Implications of Exposure to Air Pollution on Male Reproduction: The Role of Oxidative Stress.

Air pollution, either from indoor (household) or outdoor (ambient) sources, occurs when there is presence of respirable particles in the form of chemical, physical, or biological agents that modify the natural features of the atmosphere or environment. Today, almost 2.4 billion people are exposed to hazardous levels of indoor pollution, while 99% of the global population breathes air pollutants that exceed the World Health Organization guideline limits. It is not surprising that air pollution is the world's leading environmental cause of diseases and contributes greatly to the global burden of diseases. Upon entry, air pollutants can cause an increase in reactive oxygen species (ROS) production by undergoing oxidation to generate quinones, which further act as oxidizing agents to yield more ROS. Excessive production of ROS can cause oxidative stress, induce lipid peroxidation, enhance the binding of polycyclic aromatic hydrocarbons (PAHs) to their receptors, or bind to PAH to cause DNA strand breaks. The continuous and prolonged exposure to air pollutants is associated with the development or exacerbation of pathologies such as acute or chronic respiratory and cardiovascular diseases, neurodegenerative and skin diseases, and even reduced fertility potential. Males and females contribute to infertility equally, and exposure to air pollutants can negatively affect reproduction. In this review, emphasis will be placed on the implications of exposure to air pollutants on male fertility potential, bringing to light its effects on semen parameters (basic and advanced) and male sexual health. This study will also touch on the clinical implications of air pollution on male reproduction while highlighting the role of oxidative stress.

The Effect of Statins on Male Reproductive Parameters: A Mechanism Involving Dysregulation of Gonadal Hormone Receptors and TRPV1.

Statins have been shown to cause diverse male reproductive function impairment, and in some cases, orchialgia. Therefore, the current study investigated the possible mechanisms through which statins may alter male reproductive parameters. Thirty adult male Wistar rats (200-250 g) were divided into three groups. The animals were orally administered rosuvastatin (50 mg/kg), simvastatin (50 mg/kg), or 0.5% carboxy methyl cellulose (control), for a 30-day period. Spermatozoa were retrieved from the caudal epididymis for sperm analysis. The testis was used for all biochemical assays and immunofluorescent localization of biomarkers of interest. Rosuvastatin-treated animals presented with a significant decrease in sperm concentration when compared to both the control and simvastatin groups (p < 0.005). While no significant difference was observed between the simvastatin and the control group. The Sertoli cells, Leydig cells and whole testicular tissue homogenate expressed transcripts of solute carrier organic anion transporters (SLCO1B1 and SLCO1B3). There was a significant decrease in the testicular protein expression of the luteinizing hormone receptor, follicle stimulating hormone receptor, and transient receptor potential vanilloid 1 in the rosuvastatin and simvastatin-treated animals compared to the control. The expression of SLCO1B1, SLCO1B2, and SLCO1B3 in the different spermatogenic cells portray that un-bio transformed statin can be transported into the testicular microenvironment, which can subsequently alter the regulation of the gonadal hormone receptors, dysregulate pain-inflammatory biomarkers, and consequently impair sperm concentration.

The effect of Aspalathin linearis, Cyclopia intermedia and Sutherlandia frutescene on sperm functional parameters of healthy male wistar rats.

Introduction: Rooibos (Aspalathin linearis), honeybush (Cyclopia intermedia), and sutherlandia (Sutherlandia frutescene) are three Southern Africa indigenous plants, of which the extracts have become house-hold items and are consumed on a large scale. Although, they are known for their antioxidant properties, studies have highlighted danger in the excessive intake. Therefore, the current study investigated whether treatment with rooibos, honeybush, and sutherlandia will impact sperm functional parameters positively or otherwise, in healthy rats. Methods: Fourteen-week-old pathogen-free adult male Wistar rats (250-300 g) were randomly divided into four groups of ten, including a control, rooibos (RF), honeybush (HB) and a sutherlandia (SL) group. After 7 weeks of treatment, animals were sacrificed. Spermatozoa were retrieved from the cauda epididymis for motility, morphology and concentration analysis and the testis was used for all biochemical assays. Results: The infusion treated animals (RF, HB, and SL) presented with a non-significant decrease of -14.3%, -18.2%, -17.2% and -24.8%, -20.7%, -27.3% in total motility and progressive motility when compared to the control group, respectively. There was a significant increase in number of spermatozoa with slow speed (p = 0.03), especially in SL treated group compared to the control (p = 0.03). Additionally, there was an increase of 28.8%, 31.7%, 23% in superoxide dismutase (SOD) activity of RF, HB and SL compared to control, respectively. This was accompanied with a percentage decrease of -21.1%, -23.7%, 45.9% in malondialdehyde (MDA) levels compared to the control group. Conclusion: In summary, animals treated with the respective infusions presented with a percentage increase in SOD activity but have reduced sperm motility and decreased normal morphology. Paradoxically, they presented with increased sperm concentration. Hence, it is presumed that rooibos, honeybush and sutherlandia may enhance sperm quantity (concentration) but may impair sperm quality (motility morphology) when consumed by healthy animals.

Could exposure to spaceflight cause mutations in genes that affect male fertility?

Recently, a study reported that upon analyzing blood samples from 14 astronauts that flew Space Transportation System missions between 1998 and 2001, 34 somatic nonsynonymous single nucleotide variants were detected in 17 CH-driver genes. Of interest is that the cohort consisted of relatively young astronauts, 85% of which were males of reproductive age. Having investigated the genes with nonsynonymous substitutes from the literature, it was found that twelve of these 17 genes appear to play essential roles in male reproduction. Changes in telomere length and gene regulation were also reported in another study conducted on an astronaut during a long duration stay on the International Space Station. Realizing the impact of spaceflight on gene sequence with potential influence on male fertility, it is important that more studies are conducted in this field. Specifically, in light of ultimately colonizing space, multi-generational survival is crucial and strategies to mitigate or counteract such effects should be explored.

Bisphenol A and Male Infertility: Role of Oxidative Stress.

Bisphenol A (BPA) is an endocrine-disrupting chemical that is capable of mimicking, antagonizing, and interfering with the normal biological functioning of the endocrine system. BPA is used in diverse industries, hence its vast sources of exposure. Although the half-life of BPA is relatively short (<24 hours), studies have reported its detection in the urine of different populations. It, therefore, became important to investigate its effect on general health, including male reproductive health. The adverse effects of BPA on male fertility have been evaluated and reported from both in vivo and in vitro studies. Up to date, reports from randomized controlled trials remain controversial, as some revealed decreased sperm quality, sperm concentration, and total sperm count, while others reported that no adverse effect was seen after exposure. Findings from animal model studies and in vitro experiments have shown that exposure to BPA led to a reduction in sperm quality and increased sperm DNA fragmentation, and some even revealed altered expression of the gene that encodes gonadotropin-releasing hormone. This shows that BPA not only may adversely affect male fertility by acting as an endocrine disruptor but also can potentially impact male fertility via its possible contribution to oxidative stress. Therefore, this book chapter aims to identify and elucidate the effect of BPA exposure on male fertility, and to as well illustrate the mechanisms through which this occurs, while emphasizing the role of oxidative stress as a potential pathway.

The genetic causes of male infertility: a Middle East and North Africa perspective.

Male infertility is attributable to 60% of total infertility cases and about 30-50% of these cases remain idiopathic. In the Middle East and North Africa region (MENA), male infertility affects about 22.6% of men of reproductive age. Male infertility is caused by a variety of factors, including endocrine disruption, exposure to toxins, lifestyle, genetic and epigenetic modifications. Genetic modifications, including chromosomal abnormalities, chromosomal rearrangements, Y chromosome microdeletions and single-gene mutations, explain for about 10-15% of infertility cases. Since genetic aberration is a key player in the pathogenesis of male infertility, it is important to explore the impact in the MENA region due to the high incidence of male infertility. Therefore, the current study aims to systematically analyse the literature regarding the impact and common causes of male infertility in the MENA region. To achieve this aim, a comprehensive literature search was performed on PubMed, Google Scholar, and Science Direct databases. Following the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria, totaling the exclusion of 81 articles. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age. Findings showed that the frequent genetic aberration leading to male infertility in these regions include Y chromosome microdeletions, gene polymorphisms or copy number variations, mitochondrial microdeletions and other genetic deletions or mutations. In lieu of this, diverse clinical genetic tests should be made available for the proper diagnosis of male infertility.

Statins and Male Fertility: Is There a Cause for Concern?

The well-known 3-hydroxyl 3-methyl glutaryl-Coenzyme A reductase inhibitors, called statins, have been the main medication used in the treatment of hypercholesterolemia and some cases of cardiovascular diseases. The effectiveness of this drug in controlling cholesterol production is impeccable, however, patients often complain of a variety of side effects, such as myalgia, muscle atrophy, and in some cases, rhabdomyolysis. Not only has the use of statins caused the aforementioned side effects, but they are also shown to cause testicular discomfort, erectile dysfunction, altered semen parameters, and modified steroid hormone production. These reported adverse effects on male fertility are not generally agreed upon, as some have shown the use to be beneficial. Hence, this makes the aftermath effect of statin use on male fertility debatable and controversial. The negative effects have been associated with imbalanced or reduced steroid hormones, which are necessary for proper spermatogenesis and other sexual functions. Meanwhile, the beneficial effects are related to statin's anti-inflammatory and cardioprotective properties. These contradictory findings are in part due to the different age of users, concentrations of statins, the type and duration of treatment, and the underlying disease and/or comorbidities. Therefore, the current study aims to analyze the literature and gather evidence as to the effects of statin on male sexual health and reproductive parameters, and subsequently give recommendations for the direction of future studies.

Oxidative Stress and Male Infertility: Evidence From a Research Perspective.

Male fertility potential can be influenced by a variety of conditions that frequently coincide. Spermatozoa are particularly susceptible to oxidative damage due to their limited antioxidant capacity and cell membrane rich in polyunsaturated fatty acids (PUFAs). The role of oxidative stress (OS) in the etiology of male infertility has been the primary focus of our Stellenbosch University Reproductive Research Group (SURRG) over the last 10 years. This review aims to provide a novel insight into the impact of OS on spermatozoa and male reproductive function by reviewing the OS-related findings from a wide variety of studies conducted in our laboratory, along with those emerging from other investigators. We will provide a concise overview of the production of reactive oxygen species (ROS) and the development of OS in the male reproductive tract along with the physiological and pathological effects thereof on male reproductive functions. Recent advances in methods and techniques used for the assessment of OS will also be highlighted. We will furthermore consider the current evidence regarding the association between OS and ejaculatory abstinence period, as well as the potential mechanisms involved in the pathophysiology of various systemic diseases such as obesity, insulin resistance, hypertension, and certain mental health disorders which have been shown to cause OS induced male infertility. Finally, special emphasis will be placed on the potential for transferring and incorporating research findings emanating from different experimental studies into clinical practice.

Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

Computational Analysis of Short Linear Motifs in the Spike Protein of SARS-CoV-2 Variants Provides Possible Clues into the Immune Hijack and Evasion Mechanisms of Omicron Variant.

Short linear motifs (SLiMs) are short linear sequences that can mediate protein-protein interaction. Mimicking eukaryotic SLiMs to compete with extra- or intracellular binding partners, or to sequester host proteins is the crucial strategy of viruses to pervert the host system. Evolved proteins in viruses facilitate minimal protein-protein interactions that significantly affect intracellular signaling networks. Unfortunately, very little information about SARS-CoV-2 SLiMs is known, especially across SARS-CoV-2 variants. Through the ELM database-based sequence analysis of spike proteins from all the major SARS-CoV-2 variants, we identified four overriding SLiMs in the SARS-CoV-2 Omicron variant, namely, LIG_TRFH_1, LIG_REV1ctd_RIR_1, LIG_CaM_NSCaTE_8, and MOD_LATS_1. These SLiMs are highly likely to interfere with various immune functions, interact with host intracellular proteins, regulate cellular pathways, and lubricate viral infection and transmission. These cellular interactions possibly serve as potential therapeutic targets for these variants, and this approach can be further exploited to combat emerging SARS-CoV-2 variants.

Effects of space flight on sperm function and integrity: A systematic review.

With the advancement in space exploration and the intention to establish an inhabitable human settlement on Mars, it is important to investigate the effects of exposure to space/microgravity and the associated radiations on procreation. Sperm function and integrity are fundamental to male reproduction and can potentially be affected by the environmental changes experienced in space. Therefore, this study was conducted to systematically gather, filter, and collate all the relevant information on the effects of spaceflight on male reproductive parameters and functions. A search was performed utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted from the major electronic databases including PubMed, and other credible literature sources. MeSH search terms that were employed included "spermatozoa", "microgravity", and "ionizing radiation". The literature search did not discriminate against papers published before a certain date due to the very limited number of articles available. However, there was a restriction on the male gender and language (English). The parameters included in this study are sperm motility, total sperm count, sperm DNA fragmentation hormonal levels and testicular histology. Following a comprehensive literature search, a total of 273 articles were retrieved and screened, 252 articles were excluded due to the irrelevance to the topic, duplication, and non-original articles. A total of 21 articles met the inclusion criteria and are included in the current study. Findings from these studies showed that sperm motility was decreased after exposure to microgravity and ionizing radiation. Total sperm count was also found to be reduced by microgravity only. Sperm DNA fragmentation was increased by both ionizing radiation and microgravity. Testosterone levels and testicular weight were also decreased by microgravity. Although there is a dearth in the literature regarding the effects of microgravity and ionizing radiation on male reproductive parameters, the available findings showed that exposure to microgravity poses a risk to male reproductive health. Therefore, it is essential to develop countermeasures to either manage, treat, or prevent these consequential adverse effects. Hence, this review also highlights some potential countermeasure approaches that may mitigate the harmful effects of microgravity and associated exposures on male reproductive health.

Mechanisms of SARS-CoV-2 and Male Infertility: Could Connexin and Pannexin Play a Role?

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male infertility has lately received significant attention. SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) in humans, has been shown to impose adverse effects on both the structural components and function of the testis, which potentially impact spermatogenesis. These adverse effects are partially explained by fever, systemic inflammation, oxidative stress, and an increased immune response leading to impaired blood-testis barrier. It has been well established that efficient cellular communication via gap junctions or functional channels is required for tissue homeostasis. Connexins and pannexins are two protein families that mediate autocrine and paracrine signaling between the cells and the extracellular environment. These channel-forming proteins have been shown to play a role in coordinating cellular communication in the testis and epididymis. Despite their role in maintaining a proper male reproductive milieu, their function is disrupted under pathological conditions. The involvement of these channels has been well documented in several physiological and pathological conditions and their designated function in infectious diseases. However, their role in COVID-19 and their meaningful contribution to male infertility remains to be elucidated. Therefore, this review highlights the multivariate pathophysiological mechanisms of SARS-CoV-2 involvement in male reproduction. It also aims to shed light on the role of connexin and pannexin channels in disease progression, emphasizing their unexplored role and regulation of SARS-CoV-2 pathophysiology. Finally, we hypothesize the possible involvement of connexins and pannexins in SARS-CoV-2 inducing male infertility to assist future research ideas targeting therapeutic approaches.

Omics and Male Infertility: Highlighting the Application of Transcriptomic Data.

Male infertility is a multifaceted disorder affecting approximately 50% of male partners in infertile couples. Over the years, male infertility has been diagnosed mainly through semen analysis, hormone evaluations, medical records and physical examinations, which of course are fundamental, but yet inefficient, because 30% of male infertility cases remain idiopathic. This dilemmatic status of the unknown needs to be addressed with more sophisticated and result-driven technologies and/or techniques. Genetic alterations have been linked with male infertility, thereby unveiling the practicality of investigating this disorder from the "omics" perspective. Omics aims at analyzing the structure and functions of a whole constituent of a given biological function at different levels, including the molecular gene level (genomics), transcript level (transcriptomics), protein level (proteomics) and metabolites level (metabolomics). In the current study, an overview of the four branches of omics and their roles in male infertility are briefly discussed; the potential usefulness of assessing transcriptomic data to understand this pathology is also elucidated. After assessing the publicly obtainable transcriptomic data for datasets on male infertility, a total of 1385 datasets were retrieved, of which 10 datasets met the inclusion criteria and were used for further analysis. These datasets were classified into groups according to the disease or cause of male infertility. The groups include non-obstructive azoospermia (NOA), obstructive azoospermia (OA), non-obstructive and obstructive azoospermia (NOA and OA), spermatogenic dysfunction, sperm dysfunction, and Y chromosome microdeletion. Findings revealed that 8 genes (LDHC, PDHA2, TNP1, TNP2, ODF1, ODF2, SPINK2, PCDHB3) were commonly differentially expressed between all disease groups. Likewise, 56 genes were common between NOA versus NOA and OA (ADAD1, BANF2, BCL2L14, C12orf50, C20orf173, C22orf23, C6orf99, C9orf131, C9orf24, CABS1, CAPZA3, CCDC187, CCDC54, CDKN3, CEP170, CFAP206, CRISP2, CT83, CXorf65, FAM209A, FAM71F1, FAM81B, GALNTL5, GTSF1, H1FNT, HEMGN, HMGB4, KIF2B, LDHC, LOC441601, LYZL2, ODF1, ODF2, PCDHB3, PDHA2, PGK2, PIH1D2, PLCZ1, PROCA1, RIMBP3, ROPN1L, SHCBP1L, SMCP, SPATA16, SPATA19, SPINK2, TEX33, TKTL2, TMCO2, TMCO5A, TNP1, TNP2, TSPAN16, TSSK1B, TTLL2, UBQLN3). These genes, particularly the above-mentioned 8 genes, are involved in diverse biological processes such as germ cell development, spermatid development, spermatid differentiation, regulation of proteolysis, spermatogenesis and metabolic processes. Owing to the stage-specific expression of these genes, any mal-expression can ultimately lead to male infertility. Therefore, currently available data on all branches of omics relating to male fertility can be used to identify biomarkers for diagnosing male infertility, which can potentially help in unravelling some idiopathic cases.

Using publicly available transcriptomic data to identify mechanistic and diagnostic biomarkers in azoospermia and overall male infertility.

Azoospermia, which is the absence of spermatozoa in an ejaculate occurring due to defects in sperm production, or the obstruction of the reproductive tract, affects about 1% of all men and is prevalent in up to 10-15% of infertile males. Conventional semen analysis remains the gold standard for diagnosing and treating male infertility; however, advances in molecular biology and bioinformatics now highlight the insufficiency thereof. Hence, the need to widen the scope of investigating the aetiology of male infertility stands pertinent. The current study aimed to identify common differentially expressed genes (DEGs) that might serve as potential biomarkers for non-obstructive azoospermia (NOA) and overall male infertility. DEGs across different datasets of transcriptomic profiling of testis from human patients with different causes of infertility/ impaired spermatogenesis and/or azoospermia were explored using the gene expression omnibus (GEO) database. Following the search using the GEOquery, 30 datasets were available, with 5 meeting the inclusion criteria. The DEGs for datasets were identified using limma R packages through the GEO2R tool. The annotated genes of the probes in each dataset were intersected with DEGs from all other datasets. Enriched Ontology Clustering for the identified genes was performed using Metascape to explore the possible connection or interaction between the genes. Twenty-five DEGs were shared between most of the datasets, which might indicate their role in the pathogenesis of male infertility. Of the 25 DEGs, eight genes (THEG, SPATA20, ROPN1L, GSTF1, TSSK1B, CABS1, ADAD1, RIMBP3) are either involved in the overall spermatogenic processes or at specific phases of spermatogenesis. We hypothesize that alteration in the expression of these genes leads to impaired spermatogenesis and, ultimately, male infertility. Thus, these genes can be used as potential biomarkers for the early detection of NOA.