Reduction In Number Of Spermatozoa Research Articles

Normal male fertility in a mouse model of KPNA2 deficiency.

The nuclear transport of proteins is mediated by karyopherins and has been implicated to be crucial for germ cell and embryonic development. Deletion of distinct members of the karyopherin alpha family has been shown to cause male and female infertility in mice. Using a genetrap approach, we established mice deficient for KPNA2 (KPNA2 KO) and investigated the role of this protein in male germ cell development and fertility. Breeding of male KPNA2 KO mice leads to healthy offsprings in all cases albeit the absence of KPNA2 resulted in a reduction in sperm number by 60%. Analyses of the KPNA2 expression in wild-type mice revealed a strong KPNA2 presence in meiotic germ cells of all stages while a rapid decline is found in round spermatids. The high KPNA2 expression throughout all meiotic stages of sperm development suggests a possible function of KPNA2 during this phase, hence in its absence the spermatogenesis is not completely blocked. In KPNA2 KO mice, a higher portion of sperms presented with morphological abnormalities in the head and neck region, but a severe spermiogenesis defect was not found. Thus, we conclude that the function of KPNA2 in round spermatids is dispensable, as our mice do not show any signs of infertility. Our data provide evidence that KPNA2 is not crucial for male germ cell development and fertility.

Impaired Spermatogenesis in Infertile Patients with Orchitis and Experimental Autoimmune Orchitis in Rats.

Experimental autoimmune orchitis (EAO) is a well-established rodent model of organ-specific autoimmunity associated with infertility in which the testis immunohistopathology has been extensively studied. In contrast, analysis of testis biopsies from infertile patients associated with inflammation has been more limited. In this work, testicular biopsies from patients with idiopathic non-obstructive azoospermia diagnosed with hypospermatogenesis (HypoSp) [mild: n = 9, and severe: n = 11], with obstructive azoospermia and complete Sp (spermatogenesis) (control group, C, n = 9), and from Sertoli cell-only syndrome (SCOS, n = 9) were analyzed for the presence of immune cells, spermatogonia and Sertoli cell (SCs) alterations, and reproductive hormones levels. These parameters were compared with those obtained in rats with EAO. The presence of increased CD45+ cells in the seminiferous tubules (STs) wall and lumen in severe HypoSp is associated with increased numbers of apoptotic meiotic germ cells and decreased populations of undifferentiated and differentiated spermatogonia. The SCs showed an immature profile with the highest expression of AMH in patients with SCOS and severe HypoSp. In SCOS patients, the amount of SCs/ST and Ki67+ SCs/ST increased and correlated with high serum FSH levels and CD45+ cells. In the severe phase of EAO, immune cell infiltration and apoptosis of meiotic germ cells increased and the number of undifferentiated and differentiated spermatogonia was lowest, as previously reported. Here, we found that orchitis leads to reduced sperm number, viability, and motility. SCs were mature (AMH-) but increased in number, with Ki67+ observed in severely damaged STs and associated with the highest levels of FSH and inflammatory cells. Our findings demonstrate that in a scenario where a chronic inflammatory process is underway, FSH levels, immune cell infiltration, and immature phenotypes of SCs are associated with severe changes in spermatogenesis, leading to azoospermia. Furthermore, AMH and Ki67 expression in SCs is a distinctive marker of severe alterations of STs in human orchitis.

Rreb1 is a key transcription factor in Sertoli cell maturation and function and spermatogenesis in mouse.

Spermatogenesis is a developmental process driven by interactions between germ cells and Sertoli cells. This process depends on appropriate gene expression, which might be regulated by transcription factors. This study focused on Rreb1, a zinc finger transcription factor, and explored its function and molecular mechanisms in spermatogenesis in a mouse model. Our results showed that RREB1 was predominantly expressed in the Sertoli cells of the testis. The decreased expression of RREB1 following injection of siRNA caused impaired Sertoli cell development, which was characterized using a defective blood-testis barrier structure and decreased expression of Sertoli cell functional maturity markers; its essential trigger might be SMAD3 destabilization. The decreased expression of RREB1 in mature Sertoli cells influenced the cell structure and function, which resulted in abnormal spermatogenesis, manifested as oligoasthenoteratozoospermia, and we believe RREB1 plays this role by regulating the transcription of Fshr and Wt1. RREB1 has been reported to activate Fshr transcription, and we demonstrated that the knockdown of Rreb1 caused a reduction in follicle-stimulating hormone receptor (FSHR) in the testis, which could be the cause of the increased sperm malformation. Furthermore, we confirmed that RREB1 directly activates Wt1 promoter activity, and RREB1 downregulation induced the decreased expression of Wt1 and its downstream polarity-associated genes Par6b and E-cadherin, which caused increased germ-cell death and reduced sperm number and motility. In conclusion, RREB1 is a key transcription factor essential for Sertoli cell development and function and is required for normal spermatogenesis.

Identification and functional verification of Y-chromosome-specific gene typo-gyf in Bactrocera dorsalis.

Genes on the Y chromosome play important roles in male sex determination and development. The identification of Y-chromosome-specific genes not only provides a theoretical basis for the study of male reproductive development, but also offers genetic control targets for agricultural pests. However, Y-chromosome genes are rarely characterized due to their high repeatability and high heterochromatinization, especially in the oriental fruit fly. In this study, 1011 Y-chromosome-specific candidate sequences were screened from 2 to 4h Bactrocera dorsalis embryo datasets with the chromosome quotient method, 6 of which were identified as Y-chromosome-specific sequences by polymerase chain reaction, including typo-gyf, a 19126-bp DNA sequence containing a 575-amino acid open reading frame. Testicular deformation and a significant reduction in sperm number were observed after typo-gyf knockdown with RNA interference in embryos. After typo-gyf knockout with clustered regularly interspaced palindromic repeats (CRISPR) / CRISPR-associated protein 9 in the embryonic stage, the sex ratio of the emergent adults was unbalanced, with far more females than males. A genotype analysis of these females with the Y-chromosome gene MoY revealed no sex reversal. Typo-gyf knockout led to the death of XY individuals in the embryonic stage. We conclude that typo-gyf is an essential gene for male survival, and is also involved in testicular development and spermatogenesis. The identification of typo-gyf and its functional verification provide insight into the roles of Y-chromosome genes in male development.

Reduced sperm number of murrah (Bubalus bubalis) bull semen in French mini-straw affects kinetic and functional competence after cryopreservation

BACKGROUND: Extensive dilution of cattle semen with tris-based extender compromises certain sperm kinetic and functional traits following cryopreservation. OBJECTIVE: To study sperm functions of buffalo bulls under high dilution rates. MATERIALS AND METHODS: Twenty-four ejaculates were harvested twice a week from four buffalo bulls, and diluted to sperm concentrations of 80, 60, 40 and 20 million/mL. Diluted samples were filled in straws, equilibrated at refrigeration temperature for 4 h, and frozen in liquid nitrogen. Frozen sperm samples were thawed for evaluation of kinetic and functional attributes. RESULTS: Compared to 20 million/mL (million/mL) sperm sample, the total motility, progressive motility and rapid motility were reduced (P < 0.05) in 5 million/mL sample. The proportion of live sperm were significantly (P < 0.05) higher in 10, 15 and 20 million/mL samples than in 5 million/mL sample. The percentage of moribund sperm, dead sperm, and sperm with lipid per oxidation increased significantly (P < 0.05) in 5 million/mL sample. CONCLUSION: The reduction of sperm concentrations to < 10 million/mL affects post-thaw Buffalo sperm kinetic and functional attributes.

Titanium Dioxide Nanoparticles Induce Cell Cycle Arrest andApoptosis through Inhibiting PI3K/AKT/mTOR Pathway in Spermatogonia.

Titanium dioxide nanoparticles (TiO2 NPs) can result in the reduction of sperm numbers, but the mechanisms have not been well elucidated. The purpose of this study was to investigate the effects of TiO2 NPs on cell cycle and apoptosis in spermatogonia and to explore the role of PI3K/AKT/mTOR signaling pathway in this process. The mouse spermatogonia cell line (GC-1) was treated with TiO2 NPs at different concentrations (0, 25, 50, 75 and 100μg/mL) for 24h to detect cell viability, cell cycle, apoptosis, and key proteins related to cell cycle and PI3K/AKT/mTOR signaling pathway. The agonist (IGF-1) and inhibitor (LY294002) of PI3K were used to verify the role of PI3K/AKT/mTOR signaling pathway in cell cycle and apoptosis. TiO2 NPs significantly inhibited cell proliferation, induced cell cycle arrest at G0/G1 phase and resulted in apoptosis. TiO2 NPs downregulated the levels of cyclin-dependent kinases (CDKs) and cyclins, including CDK4, CDK2, Cyclin D1 and Cyclin E1, while upregulated the levels of p21 and p53 proteins. Furthermore, TiO2 NPs inhibited the PI3K/AKT/mTOR signaling pathway by decreasing the levels of p-PI3K, p-AKT and p-mTOR. IGF-1 reversed the G0/G1 phase arrest and apoptosis caused by TiO2 NPs. However, LY294002 aggravated the G0/G1 phase arrest and apoptosis resulting from TiO2 NPs. Collectively, TiO2 NPs induced cell cycle arrest at G0/G1 phase and apoptosis through inhibiting the activation of PI3K/AKT/mTOR pathway, which could be the main reason for the reduction in sperm numbers caused by TiO2 NPs.

Low human sperm motility coexists with sperm nuclear DNA damage and oxidative stress in semen.

Low sperm motility, one of the common causes of male infertility, is associated with abnormal sperm quality. Currently, important sperm/semen biomarkers are sperm chromatin status and oxidation‒reduction potential (ORP) in semen. Because the association between sperm motility and these biomarkers is still not fully clarified, our study was designed to verify the distribution and risk of sperm DNA fragmentation (SDF) and oxidative stress in semen in asthenozoospermic men. This study was carried out on discharged sperm cells of asthenozoospermic men (isolated asthenozoospermia or coexisted with reduced sperm number and/or morphology), nonasthenozoospermic men (reduced total sperm count and/or sperm morphology) (experimental groups) and normozoospermic men (proven and presumed fertility) (control group). Basic semen analysis was evaluated according to the 6th edition of the World Health Organization manual guidelines. SDF was assessed using the sperm chromatin dispersion test, while static(s) ORP in semen was measured by means of a MiOXSYS analyser. The men from the asthenozoospermic group had lower basic semen parameters than those from the control and nonasthenozoospermic groups. In men with poor sperm motility SDF and sORP, prevalence and risk for>20% SDF (high level of DNA damage) and for>1.37 sORP (oxidative stress) were significantly higher than those of control and nonasthenozoospermic subjects. The risk for sperm DNA damage and oxidative stress in asthenozoospermic men was over 10-fold higher and almost 6-fold higher than those in control subjects and almost or over 3-fold higher than those in nonasthenozoospermic men. Poor human sperm motility coexisted with low basic sperm quality. Sperm DNA damage and oxidative stress in semen were much more frequent in asthenozoospermia. These abnormalities can decrease the sperm fertilizing capability under both natural and medically assisted reproduction conditions. Thus, in asthenozoospermia, the evaluation of sperm chromatin status and oxidation-reduction potential in semen is justified and inevitable, and the appropriate antioxidant therapy can be suggested.

PSIII-7 Effect of Time of Estrus on Conception Rate for a Sexed Semen Artificial Insemination Protocol in Multiparous Beef Cows

Abstract Sexed semen artificial insemination is a breeding technique that allows producers to shorten breeding seasons, optimize genetics through use of superior semen, create calves based on sex preference, and increase profitability. Sexed semen is a technology that sorts semen by differences in DNA content between X (female) and Y (male) bearing sperm. However, sexed semen practices have yet to be widely used in beef cows due to reduced sperm numbers, low conception rates, and increased costs. The objective of this study was to determine the effect of time of estrus upon fixed-time artificial insemination (FTAI) of sex-sorted semen on conception rate using two different estrous synchronization protocols. Multiparous commercial beef cows (n = 73) were randomized by age, body condition score (BCS), and days post-partum at the University of Arkansas Livestock and Forestry Research Station in Batesville. Both synchronization treatments (TRT) used a controlled internal drug releasing device (Eazi-breed CIDR; 1.38g progesterone) inserted intravaginally on d -14 of the protocol simultaneous to administration of prostaglandin F2α (PGF; 500µg cloprostenol sodium; Estrumate). In the first treatment (TRT 1; 7&7 Synch), gonadotropin-releasing hormone (GnRH; 86µg gonadorelin; Fertagyl) was administered on d -7. In the second treatment (TRT 2; 8&6 Synch), GnRH was administered on d -6. Both treatments were then administered PGF simultaneous to CIDR removal on d 0, 66 ± 2h before FTAI and administration of GnRH. Standing heat (estrus) was visually detected every 3 h for 30 min intervals between CIDR removal and FTAI. Heat detection patches were used in conjunction with visual detection of estrus. Time of estrus was signified as time of standing immobile when mounted in combination with presenting a patch score of 4 (>75% color removed). Time of estrus (TD) was deviated from time of FTAI and categorized into three equal time groups (Grp 1 = 0 to 11.0 h; Grp 2 = 11.01 to 22.0 h; and Grp 3 = 22.01 to 33.0 h). Conception rate (CR) was determined via ultrasound 37 ± 2 d after FTAI. Data were analyzed using the GLIMMIX procedure of SAS 9.4. CR did not differ by age of dam (P = 0.58), BCS (P = 0.48), or TRT (P = 0.83). However, TD had an effect on CR (P = 0.002); and resulted in CR of 45% (Grp 1), 87% (Grp 2), and 42% (Grp 3). In conclusion, these results indicate artificially inseminating cows with sexed semen between 11.01 and 22.0 h after time of standing estrus will increase pregnancy rates for multiparous commercial beef cattle.

Wolbachia Induces Structural Defects Harmful to Drosophila simulans Riverside Spermiogenesis.

The relationship between cytoplasmic incompatibility and the obligate intracellular alphaproteobacteria Wolbachia has for a long time been reported. Although the molecular mechanisms responsible for this reproductive alteration are beginning to be understood, the effects of Wolbachia on germ cell structure and dynamics have not yet been fully investigated. We report here that the presence of Wolbachia in infected cysts of elongating spermatids is associated with major structural defects that become more evident in mature sperm. We find mitochondrial defects, an improper axoneme structure, reduced sperm numbers, and individualization failures. The large heterogeneous variety of the ultrastructural defects found in elongating spermatids and mature sperm provide the first cytological evidence for the reduced fertility associated with Wolbachia infection in Drosophila simulans males. The observed abnormalities could be the result of the mechanical stress induced by the high bacteria numbers during the process of spermatid elongation, rather than the result of the released factors affecting the proper morphogenesis of the germ cells. Moreover, high Wolbachia densities in male germ cells may not be appropriate for causing cytoplasmic incompatibility as the bacteria are harmful for spermatid differentiation, leading to abnormal sperm that is unlikely to be functional.

Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility

Regulatory T cells (Tregs) modulate tissue homeostatic processes and immune responses. Understanding tissue-Treg biology will contribute to developing precision-targeting treatment strategies. Here, we show that Tregs maintain the tolerogenic state of the testis and epididymis, where sperm are produced and mature. We found that Treg depletion induces severe autoimmune orchitis and epididymitis, manifested by an exacerbated immune cell infiltration [CD4 T cells, monocytes, and mononuclear phagocytes (MPs)] and the development of antisperm antibodies (ASA). In Treg-depleted mice, MPs increased projections toward the epididymal lumen as well as invading the lumen. ASA-bound sperm enhance sperm agglutination and might facilitate sperm phagocytosis. Tolerance breakdown impaired epididymal epithelial function and altered extracellular vesicle cargo, both of which play crucial roles in the acquisition of sperm fertilizing ability and subsequent embryo development. The affected mice had reduced sperm number and motility and severe fertility defects. Deciphering these immunoregulatory mechanisms may help to design new strategies to treat male infertility, as well as to identify potential targets for immunocontraception.

From Nose to Lumbar Spinal Cord – Reduced Sperm Numbers Occur by Olfactory Bulbectomy-Related Onuf’s Nucleus Degeneration: New Experimental Evidence for Kallmann Syndrome

Introduction: Olfaction and its relation to human health is an area of growing interest. Although olfaction disorders have been considered a part of Kallmann syndrome, the role of olfactory dysfunction on spermatogenesis has not been studied yet. We studied if olfactory bulbectomy (OBX) causes dysfunction in spermatogenesis as a result of Onuf’s nucleus damage. Methods: Twenty-eight male rats were divided into three groups: six as the control (G-1; n = 6), six as the only frontal burr hole applied animals SHAM (G-2; n = 6), and 16 as the study group (G-3; n = 16) in which OBX was performed. The animals were followed for 2 months. After the decapitation of the animals, olfactory bulb (OB) volumes (mm3), the neuron density of the Onuf’s nucleus (n/mm3), and sperm density (n/mm3) were estimated stereologically and analyzed. Results: OB volumes (mm3), degenerated neuron density of Onuf’s nucleus (n/mm3), and sperm numbers of control, SHAM, and study groups were estimated as: 4 ± 0.5; 6 ± 2 and 103.245 ± 10.841 in G-1; 3.5 ± 0.7; 14 ± 4 and 96.891 ± 9.569 in G-2; and 1.3 ± 0.3; 91 ± 17 and 73.561 ± 6.324 in G-3. The statistical results of degenerated neuron density of Onuf’s nucleus and sperm numbers between groups are p < 0.005 for G-1/G-2; p < 0.0005 for G-2/G-3; and p < 0.00001 for G-1/G-3. Discussion: This study first time indicates that Onuf’s nucleus degeneration secondary to OBX seems to be responsible for reduced sperm numbers.

Identification of follicle-stimulating hormone-responsive genes in Sertoli cells during early postnatal mouse testis development.

In the mouse testis, Sertoli cells rapidly divide during a narrow window of time pre-pubertally and differentiate thereafter. The number of Sertoli cells determines the testis size and germ cell-carrying capacity. Follicle-stimulating hormone (FSH) binds its cognate FSH-receptors expressed on Sertoli cells and acts as a mitogen to regulate their proliferation. Fshb-/- mutant adult male mice have reduced Sertoli cell number and testis size and reduced sperm number and motility. However, FSH-responsive genes in early postnatal mouse Sertoli cells are unknown. To identify FSH-responsive genes in early postnatal mouse Sertoli cells. A fluorescence-activated cell sorting method was developed to rapidly purify Sertoli cells from control and Fshb-/- mice carrying a Sox9 GfpKI allele. These pure Sertoli cells were used for large-scale gene expression analyses. We show that mouse Sertoli cells rarely divide beyond postnatal day 7. Our in vivo BrdU labeling studies indicate loss of FSH results in a 30% reduction in Sertoli cell proliferation in mice at 5 days of age. Flowsorted GFP+ Sertoli cells with maximal Fshr expression were 97%-98% pure and mostly devoid of Leydig and germ cells as assessed by Taqman qPCR quantification of gene expression and immunolabeling of the corresponding cell-specific markers. Large-scale gene expression analysis identified several differentially regulated genes in flow-sorted GFP+ Sertoli cells obtained from testis of control and Fshb-/- mice at 5 days of age. The top 25 networks identified by pathway analysis include those related to the cell cycle, cell survival and most importantly, carbohydrate and lipid metabolism and molecular transport. Several of the FSH-responsive genes identified in this study could serve as useful markers for Sertoli cell proliferation in normal physiology, toxicant-induced Sertoli cell/testis injury, and other pathological conditions. Our studies reveal that FSH-regulates macromolecular metabolism and molecular transport networks of genes in early postnatal Sertoli cells most likely in preparation for establishment of functional associations with germ cells to successfully coordinate spermatogenesis.

Loss-of-function mutations in CEP78 cause male infertility in humans and mice.

Centrosomal protein dysfunction might cause ciliopathies. However, the role of centrosomal proteins in male infertility remains poorly defined. Here, we identified a pathogenic splicing mutation in CEP78 in male infertile patients with severely reduced sperm number and motility, and the typical multiple morphological abnormalities of the sperm flagella phenotype. We further created Cep78 knockout mice, which showed an extremely low sperm count, completely aberrant sperm morphology, and approximately null sperm motility. The infertility of the patients and knockout mice could not be rescued by an intracytoplasmic sperm injection treatment. Mechanistically, CEP78 might regulate USP16 expression, which further stabilizes Tektin levels via the ubiquitination pathway. Cep78 knockout mice also exhibited impairments in retina and outer hair cells of the cochlea. Collectively, our findings identified nonfunctional CEP78 as an indispensable factor contributing to male infertility and revealed a role for this gene in regulating retinal and outer hair cell function in mice.

Kpna6 deficiency causes infertility in male mice by disrupting spermatogenesis.

ABSTRACTSpermatogenesis is driven by an ordered series of events, which rely on trafficking of specific proteins between nucleus and cytoplasm. The karyopherin α family of proteins mediates movement of specific cargo proteins when bound to karyopherin β. Karyopherin α genes have distinct expression patterns in mouse testis, implying they may have unique roles during mammalian spermatogenesis. Here, we use a loss-of-function approach to determine specifically the role of Kpna6 in spermatogenesis and male fertility. We show that ablation of Kpna6 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells. Kpna6-deficient mice exhibit impaired Sertoli cell function, including loss of Sertoli cells and a compromised nuclear localization of the androgen receptor. Furthermore, our data demonstrate devastating defects on spermiogenesis, including incomplete sperm maturation and a massive reduction in sperm number, accompanied by disturbed histone-protamine exchange, differential localization of the transcriptional regulator BRWD1 and altered expression of RFX2 target genes. Our work uncovers an essential role of Kpna6 in spermatogenesis and, hence, in male fertility.

Pluripotency Factor Tex10 Finetunes Wnt Signaling for PGCLC Specification and Spermatogenesis

The appropriate specification and differentiation of primordial germ cells (PGCs) are critical in promoting human reproductive health. This study establishes the testis-specific transcript 10 (Tex10) as a previously unappreciated molecular player in PGC specification in culture. Mechanistically, Tex10 binds the Wnt negative regulator genes marked by H3K4me3 at the PGCLC stage in restraining Wnt signaling. Tex10 depletion hyperactivates Wnt signaling compromising the specification efficiency, whereas Tex10 overexpression attenuates the Wnt signaling promoting efficient PGC specification. We also explored the in vivo roles of Tex10 in germ cell development using the Tex10 conditional knockout mouse model, revealing compromised male fertility with reduced sperm number and motility. In addition, defective spermatogenesis in Tex10 knockout mice is correlated with aberrant Wnt signaling upregulation. Taken together, our study uncovers a new role of Tex10 in PGC specification and male germline development through finetuning the Wnt signaling.

First emerging evidence of the relationship between Onuf's nucleus degeneration and reduced sperm number following spinal subarachnoid haemorrhage: Experimental study.

Lumbosacral pathologies can lead to infertility. Onuf's nucleus changes in these pathologies may have a role in low sperm number. This study aims to investigate the relationship between Onuf's nucleus degeneration and sperm number following spinal subarachnoid haemorrhage. 22 rabbits were used. They were divided into three groups; five of them were used as the control (GI), five as the SHAM (GII) and twelve as the study groups (GIII). The study group received 0.7ccs autologous blood into the spinal subarachnoid space at the T12-L1 level. After two weeks, all animals were decapitated, and S1-S3 laminectomy was done. Neurodegenerative changes of Onuf's nucleus, pudendal ganglia (S3) following two weeks after spinal SAH, were examined; sperm numbers were calculated. Degenerated neuron density of the Onuf's nucleus (n/mm3 ), the pudendal ganglia (S3) (n/mm3 ) and mean sperm numbers were calculated as 5±2, 8±3/mm3 and 98.345±12.776/mm3 in the control (GI), 20±5/mm3 , 243±66/mm3 and 91.841±9.654/mm3 in the SHAM (GII), 143±39/mm3 , 2,350±320/mm3 and 68.549±5.540/mm3 in the study group (GIII). In conclusion, there were statistically significant differences between groups. Onuf's nucleus may be responsible for decreased sperm number following spinal SAH.

Adverse effects of metabolic disorders in childhood on adult reproductive function and fertility in the male.

Over the last 50 years, there has been a steady decline in fertility rates in humans, which has occurred in parallel with an increasing incidence of obesity and metabolic disorders. The potential impact of these disorders and plausible mechanisms by which they negatively influence male reproduction are only partly understood and published data are often controversial. Obesity is one of the most important health challenges worldwide and is becoming more prevalent in children and adolescents. Obesity, the metabolic syndrome and related co-morbidities can lead to impaired male reproductive function, including adverse effects on spermatogenesis and steroidogenesis as illustrated by reduced sperm number and quality, decreased testosterone levels and elevated inflammatory markers. The incidence of diabetes mellitus type I is also dramatically increasing and may negatively impact spermatogenesis and testicular function, resulting in decreased serum testosterone and epididymal weight. In this review, we summarize and discuss the effects of metabolic diseases that typically develop during childhood and adolescence on later reproductive function and fertility. While impact on reproductive health is likely observed in both sexes, we have chosen to focus on the male in the current review. Specifically, we illustrate adverse effects of obesity, type 1 diabetes, the metabolic syndrome and insulin resistance on sperm function and testosterone metabolism. Identification of pathophysiological mechanisms during childhood may open up new avenues for early prevention and treatment resulting in better reproductive outcomes and improved fertility rates during adulthood.

Cadmium mediated redox modulation in germline stem cells homeostasis affects reproductive health of Drosophila males

Maintenance of male germline stem cells (GSCs) homeostasis is crucial for successful reproductive life of adults. New insights gained on dysfunction in stem cell maintenance could be the basis of stem cell dependent ailment during adulthood. Cadmium (Cd), a reported male reproductive toxicant, has been explored inadequately for its impact on male GSCs maintenance. The present study, therefore, has been aimed to evaluate the adverse effect of Cd on the homeostasis of GSCs by using Drosophila testis as an in vivo model. Following developmental exposure of environmentally relevant concentrations of Cd (5.0, 10.0 and 20.0 μg/mL) to Drosophila, we showed that a significantly increased level of reactive oxygen species (ROS) at 20.0 μg/mL of Cd resulted in alteration of GSCs number accompanied by inappropriate differentiation leading to reduced sperm number and eventually poor reproductive performance in exposed organism. Rescuing effect was evident by overexpressing sod in the early germ cell stage. The study suggests that an alteration in GSCs homeostasis due to redox imbalance plays a pivotal role in Cd induced failure in male fertility. The study further advocates for the use of Drosophila as an alternative animal model for in vivo evaluation of male GSCs toxicity with minimal ethical concern.

The mitochondrial metal transporters mitoferrin1 and mitoferrin2 are required for liver regeneration and cell proliferation in mice

Mitochondrial iron import is essential for iron-sulfur cluster formation and heme biosynthesis. Two nuclear-encoded vertebrate mitochondrial high-affinity iron importers, mitoferrin1 (Mfrn1) and Mfrn2, have been identified in mammals. In mice, the gene encoding Mfrn1, solute carrier family 25 member 37 (Slc25a37), is highly expressed in sites of erythropoiesis, and whole-body Slc25a37 deletion leads to lethality. Here, we report that mice with a deletion of Slc25a28 (encoding Mfrn2) are born at expected Mendelian ratios, but show decreased male fertility due to reduced sperm numbers and sperm motility. Mfrn2-/- mice placed on a low-iron diet exhibited reduced mitochondrial manganese, cobalt, and zinc levels, but not reduced iron. Hepatocyte-specific loss of Slc25a37 (encoding Mfrn1) in Mfrn2-/- mice did not affect animal viability, but resulted in a 40% reduction in mitochondrial iron and reduced levels of oxidative phosphorylation proteins. Placing animals on a low-iron diet exaggerated the reduction in mitochondrial iron observed in liver-specific Mfrn1/2-knockout animals. Mfrn1-/-/Mfrn2-/- bone marrow-derived macrophages or skin fibroblasts in vitro were unable to proliferate, and overexpression of Mfrn1-GFP or Mfrn2-GFP prevented this proliferation defect. Loss of both mitoferrins in hepatocytes dramatically reduced regeneration in the adult mouse liver, further supporting the notion that both mitoferrins transport iron and that their absence limits proliferative capacity of mammalian cells. We conclude that Mfrn1 and Mfrn2 contribute to mitochondrial iron homeostasis and are required for high-affinity iron import during active proliferation of mammalian cells.

Alteration of sperm parameters and reproductive hormones in Swiss mice via oxidative stress after co-exposure to titanium dioxide and zinc oxide nanoparticles.

In this study, Swiss male mice were intraperitoneally administered with titanium dioxide (TiO2 ) and zinc oxide (ZnO) nanoparticles (NPs) and their mixture (1:1) at doses between 9.38 and 75mg/kg for 5weeks to evaluate reproductive toxicity. Both NPs and their mixture significantly (p<.001) altered sperm motility, reduced sperm numbers and increased abnormalities, while their mixture induced more sperm abnormalities than either TiO2 NPs or ZnO NPs. Both NPs and their mixture significantly (p<.05) reduced the LH level, while ZnO NPs alone and their mixture (p<.001) increased the testosterone levels at tested doses. The testes of exposed mice showed pathological changes and altered histomorphometrics. TiO2 NPs and ZnO NPs individually induced a significant (p<.01) reduction in SOD and CAT activities, while the mixture significantly (p<.001) decreased CAT activity and increased SOD activity. TiO2 NPs alone at 9.38mg/kg induced a significant (p<.001) reduction in the GSH level, while both NPs and their mixture increased the MDA level significantly (p<.05). The data showed that the mixture had a synergistic interaction to induce testicular damage. Overall, oxidative stress may be involved in the NP-mediated testicular damage observed.