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Polystyrene nanoplastics (PS-NPs) have been reported to accumulate in the testes and constitute a new threat to reproductive health. However, the exact effects of PS-NPs exposure on testicular cells and the underlying mechanisms remain largely unknown. The C57BL/6 male mice were orally administered with PS-NPs (80 nm) at different dosages (0, 10, and 40 mg/kg/day) for 60 days, and GC-1 cells were treated with PS-NPs in this study. Enlarged seminiferous tubule lumens and a loose and vacuolated layer of spermatogenic cells were observed in PS-NPs-exposed mice. Spermatogenic cells which may be one of the target cells for this reproductive damage, were decreased in the mice from PS-NPs group. PS-NPs caused spermatogenic cells to undergo senescence, manifested as elevated SA-β-galactosidase activity and activated senescence-related signaling p53-p21/Rb-p16 pathways, and induced cell cycle arrest. Mechanistically, Gene Ontology (GO) enrichment suggested the key role of reactive oxygen species (ROS) in PS-NPs-induced spermatogenic cell senescence, and this result was confirmed by measuring ROS levels. Moreover, ROS inhibition partially attenuated the senescence phenotype of spermatogenic cells and DNA damage. Using the male health atlas (MHA) database, Sirt1 was filtrated as the critical molecule in the regulation of testicular senescence. PS-NPs induced overexpression of the main ROS generator Nox2, downregulated Sirt1, increased p53 and acetylated p53 in vivo and in vitro, whereas these disturbances were partially restored by pterostilbene. In addition, pterostilbene intervention significantly alleviated the PS-NPs-induced spermatogenic cell senescence and attenuated ROS burst. Collectively, our study reveals that PS-NPs exposure can trigger spermatogenic cell senescence mediated by p53-p21/Rb-p16 signaling by regulating the Sirt1/ROS axis. Importantly, pterostilbene intervention may be a promising strategy to alleviate this damage. • Nanoplastics induced reproductive damage in male mice. • Nanoplastics triggered spermatogenic cell senescence. • Sirt1/ROS axis was involved in the nanoplastic induced spermatogenic cell senescence. • Pterostilbene intervention may be a promising strategy to alleviate nanoplastic damage. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (B[a]P), a representative of polycyclic aromatic hydrocarbons (PAHs), is ubiquitously spread in the environment and showing deleterious impacts on male steroidogenesis, including testosterone synthesis disorder. However, the precise mechanisms involved in B[a]P-induced steroidogenesis perturbation remains obscure. In the present study, we integrated in vivo tests, transcriptome profiling, in vitro assays, and conjoint in silico toxicological approaches to delineate the detailed mechanisms. In mouse models, we observed that B[a]P administration remarkably inhibited testosterone synthesis accompanied by ultrastructural impairments of mitochondria and mitophagosome formation in mouse Leydig cells. Transcriptome profiling showed that B[a]P down-regulated the expression of Ndufa9 , Ndufa6 , Ndufa10 , and Ndufa5 in mouse testes, which are identified as critical genes involved in the assembly and functionality of mitochondrial complex I. In the in vitro tests, the bioactive B[a]P metabolite BPDE induced perturbation of testosterone synthesis by NDUFA10-mediated mitochondrial impairment, which was further exacerbated by mitophagy in TM3 Leydig cells. The findings of in silico toxicological analyses were highly consistent with the experimental observations and further unveiled that B[a]P/BPDE-involved PPARα activation could serve as a molecular initiating event to trigger the decline in Ndufa10 expression and testosterone synthesis. Overall, we have shown the first evidence that mitochondrial compromise in Leydig cells is the extremely crucial target in B[a]P-induced steroidogenesis perturbation. [Display omitted] • B[a]P-induced mitochondrial damage inhibits testosterone synthesis in Leydig cells. • Mitophagy exacerbates B[a]P-induced mitochondrial damage and decline in testosterone. • NDUFA10 participates in B[a]P-mediated impairment of complex Ⅰ and steroidogenesis. • B[a]P-activated PPARα triggers declines in NDUFA10 expression and steroidogenesis. [ABSTRACT FROM AUTHOR]

Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM 2.5 on Sertoli cells using the TM4 cell line and a real time whole-body PM 2.5 exposure mouse model, and further explore the underlying mechanisms through the application of metabolomics and transcriptomics. The results in vivo and in vitro showed that PM 2.5 reduced Sertoli cells number in seminiferous tubules and inhibited cell proliferation. PM 2.5 exposure also induced Sertoli cell dysfunction by increasing androgen binding protein (ABP) concentration, reducing the blood-testis barrier (BTB)-related protein expression, and decreasing glycolysis capacity and lactate production. The results of transcriptomics, metabolomics, and integrative analysis of multi-omics in the TM4 Sertoli cells revealed the activation of xenobiotic metabolism, and the disturbance of glutathione and purine metabolism after PM 2.5 exposure. Further tests verified the reduced GSH/GSSG ratio and the elevation of xanthine oxidase (XO) activity in the PM 2.5 -exposed TM4 cells, indicating that excessive reactive oxygen species (ROS) was generated via metabolic disorder caused by PM 2.5. Moreover, the redox imbalance was proved by the increase in the mitochondrial ROS level, superoxide dismutase (SOD) and catalase (CAT) activity, as well as the activation of the Nrf2 antioxidative pathway. Further study found that the redox imbalance caused by PM 2.5 induced DNA damage response and cell cycle arrest. Additionally, PM 2.5 induced ferroptosis through iron overload and lipid peroxidation. Taken all together, our study provided new insights for understanding proliferation inhibition and dysfunction of TM4 Sertoli cells exposed to PM 2.5 via metabolic disorder and redox imbalance-mediated DNA damage response and ferroptosis. [Display omitted] • PM 2.5 exposure induces Sertoli cell proliferation inhibition and dysfunction. • PM 2.5 disturbs glutathione, purine, and xenobiotic metabolism in TM4 cells. • PM 2.5 induces redox imbalance and causes ferroptosis and DNA damage response in TM4 cells. [ABSTRACT FROM AUTHOR]

In China, studies on lead exposure to grownup are scarce compared to children, although relevant disease burdens for adults are much severe than that in developed countries. The present study evaluated blood lead levels (BLLs) in Chinese adults by data mining using Monte Carlo simulation. A total of 115 scientific studies published between January 1980 and March 2021 reflecting 45,514 Chinese adults were included in the study. After a continuous increase in Chinese adult BLLs from 1980–1983 (GM 74.84 μg/L) to 1994–1996 (GM 92.27 μg/L), BLLs began to decline from 2000–-2002 (GM 80.32 μg/L) to 2016–2018 (GM 21.57 μg/L). This decline implied that the lead phase-out policy in gasoline was effective over the past two decades. The study indicated that North, South, and Southwest China were still relatively high compared to other regions in the past decade. Statistical analysis showed that BLLs of males (GM 68.45 μg/L) were higher than females (GM 56.51 μg/L), smokers (GM 80.96 μg/L) higher than nonsmokers (GM 58.95 μg/L), and populations over 40 (GM 40.43 μg/L) higher than younger populations (GM 40.37 μg/L). The significantly positive correlation between the concentrations of PM2.5 and topsoil lead and BLLs in Chinese adults indicated that air and soil pollution affect adult BLLs. Taken together, our results showed that strict lead control strategies and regular bio-monitoring are needed to maintain low BLLs in the population. [Display omitted] • Blood lead levels of Chinese adults declined since 2002, as determined by Monte Carlo simulation. • Adult blood lead levels were still high in Southwest, North, and South China compared to the rest of China. • Blood lead levels were higher in men, smokers, and people 40 years of age and older. • The concentration of PM2.5 in ambient air had the strongest association with adult blood lead levels. [ABSTRACT FROM AUTHOR]

There is increasing evidence that indicates benzo[ a ]pyrene (B[ a ]P) and its active metabolite benzo[ a ]pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE) are endocrine disruptors that can cause reproductive toxicity. Nevertheless, the underlying mechanisms are still obscure. The present study investigates the impacts of B[ a ]P and BPDE on mitochondria, a sensitive target affected by multiple chemicals, in spermatogenic cells. It showed that BPDE treatment induced mitochondrial dysfunction and the inhibition of mitochondrial biogenesis in mouse spermatocyte-derived cells (GC-2). These effects were efficiently mitigated by pretreatment with ZLN005, an activator of PGC-1α, in GC-2 cells. TERT knockdown and re-expression cell models were established to demonstrate that TERT regulated the BPDE-induced mitochondrial damage via PGC-1α signaling in GC-2 cells. Moreover, upregulating or knockdown SIRT1 expression attenuated or aggravated BPDE-induced mitochondrial compromise by activating or inhibiting, respectively, the TERT and PGC-1α molecules in GC-2 cells. Finally, we observed that BPDE markedly elevated oxidative stress in GC-2 cells. Resveratrol and N -acetylcysteine, as reactive oxygen species (ROS) scavengers, attenuated BPDE-mediated mitochondrial damage by increasing SIRT1 activity and expression in GC-2 cells. The in vitro results were corroborated by in vivo experiments in rats treated with B[ a ]P for 4 weeks. B[ a ]P administration caused mitochondrial damage and mitochondria-dependent apoptosis in spermatogenic cells, as well as the decreased expression of SIRT1, TERT, and PGC-1α. In summary, the results of the present study demonstrate that B[ a ]P and BPDE induce mitochondrial damage through ROS production that suppresses SIRT1/TERT/PGC-1a signaling and mediate B[ a ]P- and BPDE-mediated reproductive toxicity. Unlabelled Image • Mitochondria are the target of male reproductive toxicity induced by BPDE/B[ a ]P. • BPDE and B[ a ]P induce mitochondrial compromise in spermatogenic cells. • SIRT1/TERT/PGC-1α pathway accounts for BPDE/B[ a ]P-induced mitochondrial damage. • BPDE/B[ a ]P-induced ROS causes the suppression of SIRT1/TERT/PGC-1α pathway. [ABSTRACT FROM AUTHOR]

Telomere and mitochondria may be the targets of Benzo[ a ]pyrene (BaP) -induced male reproductive damage, and further elucidation of the toxic molecular mechanisms is necessary. In this study, we used in vivo and in vitro exposure models to explore the molecular mechanisms of TERT regulation in BaP-induced telomere and mitochondrial damage in spermatocytes. The results showed that the treatment of benzo[ a ]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the active metabolite of BaP, caused telomere dysfunction in mouse spermatocyte-derived GC-2 cells, resulting in S-phase arrest and increased senescence-associated secretory phenotype (SASP). These effects were significantly alleviated by telomerase agonist (ABG) pretreatment in GC-2 cells. SIRT1, FOXO3a, or c-MYC overexpressing GC-2 cell models were established to demonstrate that BPDE inhibited TERT transcriptional expression through the SIRT1/FOXO3a/c-MYC pathway, leading to telomere dysfunction. We also observed that BPDE induced mitochondrial compromise, including complex I damage, accompanied by reduced mitochondrial TERT expression. Based on this, we constructed wild-type TERT-overexpressing (OE-TERTwt) and mitochondria targeting TERT-overexpressing (OE-TERTmst) GC-2 cell models and found that OE-TERTmst GC-2 cells improved mitochondrial function better than OE-TERTwt GC-2 cells. Finally, ICR mice were given BaP by intragastric administration for 35 days, which verified the results of the in vitro study. The results shown that BaP exposure can lead to spermatogenesis disturbance, which is related to the telomere and mitochondrial damage in spermatocytes. In conclusion, our results suggest that BPDE causes telomere and mitochondrial damage in spermatocytes by inhibiting TERT transcription and mitochondrial TERT expression. This study elucidates the molecular mechanism of male reproductive toxicity due to environmental pollutant BaP, and also provides a new perspective for the exploration of interventions and protective measures against male reproductive damage by BaP. • TERT transcription and mitochondrial translocation play a major role in BaP/BPDE-induced spermatogenic disorders in mice. • Astramembrangenin (ABG) improves BaP-induced spermatogenic disorders by activating TERT transcription. • BaP/BPDE inhibits TERT transcription via the SIRT1-FOXO3a-c-MYC pathway causing mouse spermatocyte senescence. • BPDE inhibits mitochondrial TERT expression, leading to mitochondrial damage and senescence in mouse spermatocytes. [ABSTRACT FROM AUTHOR]

Several methods are currently available for selection when conducting sperm cryopreservation, however, these methods might cause different degrees of damage on sperm DNA. The aim of the this study is to compare the effects of storage at −80 °C (in ultra-low temperature refrigerator) and at −196 °C (in liquid nitrogen) on sperm DNA damage, thus to provide a reference for choosing the right method according to different aims. We randomly collected 28 semen samples from college students of Chongqing city. The samples stored at −80 °C were neat semen samples and the samples stored at −196 °C were mixed with additional cryoprotectants. Each sample was subjected to two freezing-thawing cycles, and the sperm DNA damage levels of fresh and thawed samples were measured by single cell gel electrophoresis (SCGE) and sperm chromatin structure assay (SCSA). Both SCGE and SCSA assays showed cryopreservation induced significant damage to sperm DNA. However, storage at −196 °C lead to more severe damage to sperm DNA than storage at −80 °C measured by SCSA. Sperm DNA damage increased simultaneously with the higher frequency of freezing-thawing cycles. We concluded that storage of neat semen samples at −80 °C had milder damage to sperm DNA than storage at −196 °C mixed with cryoprotectants. To avoid additional sperm DNA damage, repeated freezing and thawing should be prevented. [ABSTRACT FROM AUTHOR]

Inorganic arsenic (iAs) is a worldwide environmental pollutant which exerts complicated and various toxic effects in organisms. Increasingly epidemic studies have revealed the association between iAs exposure and adult male reproductive impairment. Consistent with the proposal for toxicity testing in the 21st century (TT21C), the adverse outcome pathway (AOP) framework may help unravel the iAs-caused molecular and functional changes leading to male reproductive impairment. Combining CTD's phenotype-disease inference data, iAs-phenotypes were anchored to five male reproductive diseases induced by iAs, and local network topological algorithm was applied in prioritizing their interference significance. Through integrating analysis in AOP Wiki knowledge base, filtered phenotypes were linked to key events consisting of AOPs and assembled together based on evidentially upstream and downstream relationships. A subset of 655 phenotypes were filtered from CTD as potential key events and showed a significant coherence in five reproductive diseases wherein 39 significant phenotypes showed a good clustering features involving cell cycle, ROS and mitochondria function. Two AOP subnetworks were enriched in AOP Wiki where testosterone reduction and apoptosis of sperm served as focus events respectively. Besides, a candidates list of molecular initialing events was provided of which glucocorticoid receptor activation was overall assessed as an example. This study applied computational and bioinformatics methods in generating AOPs for arsenic reproductive toxicity, which identified the imperative roles of testosterone reduction, response to ROS, spermatogenesis and provided a global view about their internal association. Furthermore, this study helped address the existing knowledge gaps for future experimental verification. • Predicted AOPs were generated by combing the curated evidences in CTD database and the knowledge context in AOP Wiki. • The essential roles of testosterone decrease and apoptosis were identified in arsenic-induced male reproductive impairment. • Existing knowledge gaps were pointed out and potential molecular initiating events were clued in this model. [ABSTRACT FROM AUTHOR]