Obesity and Male Reproduction: Do Sirtuins Play a Role?

Obesity is a major current public health problem of global significance. A progressive sperm quality decline, and a decline in male fertility, have been reported in recent decades. Several studies have reported a strict relationship between obesity and male reproductive dysfunction. Among the many mechanisms by which obesity impairs male gonadal function, sirtuins (SIRTs) have an emerging role. SIRTs are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that play a role in gene regulation, metabolism, aging, and cancer. SIRTs regulate the energy balance, the lipid balance, glucose metabolism, and adipogenesis, but current evidence also indicates a role for SIRTs in male reproduction. However, the majority of the studies have been conducted in animal models and very few have been conducted with humans. This review shows that SIRTs play an important role among the molecular mechanisms by which obesity interferes with male fertility. This highlights the need to deepen this relationship. It will be of particular interest to evaluate whether synthetic and/or natural compounds capable of modifying the activity of SIRTs may also be useful for the treatment of obesity and its effects on gonadal function. Although few studies have explored the role of SIRT activators in obesity-induced male infertility, some molecules, such as resveratrol, appear to be effective in modulating SIRT activity, as well as counteracting the negative effects of obesity on male fertility. The search for strategies to improve male reproductive function in overweight/obese patients is a challenge and understanding the role of SIRTs and their activators may open new interesting scenarios in the coming years.

Mesenchymal Stem-Cell Derived Exosome Therapy as a Potential Future Approach for Treatment of Male Infertility Caused by Chlamydia Infection

Some microbial sexually transmitted infections (STIs) have adverse effects on the reproductive tract, sperm function, and male fertility. Given that STIs are often asymptomatic and cause major complications such as urogenital inflammation, fibrosis, and scarring, optimal treatments should be performed to prevent the noxious effect of STIs on male fertility. Among STIs, Chlamydia trachomatis is the most common asymptomatic preventable bacterial STI. C. trachomatis can affect both sperm and the male reproductive tract. Recently, mesenchymal stem cells (MSCs) derived exosomes have been considered as a new therapeutic medicine due to their immunomodulatory, anti-inflammatory, anti-oxidant, and regenerative effects without consequences through the stem cell transplantation based therapies. Inflammation of the genital tract and sperm dysfunction are the consequences of the microbial infections, especially Chlamydia trachomatis. Exosome therapy as a noninvasive approach has shown promising results on the ability to regenerate the damaged sperm and treating asthenozoospermia. Recent experimental methods may be helpful in the novel treatments of male infertility. Thus, it is demonstrated that exosomes play an important role in preventing the consequences of infection, and thereby preventing inflammation, reducing cell damage, inhibiting fibrogenesis, and reducing scar formation. This review aimed to overview the studies about the potential therapeutic roles of MSCs-derived exosomes on sperm abnormalities and male infertility caused by STIs.

Review on the role of antioxidant supplementation against oxidative stress: a human and animal approach to male fertility

Male infertility is one important factor among the multifactorial causes of couple infertility, being oxidative stress one of the main related sources. Sperm is a specialized cell extremely susceptible to stress. To understand and mitigate this event, many studies have used different antioxidants, orally or in vitro supplementation, trying to improve sperm quality and function. Considering the extensive available literature regarding approaches and attempts to solve male fertility issues, the aim of this review is evaluating the effects of antioxidant supplementation on sperm, in both humans and experimental models with animals. This review selected original data from PubMed. The keywords used were: antioxidant, sperm, male fertility, antioxidant supplementation, male infertility; and the term "rodents" was added to the descriptors “antioxidant” and “male fertility”. Only studies published in indexed journals, in English, between 2015 and 2019 were included. This review involves i) human sperm and ii) rodent sperm. For the human approach, the search retrieved 496 articles and 80 were included, among which 28 studies were of in vitro antioxidant supplementation, 19 involved oral antioxidant supplementation and the remaining 33 concerned quantification of oxidants and antioxidants already present in the seminal samples. For the rodent approach, 152 articles were retrieved and 52 were included: 3 of varicocele, 11 of diabetes, 10 of therapeutic drugs, 3 of physical exercise, 10 of environmental exposure and 3 of heat stress. The remaining studies involved oxidative stress status in experimental models. Antioxidants use for reproductive purposes is increasing in an attempt to achieve better gametes and embryos. Vitamins C, B and E, selenium and zinc are the most commonly used antioxidants, with remarkable evidences in improving pathophysiological seminal conditions.

Ccdc38 is required for sperm flagellum biogenesis and male fertility in mouse

Sperm flagellum is essential for male fertility, defects in flagellum biogenesis are associated with male infertility. Deficiency of CCDC42 is associated with malformation of the mouse sperm flagella. Here, we find that the testis-specific expressed protein CCDC38 (coiled coil domain containing 38) interacts with CCDC42 and localizes on manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in distorted manchette, multiple morphological abnormalities of the flagella (MMAF) of spermatozoa, and eventually male sterility. Furthermore, we find that CCDC38 interacts with intra-flagellar transport protein 88 (IFT88) as well as the outer dense fibrous 2 (ODF2), and its depletion reduces the transportation of ODF2 to flagellum. Altogether, our results uncover the essential role of CCDC38 during sperm flagellum biogenesis, and suggesting the defects of these genes might be associated with male infertility in human being.

Impact of environmental factors on human semen quality and male fertility: a narrative review

Background Worldwide rising trend in infertility has been observed in the past few years with male infertility arising as a major problem. One main reason for the rise in male infertility cases is declining semen quality. It was found that any factor that affects semen quality can affect male fertility. There are several modifiable factors affecting semen quality including air pollution, use of pesticides and harmful chemicals, exposure to excessive heat, and can lead to decreased male fertility. Main body The present review focuses on some of these environmental factors that affect semen quality and hence, can cause male infertility. The literature from 2000 till June 2021 was searched from various English peer-reviewed journals and WHO fact sheets using the USA National Library of Medicine (PubMed) database, the regional portal of Virtual Health Library, and Scientific Electronic Library Online. The search terms used were: “Air pollution and male fertility”, “Chemicals and male infertility”, “Heat exposure and infertility”, “heavy metals and male fertility”. Conclusion Adverse environmental factors have a significant impact on semen quality, leading to decreased sperm concentration, total sperm count, motility, viability, and increased abnormal sperm morphology, sperm DNA fragmentation, ultimately causing male infertility. However, all these factors are modifiable and reversible, and hence, by mere changing of lifestyle, many of these risk factors can be avoided.

A Novel Approach of Tracing in Vivo Bioluminescence Imaging Expression of Vitrified Immature Testicular Tissue Grafts Until Adulthood: A Translational Transgenic Mouse Model

Background: The optimal method for cryopreserving immature testicular tissue (ITT) remains unknown and there is no standardized protocol. Controlled slow freezing remains the mainstream method of choice in human prepubertal male fertility preservation. Currently, the outcomes for ITT vitrification are conflicting, and most data are limited to in vitro animal studies.Methods: A total of 12 pairs of donor and recipient mice were included in our experiments. The donors were immature transgenic mice, and the recipients were wild-type male mice. In the vitrification group, ITT was vitrified and thawed before transplantation. In the control group, ITT was transplanted to the recipients immediately. After thawing, we measured the expression of apoptosis-related mRNA caspase-3. More importantly, we monitored to adulthood all the transplanted grafts in vivo using noninvasive bioluminescence imaging (BLI) technology. On day 31, we removed the grafts for evaluation via hematoxylin and eosin staining and immunohistochemistry (IHC).Results: We traced the survival of the grafts by in vivo BLI on days 1, 2, 5, 7, and 31 after transplantation. In both the vitrification and the control groups, bioluminescence decreased between days 2 and 5. Subsequently, the bioluminescence showed an upward trend until day 31. Compared with day 1, the bioluminescence was significantly stronger on day 31 after transplantation (P = 0.009). The differences between the two groups were constantly insignificant after analysis. These results indicate that both fresh and frozen–thawed testicular tissues can survive for at least 31 days after transplantation. Moreover, the vitrification group showed BLI signals comparable with those of fresh tissues. Compared with the control group, expression of the caspase-3 gene was significantly increased after vitrification (P = 0.04). Histology and IHC showed that both tissue structure and protein expression were intact in both groups.Conclusions: Transplanted vitrified ITT grafts could survive till adulthood with BLI intensity comparable to that of the fresh control. Intact cells and structures for spermatogenesis in vitrified ITT grafts were as well-preserved as those in the control group. This translational model of self-repairing vitrified ITT grafts in vivo, lends weight to the role of vitrification in prepubertal male fertility preservation.

The Hydrogen Storage Nanomaterial MgH2 Improves Irradiation-induced Male Fertility Impairment by Suppressing Oxidative Stress

ObjectiveThis study aimed to reveal the protective effect of hydrogen storage nanomaterial MgH2 on radiation-induced male fertility impairment.MethodsThe characterization of MgH2 were analyzed by scanning electron microscopy (SEM) and particle size analyzer. The safety of MgH2 were evaluated in vivo and in vitro. The radioprotective effect of MgH2 on the reproductive system were analyzed in mice, including sperm quality, genetic effect, spermatogenesis, and hormone secretion. ESR, flow cytometry and western blotting assay were used to reveal the underlying mechanisms.ResultsMgH2 had an irregular spherical morphology and a particle size of approximately 463.2 nm, and the content of Mg reached 71.46%. MgH2 was safe and nontoxic in mice and cells. After irradiation, MgH2 treatment significantly protected testicular structure, increased sperm density, improved sperm motility, reduced deformity rates, and reduced the genetic toxicity. Particularly, the sperm motility were consistent with those in MH mice and human semen samples. Furthermore, MgH2 treatment could maintain hormone secretion and testicular spermatogenesis, especially the generation of Sertoli cells, spermatogonia and round sperm cells. In vitro, MgH2 eliminated the [·OH], suppressed the irradiation-induced increase in ROS production, and effectively alleviated the increase in MDA contents. Moreover, MgH2 significantly ameliorated apoptosis in testes and cells and reversed the G2/M phase cell cycle arrest induced by irradiation. In addition, MgH2 inhibited the activation of radiation-induced inflammation and pyroptosis.ConclusionMgH2 improved irradiation-induced male fertility impairment by eliminating hydroxyl free radicals.

The generation of a Nutm1 knock-in reporter mouse line for imaging post-meiotic spermatogenesis

Spermiogenesis, the post-meiotic stage of sperm development, is critical for normal male fertility. Many genetic defects and environmental assaults that affect spermiogenesis have been shown to be associated with male infertility. In addition, this later stage of spermatogenesis has been proposed to be an ideal target for male contraceptive development. The mouse is a widely used model for studying the mechanisms of spermatogenesis and spermiogenesis. However, due to the complexity and the asynchronous nature of spermatogenesis in adult testis, it is challenging to study molecular processes restricted to this specific developmental stage. It is also challenging to monitor the spermiogenesic activity in live mice, which is critical for screening for fertility-modulating interventions such as contraceptives. Here we reported the development of a Nutm1-T2A- luciferase 2(Luc2)-tandem Tomato(TdTomato) knock-in reporter mouse model that specifically labels post-meiotic spermatids. Homozygous reporter mice are healthy and fully fertile, demonstrating no interference with the normal functions of the Nutm1 gene by the reporter. We demonstrated the visualization of post-meiotic spermatids by fluorescent imaging of the TdTomato reporter in both live and fixed testis tissues. We also demonstrated bioluminescence imaging of Nutm1 expressing cells in live mice. The Nutm1-T2A-Luc2TdTomato reporter mouse can serve as a valuable tool for studying spermiogenesis.