Assessing Variance in Male Reproductive Skew Based on Long-Term Data in Free-Ranging Rhesus Macaques.

The unequal share in male reproduction (male reproductive skew) has been reported across primate species. To explain the distribution of male reproduction within groups various skew models have been applied to primates, however the "dynamic tug-of-war" model first accounted for the specifics of primate sociality. This model assumes that an increase in the number of competing males, a high degree of female cycle synchrony and their interaction will result in a lower degree of male reproductive skew. Here, we first tested the predictors of this model in rhesus macaques (Macaca mulatta) using long-term demographic and genetic data (up to 9 groups over 22 seasons) of the Cayo Santiago population (Puerto Rico). We also tested an extended version including group size and sex ratio and their interaction with female cycle synchrony. Finally, we investigated which male attributes determine the probability to become a top sire (highest paternity share per group and season). Confirming studies, male rhesus macaques exhibited low to medium degrees of reproductive skew based on the multinomial index, M. Unlike predicted, reproductive skew was higher in groups with more males. The extended analysis suggested that reproductive skew increased with group size in more male-biased groups, but decreased with group size in female-biased groups indicating that the numbers of male and female group members matter. We detected no effect of female cycle synchrony on the variance of reproductive skew. Finally, only maternal rank predicted the probability to become a top sire as long as males resided in their natal group. Together, our results did not support predictions by the dynamic skew model in rhesus macaques, but strengthen studies suggesting that other factors in addition to male-male competition predict male reproductive output in rhesus macaques. Future skew studies should consider female choice and alternative male mating strategies.

The Role of Ferroptosis in Environmental Pollution-Induced Male Reproductive System Toxicity.

This article provides a comprehensive review of the toxic effects of environmental pollution on the male reproductive system, with a particular emphasis on ferroptosis, a form of programmed cell death. Research has shown that environmental pollutants, such as heavy metals, pesticide residues, and plastic additives, can disrupt oxidative stress, increasing the production of reactive oxygen species (ROS) in germ cells. This disruption damages cellular lipids, proteins, and DNA, culminating in cell dysfunction or death. Ferroptosis, a cell death pathway closely linked to oxidative stress, is characterized by the accumulation of intracellular iron ions and elevated levels of lipid ROS. This review also explores the role of ferroptosis in male reproductive disorders, including its contributions to reduced sperm count, decreased motility, and abnormal morphology. Environmental pollutants, particularly heavy metals, can induce ferroptosis by interfering with intracellular antioxidant systems, notably the NRF2, GSH, and GPX4 pathways, accumulating toxic lipid peroxides. Furthermore, the article examines the potential interplay between ferroptosis and other forms of cell death, such as apoptosis, autophagy, pyroptosis, and necrosis, in the context of male reproductive health. The review underscores the critical need for further research into the link between environmental pollutants and male fertility, particularly focusing on ferroptosis. It advocates for targeted research efforts to mitigate the adverse effects of ferroptosis and protect reproductive health, emphasizing that a deeper understanding of these mechanisms could lead to innovative preventive strategies against environmental threats to fertility.

Immunoregulation and male reproductive function: Impacts and mechanistic insights into inflammation.

This paper investigates the complex relationship between the immune system and male reproductive processes, emphasizing how chronic inflammation can adversely affect male reproductive health. The immune system plays a dual role; it protects and regulates reproductive organs and spermatogenesis while maintaining reproductive health through immune privilege in the testes and the activities of various immune cells and cytokines. However, when chronic inflammation persists or intensifies, it can disrupt this balance, leading to immune attacks on reproductive tissues and resulting in infertility.This study provides a detailed analysis of how chronic inflammation can impair sperm production, sperm quality, and the secretion of gonadal hormones both directly and indirectly. It also delves into the critical roles of testicular immune privilege, various immune cells, and cytokines in sustaining reproductive health and examines the impacts of infections, autoimmune diseases, and environmental factors on male fertility.

Role of Anonychium africanum (Plantae, Fabaceae) in Metal Oxido-Inflammatory Response: Protection Evidence in Gonad of Male Albino Rat.

Male fertility is strongly affected by the overexpression of free radicals induced by heavy metals. The aim of this study was to evaluate the potential antioxidant, anti-inflammatory, and gonado-protective effects of natural compounds. Biochemical and morphological assays were performed on male albino rats divided into five groups: a control group (water only), a group orally exposed to a metal mixture of Pb-Cd-Hg-As alone and three groups co-administered the metal mixture and an aqueous extract of the Nigerian medicinal plant, Anonychium africanum (Prosopis africana, PA), at three different concentrations (500, 1000, and 1500 mg/kg) for 60 days. The metal mixture induced a significant rise in testicular weight, metal bioaccumulation, oxidative stress, and pro-inflammatory and apoptotic markers, while the semen analysis indicated a lower viability and a decrease in normal sperm count, and plasma reproductive hormones showed a significant variation. Parallel phytochemical investigations showed that PA has bioactive compounds like phlobatannins, flavonoids, polyphenols, tannins, saponins, steroids, and alkaloids, which are protective against oxidative injury in neural tissues. Indeed, the presence of PA co-administered with the metal mixture mitigated the toxic metals' impact, which was determined by observing the oxido-inflammatory response via nuclear factor erythroid 2-related factor 2, thus boosting male reproductive health.

Effects of fluoride toxicity on the male reproductive system: A review.

BACKGROUND: Fluoride toxicity and fluorosis is an emerging global problem. Fluoride has long been added to water for dental caries prevention; however, it has a variety of damaging consequences on human bodies. The aim of this paper is to analyse all the literature available on the effects of fluoride toxicity on male reproductive system. METHODS: Research papers were collected using various methods of data collection like Pubmed, Scopus, and Google Scholar from 1980 to 2024, and then reviewed thoroughly. RESULTS: Fluoride is known to cause various histopathological and biochemical alterations in the male reproductive system. It also affects fertility, semen quality, sperm number and quality,the process of spermatogenesis and spermiogenesis. Key changes caused by fluoride in male reproductive system include structural defects in the flagellum, acrosome, and nucleus of spermatids and epididymal spermatozoa. Degenerative changes in Leydig cells result in reduced testosterone production, causing regression of seminiferous tubules and structural damage to the epididymis, ultimately terminating spermatogenesis which leads to infertility. Decrease in levels of testosterone and activities of various antioxidant enzymes resulting in greater oxidative stress was also seen. CONCLUSIONS: Fluoride has various detrimental effects on male reproductive system and overall reproductive health. This type of study is important for understanding the effects of fluoride toxicity so that health officials can guide public about safe fluoride exposure limits and the damages it can cause in higher concentrations. Studies using various natural and synthetic ameliorative substances mentioned in the text later can prove to be helpful for development of various therapeutic approaches to mitigate the effects of fluoride toxicity.

Disturbance of mitochondrial dynamics led to spermatogenesis disorder in mice exposed to polystyrene micro- and nanoplastics.

The widespread presence of polystyrene micro- and nanoplastics (PS-MPs/NPs) in the environment poses a threat to the health of the population. Animal studies have shown PS-MPs/NPs had male reproductive toxicity, while its mechanisms are unclear. To investigate that, male Balb/c mice were randomized into 3 groups: the control, 1 µm PS-MPs and 70 nm PS-NPs group, and they were given PS-MPs/NPs by intratracheal instillation for 28 days. Results revealed that PS-MPs/NPs up-regulated the expression of mitochondrial fission related factors (p-DRP1/DRP1, FIS1) and down-regulated the level of mitochondrial fusion related factors (MFN1/2, OPA1), causing over mitochondrial fission, which activating mitochondrial apoptotic pathway (BAX, Cleaved-Caspase9, Cleaved-Caspase3), resulting in cell apoptosis. Moreover, the damaged structure of mitochondria and over mitochondrial fission caused mitochondrial DNA (mtDNA) to translocate from mitochondria to cytoplasm, which activated DNA sensing pathway (cGAS-STING) and induced cell pyroptosis in testis by raising the expression of inflammation factors (NLRP3, ASC, Caspase1 p20, IL-1ß). In vitro, by using the mitochondrial fission inhibitor Mdivi-1, it is found that PS-NPs-induced cell apoptosis and pyroptosis were associated with over mitochondrial fission. Taken together, we conclude that PS-MPs/NPs cause spermatogenesis disorder possibly through damaging mitochondrial structure and dynamic homeostasis, which on the one hand results in mitochondria-mediated apoptosis, and on the other hand leads to mtDNA mislocalization, activating cGAS-STING pathway and inflammation, ultimately resulting in pyroptosis. This study may provide a new reference to the potential mechanisms of male reproductive toxicity caused by PS-MPs/NPs.

RNA reading protein YTHDF2 mediates Benzo(k)fluoranthene induced male reproductive injury by regulating the stability of BCL2.

Benzo (k) fluoranthene (BkF) has adverse effects on male reproduction, but its specific mechanism of action is still unclear. This study focused on the role of RNA reading protein YTHDF2 and its mechanism in BkF induced male reproductive injury. Mouse GC-2 spermatocytes were exposed to 0, 40, 80, 160 µM BkF. It was found that BkF significantly increased the apoptosis of GC-2 cell and decreased its survival rate. BCL2 in spermatocytes decreased significantly, while the expression of P53 and BAX exhibited a notable increase. Interestingly, the expression of RNA reading protein YTHDF2 progressively rose in tandem with the escalating BkF exposure dosage. Overexpression of YTHDF2 significantly reduced the viability of cells and increased the apoptosis rate. Meanwhile, there was a substantial increase in the expression of P53 and BAX, BCL2 was significantly down-regulated. On the contrary, interfering with YTHDF2 increased cell proliferation and reduced cell apoptosis. Furthermore, YTHDF2 overexpression exacerbated the decrease in cell viability under BkF exposure, while YTHDF2 knockdown was the opposite. The results from the RIP assay demonstrated a significant enhancement in the interaction of YTHDF2 protein with BCL2 mRNA following the overexpression of YTHDF2. In addition, animal experiments showed that there was an increase in apoptosis and a decrease in proliferation of testicular cells in mice in the high-dose (30 mg/kg) BkF group by TUNEL staining and Ki67 staining. Immunohistochemical analysis showed that BCL2 levels were significantly lower in the high-dose group than in the control group, while YTHDF2, P53 and BAX were dramatically increased. In summary, our study suggests that YTHDF2 has been implicated in BkF-induced male reproductive injury by promoting the degradation of BCL2.

Short Chain Chlorinated Paraffins Impaired Spermatogenesis Process in Mice via Inhibiting α-KG/TET Enzyme Activity.

Short chain chlorinated paraffins (SCCPs) are widely found in various environmental media and potentially threaten human health. However, the toxicity mechanisms of SCCPs to the male reproductive system remain unclear. In this study, male BALB/c mice and GC-1 cells were used to investigate the reproductive toxicity of SCCPs and their molecular mechanisms. SCCPs decreased the content of the tricarboxylic acid cycle intermediate α-KG in testicular cells, thus inhibiting the activity of the DNA demethylase TET enzyme and resulting in an increase in the overall methylation level of the testicular genome. Correspondingly, the promoter demethylation and expression of spermatogenesis-related genes Rbm46, Sohlh1, Kit, and Dmrt1 were significantly reduced by SCCPs, which further prevented the transformation of spermatogonia to spermatocytes and reduced sperm quality in mice. The in vitro experiments suggested that the TGFß pathway activated by oxidative stress might be an essential reason for inhibiting the tricarboxylic acid cycle and the reduction of α-KG content in testicular cells induced by SCCPs. Overall, this study reveals a novel metabolic regulatory mechanism of SCCPs-induced spermatogenesis disorders, which provides an essential theoretical basis for the prevention of reproductive toxicity of SCCPs.

Transcriptomic Characterization of Male Formosan Pangolin (Manis pentadactyla pentadactyla) Reproductive Tract and Evaluation of Domestic Cat (Felis catus) as a Potential Model Species.

The Formosan pangolin (Manis pentadactyla pentadactyla) is an endemic animal of Taiwan. Due to their reduced population and behavior, very little is known about this enigmatic species. To unravel male pangolin reproduction, in the present study, we built a complete genomic database of the male Formosan pangolin reproductive tract and revealed highly expressing genes as well as critical signaling pathways and their associated biological processes in both the testis and the epididymis. Moreover, we evaluated the domestic cat (Felis catus) as a potential model species for male pangolin reproduction by comparing their testicular transcriptomes. We demonstrated a clear tissue-specific gene expression supporting the unique biological signature of each reproductive tissue and identified critical genes of the different reproductive organs. Pathway enrichment analysis revealed unique pathways in the testis as well as a clear epididymal transition. Furthermore, domestic cats, despite being the closest domestic species to pangolin, demonstrated their unfitness as a male reproduction model species as clear differences in spermatid differentiation and metabolism were observed. These results enable a better understanding of male pangolin reproduction characteristics and may inspire improvements in in Formosan pangolin conservation strategies.

EHDPP induces proliferation inhibition and apoptosis to spermatocyte: Insights from transcriptomic and metabolomic profiles.

BACKGROUND: 2-ethylhexyldiphenyl phosphate (EHDPP) was used widespread in recent years and it was reported to impair reproductive behaviors and decrease fertility in male Japanese medaka. However, whether EHDPP causes spermatogenesis disturbance remains uncertain. OBJECTIVES: We aimed to study the male reproductive toxicity of EHDPP and its related mechanism. METHODS: Human spermatocyte cell line GC-2 was treated with 10 µM, 50 µM or 100 µM EHDPP for 24 h. Male CD-1 mice aged 6 weeks were given 1, 10, or 100 mg/kg/d EHDPP daily for 42 days and then euthanized to detect sperm count and motility. Proliferation, apoptosis, oxidative stress was detected in mice and cell lines. Metabolome and transcriptome were used to detect the related mechanism. Finally, anti-oxidative reagent N-Acetylcysteine was used to detect whether it could reverse the side-effect of EHDPP both in vivo and in vitro. RESULTS: Our results showed that EHDPP inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Metabolome and transcriptome showed that nucleotide metabolism disturbance and DNA damage was potentially involved in EHDPP-induced reproductive toxicity. Finally, we found that excessive ROS production caused DNA damage and mitochondrial dysfunction; NAC supplement reversed the side effects of EHDPP such as DNA damage, proliferation inhibition, apoptosis and decline in sperm motility. CONCLUSION: ROS-evoked DNA damage and nucleotide metabolism disturbance mediates EHDPP-induced germ cell proliferation inhibition and apoptosis, which finally induced decline of sperm motility.

Negative association of atmospheric pollutants with semen quality: A cross-sectional study in Taiyuan, China.

BACKGROUND: In recent decades, the quality of male semen has decreased worldwide. Air pollution has been linked to lower semen quality in several studies. However, the effects of atmospheric pollutants on different semen characteristics have not always been consistent. The aim of this study was to investigate the association between the Air Quality Index (AQI) and six atmospheric pollutants (PM2.5, PM10, SO2, NO2, CO, and O3), semen quality, and their key exposure window periods. METHODS: This study included 1711 semen samples collected at the reproductive clinics of the First Affiliated Hospital of Shanxi Medical University in Taiyuan, Shanxi, China, from October 10, 2021, to September 30, 2022. We evaluated the association of AQI and six atmospheric pollutants with semen quality parameters throughout sperm development and three key exposure windows in men using single-pollutant models, double-pollutant models, and subgroup analyses of semen quality-eligible groups. RESULTS: Both the single-pollutant model and subgroup analyses showed that PM, CO, and O3 levels were negatively correlated with total and progressive motility. At 70-90 d before semen collection, CO exposure and semen volume (ß =-1.341, 95 % CI: -1.805, -0.877, P <0.001), total motility (ß =-2.593, 95 % CI: -3.425, -1.761, P <0.001), and progressive motility (ß =-4.658, 95 % CI: -5.556, -3.760, P <0.001) were negatively correlated. At 0-9 days before semen collection, CO was negatively correlated with normal morphology (ß =-3.403, 95 % CI: -5.099, -1.708, P <0.001). Additionally, the AQI was adversely associated with total and progressive motility in subgroup analyses of the semen quality-eligible groups. CONCLUSIONS: During the entire sperm development process, multiple air pollutants were determined to have an adverse correlation with semen quality parameters. AQI was significant marker for the combined effects of various atmospheric pollutants on male reproductive health.

Extracellular cAMP elicits contraction of rat vas deferens: Involvement of ecto-5'-nucleotidase and adenosine A1 receptors.

AIMS: It is well established that intracellular cAMP contributes to the relaxation of vas deferens smooth muscle. In many tissues, intracellular cAMP is actively transported to the extracellular space, where it exerts regulatory functions, via its metabolite adenosine. These actions take place through the cAMP conversion to adenosine by ectoenzymes, a process called "extracellular cAMP-adenosine pathway". Herein, we investigated whether, in addition to ATP, extracellular cAMP might be an alternative source of adenosine, influencing the contraction of vas deferens smooth muscle. MAIN METHODS: The effects of cAMP, 8-Br-cAMP and adenosine were analyzed in the isometric contractions of rat vas deferens. cAMP efflux was analyzed by measuring extracellular cAMP levels after exposure of vas deferens segments to isoproterenol and forskolin in the presence or absence of MK-571, an inhibitor of MRP/ABCC transporters. KEY FINDINGS: While 8-Br-cAMP, a cell-permeable cAMP analog, induced relaxation of KCl-precontracted vas deferens, the non-permeant cAMP increased the KCl-induced contractile response, which was mimicked by adenosine, but prevented by inhibitors of ecto-5'-nucleotidase or A1 receptors. Our results also showed that isoproterenol and forskolin increases cAMP efflux via an MRP/ABCC transporter-dependent mechanism, since it is inhibited by MK-571. SIGNIFICANCE: Our data show that activation of ß-adrenoceptors and adenylyl cyclase increases cAMP efflux from vas deferens tissue, which modulates the vas deferens contractile response via activation of adenosine A1 receptors. Assuming that inhibition of vas deferens contractility has been proposed as a strategy for male contraception, the extracellular cAMP-adenosine pathway emerges as a potential pharmacological target that should be considered in studies of male fertility.

The prediction of semen quality based on lifestyle behaviours by the machine learning based models.

PURPOSE: To find the machine learning (ML) method that has the highest accuracy in predicting the semen quality of men based on basic questionnaire data about lifestyle behavior. METHODS: The medical records of men whose semen was analyzed for any reason were collected. Those who had data about their lifestyle behaviors were included in the study. All semen analyses of the men included were evaluated according to the WHO 2021 guideline. All semen analyses were categorized as normozoospermia, oligozoospermia, teratozoospermia, and asthenozoospermia. The Extra Trees Classifier, Average (AVG) Blender, Light Gradient Boosting Machine (LGBM) Classifier, eXtreme Gradient Boosting (XGB) Classifier, Logistic Regression, and Random Forest Classifier techniques were used as ML algorithms. RESULTS: Seven hundred thirty-four men who met the inclusion criteria and had data about lifestyle behavior were included in the study. 356 men (48.5%) had abnormal semen results, 204 (27.7%) showed the presence of oligozoospermia, 193 (26.2%) asthenozoospermia, and 265 (36.1%) teratozoospermia according to the WHO 2021. The AVG Blender model had the highest accuracy and AUC for predicting normozoospermia and teratozoospermia. The Extra Trees Classifier and Random Forest Classifier models achieved the best performance for predicting oligozoospermia and asthenozoospermia, respectively. CONCLUSION: The ML models have the potential to predict semen quality based on lifestyles.

Mild coronavirus disease 2019: Results of a multicentric prospective study on severe acute respiratory syndrome coronavirus 2 presence in semen fractions and cells and its effects on semen parameters.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2, the virus responsible for coronavirus disease 2019, affects multiple organs. The virus enters cells through angiotensin-converting enzyme-2 and host factors present in genital organs, leading to concern over virus shedding in semen and reproductive function. OBJECTIVES: To investigate severe acute respiratory syndrome coronavirus 2 in semen from patients with a mild infection, identify the seminal infected cells, and explore the effect of the infection on sex hormones and semen parameters. MATERIALS AND METHODS: Prospective study of 54 men with mild severe acute respiratory syndrome coronavirus 2 infection. Semen was collected at 7, 15, 30, 60, 90, 180, and 365 days after symptom onset, and severe acute respiratory syndrome coronavirus 2 RNA was measured in serum, saliva, urine, and semen. The presence of infectious severe acute respiratory syndrome coronavirus 2 in semen was assessed using Vero cell culture. Infected semen cells were identified using immunofluorescence against severe acute respiratory syndrome coronavirus 2 nucleoprotein antigen and cell markers. Semen characteristics as well as testosterone, inhibin B, luteinizing hormone, and follicle-stimulating hormone levels were determined. RESULTS: 11% of patients had at least one severe acute respiratory syndrome coronavirus 2 RNA-positive semen. One patient had viral semen shedding up to day 90 after infection onset, with replication-competent virus isolated from semen and 40% cell fraction at day 7. After sperm preparation, 90% fraction was severe acute respiratory syndrome coronavirus 2 RNA-positive at days 7 and 15. The swim-up fraction was positive only on day 7. In semen, nucleoprotein antigen was detected mainly in exfoliated epithelial cells and less frequently in Sertoli cells. Sperm count and motile sperm count were lower at day 30 than at day 7. Round cells in semen were increased during the acute phase. At days 7 and 15, sperm count and motile sperm count were lower in severe acute respiratory syndrome coronavirus 2 RNA-positive semen compared with negative semen, while semen volume and follicle-stimulating hormone levels were increased. Long-term follow-up shows no evidence of a detrimental effect on hormonal or semen characteristics. DISCUSSION AND CONCLUSION: 11% of patients with mild coronavirus disease 2019 who were not hospitalized had severe acute respiratory syndrome coronavirus 2 excretions in semen, which persisted for up to 90 days in one patient. No germ cells appeared infected by the virus, but the detection of nucleoprotein antigen-positive epithelial semen cells and Sertoli cells suggests genital tract infection. Albeit infrequent, semen may contain the replication-competent virus during the acute phase with potential risk of severe acute respiratory syndrome coronavirus 2 transmissions during sexual contact and assisted reproduction procedures. The effect of mild coronavirus disease 2019 on spermatogenesis and reproductive hormones was moderate and reversible.

Bidirectional Mendelian randomization to explore the causal relationships between the gut microbiota and male reproductive diseases.

Gut bacteria might play an important role in male reproductive disorders, such as male infertility and sperm abnormalities; however, their causal role is unclear. Herein, Mendelian randomization (MR)-Egger, weighted median, inverse variance weighting, Simple mode, and Weighted mode were used to test the causal relationship between gut microbes and male reproductive diseases. The MR results were validated using various metrics. The MR results were also consolidated using reverse causality speculation, conducted using two-way MR analysis and Steiger filtering. Biological function was analysed using enrichment analyses. The results suggested that eight intestinal microflorae were causally associated with male infertility. The Eubacterium oxidoreducens group was associated with an increased risk of male infertility, while the family Bacteroidaceae was negatively associated with male reproductive diseases. Eight intestinal microflorae were causally associated with abnormal spermatozoa. The family Streptococcaceae was associated with a high risk of abnormal spermatozoa, whereas the family Porphyromonadaceae was associated with a low risk of abnormal spermatozoa. No pleiotropy was observed, this study identified a high correlation between the gut flora and the likelihood of male reproductive diseases. Future research will attempt to advance microbial-focused treatments for such diseases.

Rosolic acid as a novel activator of the Nrf2/ARE pathway in arsenic-induced male reproductive toxicity: An in silico study.

Male reproductive toxicity as a result of arsenic exposure is linked with oxidative stress and excessive generation of reactive oxygen species (ROS). It leads to an imbalance between ROS production and antioxidant defense mechanisms ultimately resulting in male infertility. The nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor that responds to cellular stressors controlling the oxidative state, mitochondrial dysfunction, inflammation, and proteostasis. This study aims to investigate the potential of Rosolic acid (ROA) to act as a novel Nrf2 activator by mitigating oxidative stress to combat arsenic-induced male reproductive toxicity. The protein and ligands were prepared in the BIOVIA Discovery Studio, followed by protein-ligand docking using auto dock vina integrated with the PyRx-Virtual Screening Tool. Then the ADME properties were analyzed using the SwissADME tool to get a clear idea about the physicochemical properties, lipophilicity, water solubility, pharmacokinetics, and drug likeliness of ROA. It was followed by molecular dynamics simulation (MDS) studies using GROMACS. The 3D and 2D interaction maps revealed the interactions of Keap 1 with ROA. Keap1-ROA complex was found to have a binding energy of -7.8 kcal/mol. ROA showed 0 violations for Lipinski and 0 alerts each for PAINS and Brenk and a bioavailability score of 0.55. The BOILED-Egg representation showcases that ROA is predicted as passively crossing the blood-brain barrier (BBB). The MDS described 2FLU-ROA as a stable system. This work portrays that ROA can be a potent Nrf2 activator by exhibiting an inhibitory activity against the Keap1 protein and thus mitigating oxidative stress in arsenic-induced male reproductive toxicity.

Individual and joint associations of air pollutants exposure with semen quality: A retrospective longitudinal study in Wenzhou, China.

PURPOSE: The impact of air pollution on semen quality has been confirmed, yet the joint effect remains unclear. We evaluate the individual and joint associations of particulate (PM2.5 and PM10) and gaseous pollutants (NO2, SO2, O3 and CO) with semen quality. METHODS: We included 5,114 men in this study from 2014 to 2022. The individual and joint associations were measured by multiple linear regression models. RESULTS: Sperm motility and semen volume were inversely associated with pollutant concentrations during every stage of sperm development, especially at lag days 0-9 and 10-14 (all P < 0.05). Stratified analyses showed that the study pollutants (except CO) had a positive effect on semen concentration during the stage of sperm development, especially in spring and autumn, while a decreased total sperm number was associated with CO (all P < 0.05). However, joint associations of particulate and gaseous pollutants with semen quality parameters were not statistically significant (all P > 0.05). CONCLUSIONS: During all stages of sperm development, particulate and gaseous pollutants had individual negative impacts on sperm motility and semen volume, and these impacts were less pronounced in spring and autumn. Our findings highlight the importance and necessity of reducing the exposure to pollutants especially in the critical stage of sperm development to improve semen quality.

Triptolide induced spermatogenesis dysfunction via ferroptosis activation by promoting K63-linked GPX4 polyubiquitination in spermatocytes.

Triptolide (TP) is a major bioactive compound derived from Tripterygium wilfordii Hook. F. (TwHF) known for its medicinal properties, but it also exhibits potential toxic effects. It has been demonstrated to induce severe male reproductive toxicity, yet the precise mechanism behind this remains unclear, which limits its broad clinical application. This study aimed to investigate the mechanisms underlying testicular damage and spermatogenesis dysfunction induced by TP in mice, using both mouse models and the spermatocyte-derived cell line GC-2spd. In the present study, it was found that TP displayed significant testicular microstructure damaged and spermatogenesis defects including lower concentration and abnormal morphology by promoting ROS formation, MDA production and restraining GSH level, glutathione peroxidase 4 (GPX4) expression in vivo. Furthermore, Ferrostatin-1 (FER-1), a ferroptosis inhibitor, was found to significantly reduce the accumulation of lipid peroxidation, alleviate testicular microstructural damage, and enhance spermatogenic function in mice. Besides, notably decreased cell viability, collapsed mitochondrial membrane potential, and elevated DNA damage were observed in vitro. The above-mentioned phenomenon could be reversed by pre-treatment of FER-1, indicating that ferroptosis participated in the TP-mediated spermatogenesis dysfunction. Mechanistically, TP could enhance GPX4 ubiquitin degradation via triggering K63-linked polyubiquitination of GPX4, thereby stimulating ferroptosis in spermatocytes. Functionally, GPX4 deletion intensified ferroptosis and exacerbated DNA damage in GC-2 cells, while GPX4 overexpression mitigated ferroptosis induced by TP. Overall, these findings for the first time indicated a vital role of ferroptosis in TP induced-testicular injury and spermatogenic dysfunction through promoting GPX4 K63-linked polyubiquitination, which hopefully offers a potential therapeutic avenue for TP-related male reproductive damage. In addition, this study also provides a theoretical foundation for the improved clinical application of TP or TwHF in the future.

Effect of Humanin and MOTS-c on ameliorating reproductive damage induced by prepubertal cyclophosphamide chemotherapy in male mice.

Male patients who undergo prepubertal chemotherapy face the dual problems of fertility preservation in adulthood, including low testosterone, hypersexual function, and infertility. Humanin, as a small polypeptide coded within the mitochondrial DNA, with the mitochondrial short open reading frame named MOTS-c, both was believed to regulate mitochondrial homeostasis, be anti-inflammatory, improve metabolism, anti-apoptosis, and multiple pharmacological effects. However, there exists little evidence that reported Humanin and MOTS-c 's effects on moderating male spermatogenic function of patients after prepubertal chemotherapy. Here, we found that in vivo, mitochondrial polypeptides Humanin analog (HNG) and MOTS-c efficaciously protected the testicular spermatogenic function from reproductive injury. Moreover, transcriptomic sequencing analysis was performed to verify the differentially expressed genes such as Piwil2, AGT (angiotensinogen), and PTGDS (glycoprotein prostaglandin D2 synthase), which are related to the regulation of male reproductive function of male mice induced by prepubertal chemotherapy. Collectively, our data revealed that both Humanin analogs HNG and MOTS-c are the feasible approaches attached to the protective effect on the male reproductive function damaged by prepubertal chemotherapy.

Human risk assessment through development and application of a physiologically based toxicokinetic model for 4-tert-octylphenol.

4-tert-octylphenol (4-tert-OP) is an ecologically hazardous substance, and exposure to it in the environment has been consistently reported in the past. Despite the hazards and widespread exposure to 4-tert-OP, tools for scientific assessment of 4-tert-OP exposure risk level in humans are lacking. The main purpose of this study was to develop a physiologically-based-toxicokinetic (PBTK) model for 4-tert-OP and to perform quantitative risk assessment of 4-tert-OP in various population groups using the established model. Based on the results of toxicokinetic experiments on male rats, the PBTK model for 4-tert-OP was established and verified, and this was converted to a model for humans through interspecies extrapolation. Based on the previously reported no-observed-adverse-effect-levels for rats, it was possible to estimate the 4-tert-OP reference dose in humans through reverse dosimetry using the model. Biomonitoring data derived from various population groups were applied to the human PBTK model to calculate external exposures and margin of safety for 4-tert-OP for each population group. The PBTK model established in this study adequately explained the toxicokinetic experimental values at acceptable levels and was able to quantitatively predict the 4-tert-OP exposure level in the testes related to male reproductive toxicity. In addition, the degree of external exposure to 4-tert-OP could be scientifically estimated based on biomonitoring values derived from various biological matrices. The reference doses for systemic and reproductive toxicity caused by 4-tert-OP in male humans were calculated to be 0.16 and 1.12 mg/kg/day, respectively. The mean external exposure to 4-tert-OP in each population group estimated based on plasma and urine biomonitoring data was 0.04-66.24 mg/kg/day, showing very large exposure diversity between groups. Exposure risks to 4-tert-OP in populations ranged from safe to risky, suggesting the need for continued monitoring and risk management of 4-tert-OP worldwide. This study provides valuable scientific insight regarding the 4-tert-OP human risk assessment.