi and Breitbart, 2020 ); in sperm purified from the ejaculate, stimulation with low micromolar Zn 2+ concentrations evoked hyperactivated motility ( Allouche-Fitoussi et al, 2018 ; Allouche-Fitoussi and Breitbart, 2020 ).…”

“…In fact, the action of Zn 2+ in sperm and its role during fertilization are complex and only ill-defined ( Allouche-Fitoussi and Breitbart, 2020 ). It has been reported that seminal Zn 2+ decreases sperm motility and that the motility is stimulated only upon its removal ( Allouche-Fitoussi and Breitbart, 2020 ); in sperm purified from the ejaculate, stimulation with low micromolar Zn 2+ concentrations evoked hyperactivated motility ( Allouche-Fitoussi et al, 2018 ; Allouche-Fitoussi and Breitbart, 2020 ). Our results suggest an even more complex control of motility by a Zn 2+ /prostaglandin interplay, which needs to be scrutinized in future studies that investigate the motility responses of sperm upon dilution from the ejaculate and/or upon stimulation with dilutions of Zn 2+ /prostaglandin mixtures.…”

Pronounced Trace Element Variation in Follicular Fluids of Subfertile Women Undergoing Assisted Reproduction

“…Experimental and clinical studies indicate that growth and fertility are strongly affected by trace element (TE) supply, and deficiencies are known to impair both male and female gametogenesis as well as embryonic development [14][15][16][17][18]. In particular, the trace elements copper (Cu), selenium (Se), and zinc (Zn) have emerged as the most essential micronutrients for both female and male fertility [19][20][21][22][23].…”

A Comparative Analysis of the Altered Levels of Human Seminal Plasma Constituents as Contributing Factors in Different Types of Male Infertility

“…Besides analytes and enzymes, trace elements were also investigated as these act as cofactors and are essential for spermatogenesis by maintaining oxidative stress levels [39,40]. In our study, levels of three trace elements-sodium, zinc, and calcium-were examined.…”