International Journal of Molecular Sciences

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14 pages, 34071 KiB

Open AccessArticle

Cabs1 Maintains Structural Integrity of Mouse Sperm Flagella during Epididymal Transit of Sperm

by Xiaoning Zhang, Wenwen Zhou, Peng Zhang, Fengxin Gao, Xiuling Zhao, Winnie Waichi Shum and Xuhui Zeng

Int. J. Mol. Sci. 2021, 22(2), 652; https://doi.org/10.3390/ijms22020652 - 11 Jan 2021

Cited by 9 | Viewed by 3168

Abstract

The calcium-binding protein spermatid-associated 1 (Cabs1) is a novel spermatid-specific protein. However, its function remains largely unknown. In this study, we found that a long noncoding RNA (lncRNA) transcripted from the Cabs1 gene antisense, AntiCabs1, was also exclusively expressed in spermatids. Cabs1 [...] Read more.

The calcium-binding protein spermatid-associated 1 (Cabs1) is a novel spermatid-specific protein. However, its function remains largely unknown. In this study, we found that a long noncoding RNA (lncRNA) transcripted from the Cabs1 gene antisense, AntiCabs1, was also exclusively expressed in spermatids. Cabs1 and AntiCabs1 knockout mice were generated separately (using Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas9 methods) to investigate their functions in spermatogenesis. The genetic loss of Cabs1 did not affect testicular and epididymal development; however, male mice exhibited significantly impaired sperm tail structure and subfertility. Ultrastructural analysis revealed defects in sperm flagellar differentiation leading to an abnormal annulus and disorganization of the midpiece–principal piece junction, which may explain the high proportion of sperm with a bent tail. Interestingly, the proportion of sperm with a bent tail increased during transit in the epididymis. Furthermore, Western blot and immunofluorescence analyses showed that a genetic loss of Cabs1 decreased Septin 4 and Krt1 and increased cyclin Y-like 1 (Ccnyl1) levels compared with the wild type, suggesting that Cabs1 deficiency disturbed the expression of cytoskeleton-related proteins. By contrast, AntiCabs1^−/− mice were indistinguishable from the wild type regarding testicular and epididymal development, sperm morphology, concentration and motility, and male fertility. This study demonstrates that Cabs1 is an important component of the sperm annulus essential for proper sperm tail assembly and motility. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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10 pages, 1468 KiB

Open AccessArticle

Copper(II) Binding by the Earliest Vertebrate Gonadotropin-Releasing Hormone, the Type II Isoform, Suggests an Ancient Role for the Metal

by Lorraine Peacey, Charlotte Peacey, Adele Gutzinger and Christopher E. Jones

Int. J. Mol. Sci. 2020, 21(21), 7900; https://doi.org/10.3390/ijms21217900 - 24 Oct 2020

Cited by 2 | Viewed by 2002 | Correction

Abstract

In vertebrate reproductive biology copper can influence peptide and protein function both in the pituitary and in the gonads. In the pituitary, copper binds to the key reproductive peptides gonadotropin-releasing hormone I (GnRH-I) and neurokinin B, to modify their structure and function, and [...] Read more.

In vertebrate reproductive biology copper can influence peptide and protein function both in the pituitary and in the gonads. In the pituitary, copper binds to the key reproductive peptides gonadotropin-releasing hormone I (GnRH-I) and neurokinin B, to modify their structure and function, and in the male gonads, copper plays a role in testosterone production, sperm morphology and, thus, fertility. In addition to GnRH-I, most vertebrates express a second isoform, GnRH-II. GnRH-II can promote testosterone release in some species and has other non-reproductive roles. The primary sequence of GnRH-II has remained largely invariant over millennia, and it is considered the ancestral GnRH peptide in vertebrates. In this work, we use a range of spectroscopic techniques to show that, like GnRH-I, GnRH-II can bind copper. Phylogenetic analysis shows that the proposed copper-binding ligands are retained in GnRH-II peptides from all vertebrates, suggesting that copper-binding is an ancient feature of GnRH peptides. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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13 pages, 1385 KiB

Open AccessReview

IP3R Channels in Male Reproduction

by Xiaoning Zhang, Rongzu Huang, Yang Zhou, Wenwen Zhou and Xuhui Zeng

Int. J. Mol. Sci. 2020, 21(23), 9179; https://doi.org/10.3390/ijms21239179 - 2 Dec 2020

Cited by 11 | Viewed by 3719

Abstract

As a second messenger in cellular signal transduction, calcium signaling extensively participates in various physiological activities, including spermatogenesis and the regulation of sperm function. Abnormal calcium signaling is highly correlated with male infertility. Calcium signaling is mainly regulated by both extracellular calcium influx [...] Read more.

As a second messenger in cellular signal transduction, calcium signaling extensively participates in various physiological activities, including spermatogenesis and the regulation of sperm function. Abnormal calcium signaling is highly correlated with male infertility. Calcium signaling is mainly regulated by both extracellular calcium influx and the release of calcium stores. Inositol 1,4,5-trisphosphate receptor (IP3R) is a widely expressed channel for calcium stores. After being activated by inositol 1,4,5-trisphosphate (IP3) and calcium signaling at a lower concentration, IP3R can regulate the release of Ca²⁺ from stores into cytoplasm, and eventually trigger downstream events. The closure of the IP3R channel caused by a rise in intracellular calcium signals and the activation of the calcium pump jointly restores the calcium store to a normal level. In this review, we aim to discuss structural features of IP3R channels and the underlying mechanism of IP3R channel-mediated calcium signaling and further focus on the research progress of IP3R expression and function in the male reproductive system. Finally, we propose key directions and strategies for research of IP3R in spermatogenesis and the regulation of sperm function to provide more understanding of the function and mechanism of IP3R channel actions in male reproduction. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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16 pages, 2734 KiB

Open AccessReview

Molecular Regulation of Copper Homeostasis in the Male Gonad during the Process of Spermatogenesis

by Sylwia Herman, Paweł Lipiński, Mateusz Ogórek, Rafał Starzyński, Paweł Grzmil, Aleksandra Bednarz and Małgorzata Lenartowicz

Int. J. Mol. Sci. 2020, 21(23), 9053; https://doi.org/10.3390/ijms21239053 - 28 Nov 2020

Cited by 16 | Viewed by 3564

Abstract

Owing to its redox properties, copper is a cofactor of enzymes that catalyze reactions in fundamental metabolic processes. However, copper–oxygen interaction, which is a source of toxic oxygen radicals generated by the Fenton reaction, makes copper a doubled-edged-sword in an oxygen environment. Among [...] Read more.

Owing to its redox properties, copper is a cofactor of enzymes that catalyze reactions in fundamental metabolic processes. However, copper–oxygen interaction, which is a source of toxic oxygen radicals generated by the Fenton reaction, makes copper a doubled-edged-sword in an oxygen environment. Among the microelements influencing male fertility, copper plays a special role because both copper deficiency and overload in the gonads worsen spermatozoa quality and disturb reproductive function in mammals. Male gametes are produced during spermatogenesis, a multi-step process that consumes large amounts of oxygen. Germ cells containing a high amount of unsaturated fatty acids in their membranes are particularly vulnerable to excess copper-mediated oxidative stress. In addition, an appropriate copper level is necessary to initiate meiosis in premeiotic germ cells. The balance between essential and toxic copper concentrations in germ cells at different stages of spermatogenesis and in Sertoli cells that support their development is handled by a network of copper importers, chaperones, recipient proteins, and exporters. Here, we describe coordinated regulation/functioning of copper-binding proteins expressed in germ and Sertoli cells with special emphasis on copper transporters, copper transporting ATPases, and SOD1, a copper-dependent antioxidant enzyme. These and other proteins assure copper bioavailability in germ cells and protection against copper toxicity. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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18 pages, 1146 KiB

Open AccessReview

Regulation of Male Fertility by the Renin-Angiotensin System

by Marta Gianzo and Nerea Subirán

Int. J. Mol. Sci. 2020, 21(21), 7943; https://doi.org/10.3390/ijms21217943 - 26 Oct 2020

Cited by 19 | Viewed by 4100

Abstract

The renin-angiotensin system (RAS) is a peptidic system known mainly for its roles in the maintenance of blood pressure and electrolyte and fluid homeostasis. However, several tissues and cells have been described to possess an intrinsic RAS that acts locally through different paracrine [...] Read more.

The renin-angiotensin system (RAS) is a peptidic system known mainly for its roles in the maintenance of blood pressure and electrolyte and fluid homeostasis. However, several tissues and cells have been described to possess an intrinsic RAS that acts locally through different paracrine and autocrine mechanisms. In the male reproductive system, several components of this system have been observed in various organs and tissues, such as the testes, spermatozoa and seminal fluid. Some functions attributed to this local RAS are maintenance of seminal plasma electrolytes, regulation of steroidogenesis and spermatogenesis, and sperm functions. However, their specific actions in these locations are not fully understood. Therefore, a deep knowledge of the functions of the RAS at both the testicular and seminal levels could clarify its roles in male infertility and sperm physiology, and the different RAS elements could be used to design tools enabling the diagnosis and/or treatment of male infertility. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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15 pages, 481 KiB

Open AccessReview

The Role of Zinc in Male Fertility

by Deborah Allouche-Fitoussi and Haim Breitbart

Int. J. Mol. Sci. 2020, 21(20), 7796; https://doi.org/10.3390/ijms21207796 - 21 Oct 2020

Cited by 54 | Viewed by 9553

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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19 pages, 977 KiB

Open AccessReview

Approaches and Technologies in Male Fertility Preservation

by Mahmoud Huleihel and Eitan Lunenfeld

Int. J. Mol. Sci. 2020, 21(15), 5471; https://doi.org/10.3390/ijms21155471 - 31 Jul 2020

Cited by 19 | Viewed by 3800

Abstract

Male fertility preservation is required when treatment with an aggressive chemo-/-radiotherapy, which may lead to irreversible sterility. Due to new and efficient protocols of cancer treatments, surviving rates are more than 80%. Thus, these patients are looking forward to family life and fathering [...] Read more.

Male fertility preservation is required when treatment with an aggressive chemo-/-radiotherapy, which may lead to irreversible sterility. Due to new and efficient protocols of cancer treatments, surviving rates are more than 80%. Thus, these patients are looking forward to family life and fathering their own biological children after treatments. Whereas adult men can cryopreserve their sperm for future use in assistance reproductive technologies (ART), this is not an option in prepubertal boys who cannot produce sperm at this age. In this review, we summarize the different technologies for male fertility preservation with emphasize on prepubertal, which have already been examined and/or demonstrated in vivo and/or in vitro using animal models and, in some cases, using human tissues. We discuss the limitation of these technologies for use in human fertility preservation. This update review can assist physicians and patients who are scheduled for aggressive chemo-/radiotherapy, specifically prepubertal males and their parents who need to know about the risks of the treatment on their future fertility and the possible present option of fertility preservation. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)

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27 pages, 417 KiB

Open AccessReview

External and Genetic Conditions Determining Male Infertility

by Piotr Kamiński, Jędrzej Baszyński, Izabela Jerzak, Brendan P. Kavanagh, Ewa Nowacka-Chiari, Mateusz Polanin, Marek Szymański, Alina Woźniak and Wojciech Kozera

Int. J. Mol. Sci. 2020, 21(15), 5274; https://doi.org/10.3390/ijms21155274 - 24 Jul 2020

Cited by 27 | Viewed by 5272

Abstract

We explain environmental and genetic factors determining male genetic conditions and infertility and evaluate the significance of environmental stressors in shaping defensive responses, which is used in the diagnosis and treatment of male infertility. This is done through the impact of external and [...] Read more.

We explain environmental and genetic factors determining male genetic conditions and infertility and evaluate the significance of environmental stressors in shaping defensive responses, which is used in the diagnosis and treatment of male infertility. This is done through the impact of external and internal stressors and their instability on sperm parameters and their contribution to immunogenetic disorders and hazardous DNA mutations. As chemical compounds and physical factors play an important role in the induction of immunogenetic disorders and affect the activity of enzymatic and non-enzymatic responses, causing oxidative stress, and leading to apoptosis, they downgrade semen quality. These factors are closely connected with male reproductive potential since genetic polymorphisms and mutations in chromosomes 7, X, and Y critically impact on spermatogenesis. Microdeletions in the Azoospermic Factor AZF region directly cause defective sperm production. Among mutations in chromosome 7, impairments in the cystic fibrosis transmembrane conductance regulator CFTR gene are destructive for fertility in cystic fibrosis, when spermatic ducts undergo complete obstruction. This problem was not previously analyzed in such a form. Alongside karyotype abnormalities AZF microdeletions are the reason of spermatogenic failure. Amongst AZF genes, the deleted in azoospermia DAZ gene family is reported as most frequently deleted AZF. Screening of AZF microdeletions is useful in explaining idiopathic cases of male infertility as well as in genetic consulting prior to assisted reproduction. Based on the current state of research we answer the following questions: (1) How do environmental stressors lessen the quality of sperm and reduce male fertility; (2) which chemical elements induce oxidative stress and immunogenetic changes in the male reproductive system; (3) how do polymorphisms correlate with changes in reproductive potential and pro-antioxidative mechanisms as markers of pathophysiological disturbances of the male reproductive condition; (4) how do environmental stressors of immunogenetic disorders accompany male infertility and responses; and (5) what is the distribution and prevalence of environmental and genetic risk factors. Full article

(This article belongs to the Special Issue Trace Elements and Male Fertility)