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OBJECTIVE: Splenic flexure mobilization (SFM) is a major challenge in laparoscopic left hemicolectomy. This study aims to assess the safety and effectiveness of the pancreas-guided SFM technique during laparoscopic left hemicolectomy. METHODS: From January 2018 to December 2023, 352 patients with left-sided colon cancer underwent laparoscopic left hemicolectomy. Based on the SFM method used, the patients were divided into the pancreas-guided group (167 cases) or the "Three Approaches Roundabout"/classic group (185 cases). Clinicopathologic characteristics and intraoperative and postoperative variables were compared between the two groups. RESULTS: The two groups had no significant differences in baseline indicators (P > 0.05). All surgeries were successful without needing to convert to laparotomy, and there were no combined organ resections involving the spleen or pancreas in either group. The mean duration of surgery was significantly lower in the pancreas-guided group than in the classic group (P < 0.01). The median volume of intraoperative blood loss in the pancreas-guided group was lower than that in the classic group (P < 0.01). Through video playback, it was found that the retro-pancreatic space had been entered during operation in 8 cases (4.3%) in the classic group, while there were no such occurrences in the pancreas-guided group. This difference was statistically significant (P < 0.05). The difference in the number of lymph nodes cleared, postoperative hospital stays, and incidence of complications were not statistically significant (all P > 0.05) between the groups. CONCLUSION: The pancreas-guided SFM technique is a safe and feasible option for laparoscopic left hemicolectomy. Our study's findings suggest that this approach facilitates accurate access to the correct anatomic plane, potentially improving surgical efficiency.
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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 (80â¯nm) at different dosages (0, 10, and 40â¯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-ß-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.
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Senescência Celular , Camundongos Endogâmicos C57BL , Poliestirenos , Espécies Reativas de Oxigênio , Sirtuína 1 , Animais , Masculino , Sirtuína 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Senescência Celular/efeitos dos fármacos , Camundongos , Poliestirenos/toxicidade , Testículo/efeitos dos fármacos , Testículo/patologia , Espermatogênese/efeitos dos fármacos , Nanopartículas/toxicidade , Dano ao DNA , Transdução de Sinais/efeitos dos fármacosRESUMO
Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3'-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.
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Peripheral tissues become disrupted in Alzheimer's Disease (AD). However, a comprehensive understanding of how the expression of AD-associated toxic proteins, Aß42 and Tau, in neurons impacts the periphery is lacking. Using Drosophila, a prime model organism for studying aging and neurodegeneration, we generated the Alzheimer's Disease Fly Cell Atlas (AD-FCA): whole-organism single-nucleus transcriptomes of 219 cell types from adult flies neuronally expressing human Aß42 or Tau. In-depth analyses and functional data reveal impacts on peripheral sensory neurons by Aß42 and on various non-neuronal peripheral tissues by Tau, including the gut, fat body, and reproductive system. This novel AD atlas provides valuable insights into potential biomarkers and the intricate interplay between the nervous system and peripheral tissues in response to AD-associated proteins.
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S-adenosylmethionine (SAM), generated from methionine and ATP by S-adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams-1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt) and lifespan extension. In this study, we found that depleting SAMS-1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC-25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt, suggesting that the UPRmt induced by sams-1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT-10C.2 as a major downstream effector of SAMS-1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS-1 regulates UPRmt and longevity.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Longevidade/genética , S-Adenosilmetionina/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Mitocôndrias/metabolismo , Resposta a Proteínas não Dobradas , RNA de Transferência/metabolismoRESUMO
Perfluorooctane sulfonic acid (PFOS) as an archetypal representative of per- and polyfluoroalkyl substances (PFAS) is ubiquitously distributed in the environment and extensively detected in human bodies. Although accumulating evidence is suggestive of the deleterious effects of PFOS on male reproduction, the direct toxicity of PFOS towards spermatogenic cells and the relevant mechanisms remain poorly understood. The aims of the present study were to explore the direct effects and underlying molecular mechanisms of PFOS on spermatogenesis. Through integrating animal study, transcriptome profiling, in silico toxicological approaches, and in vitro validation study, we identified the molecular initiating event and key events contributing to PFOS-induced spermatogenic impairments. The mouse experiments revealed that spermatocytes were involved in PFOS-induced spermatogenic disorders and the activation of peroxisome proliferator-activated receptor delta (PPARδ) was linked to spermatocyte loss in PFOS-administrated mice. GC-2spd(ts) cells were treated with an increased gradient of PFOS, which was relevant to environmental and occupational exposure levels of PFOS in populations. Following 72-h treatment, cells was harvested for RNA sequencing. The transcriptome profiling and benchmark dose (BMD) modeling identified endoplasmic reticulum (ER) stress as the key event for PFOS-mediated spermatocyte apoptosis and determined the point-of-departure (PoD) for perturbations of ER stress signaling. Based on the calculated PoD value, further bioinformatics analyses combined with in vitro and in vivo validations showed that PFOS caused metabolic stress by activating PPARδ in mouse spermatocytes, which was responsible for Beclin 1-involved inositol 1,4,5-trisphosphate receptor (IP3R) sensitization. The disruption of IP3R-mediated ER calcium homeostasis triggered ER calcium depletion, leading to ER stress and apoptosis in mouse spermatocytes exposed to PFOS. This study systematically investigated the direct impacts of PFOS on spermatogenesis and unveiled the relevant molecular mechanism of PFOS-induced spermatogenic disorders, providing novel insights and potential preventive/therapeutic targets for PFAS-associated male reproductive toxicity.
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Ácidos Alcanossulfônicos , Fluorocarbonos , PPAR delta , Camundongos , Masculino , Humanos , Animais , Espermatócitos , PPAR delta/farmacologia , Cálcio/metabolismo , Espermatogênese , Estresse do Retículo Endoplasmático , Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/toxicidade , Retículo Endoplasmático/metabolismo , Estresse Fisiológico , Apoptose , HomeostaseRESUMO
Objective: During laparoscopic radical resection for proctosigmoid colon cancer (PCC), surgeons could inadvertently damage the arteries when following the operation path.This study investigated the variations in left colon blood vessels in order to guide the scientific protection of the marginal artery (MA) during laparoscopic surgery for PCC. Methods: Data from seven patients who underwent inferior mesenteric artery (IMA) angiography were included as imaging references to preliminarily explore the vascular structure and variation in the left colon. The clinical video data of 183 PCC patients were retrospectively analyzed to observe intraoperative MA injury. Meanwhile, a prospective cohort of 96 patients with the same disease underwent intraoperative indocyanine green (ICG) fluorescence imaging of the peripheral sigmoid artery network, the variation of marginal arteries was summarized, and the distance between vessels and the bowel was measured at different levels. Patients were divided into 'ICG group' and 'non-ICG group' according to whether ICG guidance was performed, and perioperative conditions were compared between the two groups. Taking the integrity of lymph node dissection into consideration, 18 patients underwent carbon nanonode tracing. This study was conducted under the standard consent and ethical approval of the Ethics Committee of our center. Results: 7 patients with IMA angiography shared some vascular structures, defined as 'Dangerous Triangle' and 'Secure Window'. Through intraoperative observation, the primary arch was typically located 4.2 (2.3-6.0) cm away from the intestinal canal, and 5.21% (5/96) patients had poor anastomosis at the primary arch. Moreover, secondary vascular arches (6.4 (4.6-10.0) cm from the intestinal wall) were observed in 38.54% of patients. MA injury was identified in 2 of 183 cases, and the ischemic bowel was timely dissected, whereas no such injury occurred during ICG fluorescenceguided surgery. Guided by carbon nanoparticles, the integrity of lymph node dissection can be maintained while preserving the secondary arch in all patients. Conclusions: This study demonstrated the benefits of ICG guidance in protecting the intestinal blood supply in laparoscopic PCC surgery. By enhancing the understanding of primary and secondary vascular arches, secure windows, and dangerous triangles, surgeons can safely optimize the surgical path during surgery.
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Neurodegenerative diseases are characterized by distinct protein aggregates, such as those of α-synuclein and tau. Lysosomal defect is a key contributor to the accumulation and propagation of aberrant protein aggregates in these diseases. The discoveries of common proteinopathies in multiple forms of lysosomal storage diseases (LSDs) and the identification of some LSD genes as susceptible genes for those proteinopathies suggest causative links between LSDs and the proteinopathies. The present study hypothesized that defects in lysosomal genes will differentially affect the propagation of α-synuclein and tau proteins, thereby determining the progression of a specific proteinopathy. We established an imaging-based high-contents screening (HCS) system in Caenorhabditis elegans (C. elegans) model, by which the propagation of α-synuclein or tau is measured by fluorescence intensity. Using this system, we performed RNA interference (RNAi) screening to induce a wide range of lysosomal malfunction through knock down of 79 LSD genes, and to obtain the candidate genes with significant change in protein propagation. While some LSD genes commonly affected both α-synuclein and tau propagation, our study identified the distinct sets of LSD genes that differentially regulate the propagation of either α-synuclein or tau. The specificity and efficacy of these LSD genes were retained in the disease-related phenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentially regulate the propagation of α-synuclein and tau, and offer a steppingstone to understanding disease specificity. [BMB Reports 2023; 56(12): 657-662].
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Deficiências na Proteostase , Sinucleinopatias , Tauopatias , Animais , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Agregados Proteicos , Tauopatias/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Lisossomos/genética , Lisossomos/metabolismoRESUMO
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.
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7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , Benzo(a)pireno , Camundongos , Masculino , Animais , Benzo(a)pireno/toxicidade , Benzo(a)pireno/metabolismo , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/toxicidade , Espermatócitos , Sirtuína 1/metabolismo , Camundongos Endogâmicos ICR , MitocôndriasRESUMO
BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive. OBJECTIVES: This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms. METHODS: The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders. RESULTS: The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal ß-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling. CONCLUSION: Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity.
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Ácidos Alcanossulfônicos , Doença Hepática Induzida por Substâncias e Drogas , Poluentes Ambientais , Fluorocarbonos , Transtornos do Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Ratos , Animais , PPAR alfa/genética , Inquéritos Nutricionais , Metabolismo dos Lipídeos , Estudos Transversais , Ácidos Alcanossulfônicos/toxicidade , Caprilatos , Fluorocarbonos/toxicidade , Poluentes Ambientais/toxicidadeRESUMO
Environmental hazards are an increasing concern due to the rapid pace of industrialization. Among these hazards, noise and carbon monoxide (CO) are common risk factors and have been shown to cause serious health problems. However, existing studies focused on the individual effects of noise and CO exposure and the combined effects of these two factors remain poorly understood. Our study aimed to examine the combined effects of noise and CO exposure on testicular function by constructing individual and combined exposure models. Our findings indicated that combined exposure to noise and CO was associated with a higher risk of testicular damage and male reproductive damage when compared to exposure alone. This was evidenced by poorer semen quality and more severe pathological damage to the testis. This combined exposure led to higher levels of oxidative stress and apoptosis in the testes, with bioinformatics analyses suggesting the signaling pathways involved in these responses. Specifically, activation of the P53 signaling pathway was found to contribute to the testicular damage caused by the combined exposure. Encouragingly, pterostilbene (PTE), a novel phytochemical, alleviated combined exposure-induced testicular damage by reducing oxidative stress and germ cell apoptosis. Overall, we identified joint reproductive toxicity resulting from the exposure to noise and CO, and found that PTE is a promising potential treatment for injuries caused by these factors. The cover image is based on the Research Article Effects and possible mechanisms of combined exposure to noise and carbon monoxide on male reproductive system in rats by Yingqing Li et al., https://doi.org/10.1002/tox.23927.
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Monóxido de Carbono , Análise do Sêmen , Ratos , Masculino , Animais , Monóxido de Carbono/toxicidade , Testículo , Células Germinativas , Reprodução , Estresse OxidativoRESUMO
Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.
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Traumatismos Cardíacos , Doenças Metabólicas , Humanos , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Doenças Metabólicas/metabolismo , Metabolismo Energético , Espécies Reativas de Oxigênio/metabolismo , Traumatismos Cardíacos/patologiaRESUMO
Objective: To explore the genotyping characteristics of human fecal Escherichia coli( E. coli) and the relationships between antibiotic resistance genes (ARGs) and multidrug resistance (MDR) of E. coli in Miyun District, Beijing, an area with high incidence of infectious diarrheal cases but no related data. Methods: Over a period of 3 years, 94 E. coli strains were isolated from fecal samples collected from Miyun District Hospital, a surveillance hospital of the National Pathogen Identification Network. The antibiotic susceptibility of the isolates was determined by the broth microdilution method. ARGs, multilocus sequence typing (MLST), and polymorphism trees were analyzed using whole-genome sequencing data (WGS). Results: This study revealed that 68.09% of the isolates had MDR, prevalent and distributed in different clades, with a relatively high rate and low pathogenicity. There was no difference in MDR between the diarrheal (49/70) and healthy groups (15/24). Conclusion: We developed a random forest (RF) prediction model of TEM.1 + baeR + mphA + mphB + QnrS1 + AAC.3-IId to identify MDR status, highlighting its potential for early resistance identification. The causes of MDR are likely mobile units transmitting the ARGs. In the future, we will continue to strengthen the monitoring of ARGs and MDR, and increase the number of strains to further verify the accuracy of the MDR markers.
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Infecções por Escherichia coli , Escherichia coli , Humanos , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Tipagem de Sequências Multilocus , Genótipo , Pequim , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologia , Diarreia , Testes de Sensibilidade MicrobianaRESUMO
STUDY QUESTION: Is sperm telomere length (STL) associated with sperm nuclear DNA damage and mitochondrial DNA abnormalities? SUMMARY ANSWER: Sperm telomere length is related to sperm nuclear DNA integrity and mitochondrial DNA abnormalities in healthy young college students. WHAT IS KNOWN ALREADY: Many studies have revealed the correlations between sperm genetic alterations in both the nucleus and mitochondria and sperm functionality, however, the possible associations between the telomere, an important component of chromosome, and conventional indicators of mitochondrial DNA and nuclear DNA changes have not been investigated. STUDY DESIGN, SIZE, DURATION: A prospective cohort study, Male Reproductive Health in Chongqing College Students (MARHCS), was conducted from June 2013 to June 2015. We pooled data collected from the follow-up study in 2014 and a total of 444 participants were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: STL was measured by quantitative (Q)-PCR. Sperm nuclear DNA integrity was determined using sperm chromatin structure assay (SCSA) and comet assay. Mitochondrial DNA damage was assessed by mitochondrial DNA copy number (mtDNAcn) evaluated with Q-PCR, and mtDNA integrity was determined with long PCR. MAIN RESULTS AND THE ROLE OF CHANCE: The univariable-linear regression analysis revealed that STL was significantly positively correlated with markers of sperm nuclear DNA damage including the DNA fragmentation index (DFI) and comet parameters (the percentage of DNA in the tail, tail length, comet length, and tail moment). Additionally, STL was also significantly positively correlated with mtDNAcn and significantly negatively correlated with mtDNA integrity. After adjustment for potential confounders, these relationships remained appreciable. Moreover, we investigated potential effects of biometric factors, including age, parental age at conception, and BMI on STL and found that STL was increased with paternal age at conception. LIMITATIONS, REASONS FOR CAUTION: A mechanistic explanation of the correlation between STL, sperm nuclear DNA integrity, and mtDNA abnormalities cannot be provided with a cross-sectional study design, so well-designed longitudinal studies are still necessary. In addition, a single semen samples were provided and were not all obtained at the same time point, which may increase the intraindividual bias in this study. WIDER IMPLICATIONS OF THE FINDINGS: The findings extend the literature including assessment of mitochondrial dysfunction, sperm nuclear DNA damage, and telomere length and provide new insights into the relevance of STL in male reproduction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (No. 82073590), the National Natural Science Foundation of China (No. 81903363), the National Natural Science Foundation of China (No. 82130097), and the National Key R&D Program of China (2022YFC2702900). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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DNA Mitocondrial , Sêmen , Humanos , Masculino , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Estudos Prospectivos , Seguimentos , Estudos Transversais , Espermatozoides/metabolismo , Análise do Sêmen , Mitocôndrias/genética , Telômero , EstudantesRESUMO
OBJECTIVE: To investigate the contribution of ambient air pollutants-induced semen damage to infertility risk, after identifying dose-response relationship between pollutants and semen parameters and susceptibility window. METHODS: In Preconception Reproductive Health and Birth Outcomes Cohort, 3940 male volunteers aged 22-49 were recruited from November 2018 to April 2021. At enrollment, resident address information was obtained and semen parameters were examined. During prospective follow-up, infertility was defined as failure to achieve pregnancy after unprotected intercourse within 12 months. Full coverage of ambient pollutant (PM2.5, PM10, SO2, NO2, O3, CO) concentrations was estimated by machine learning algorithms and assigned to individual level. Association between pollutants and semen parameters was analyzed by single- and two-pollutant linear regression. Four potential susceptibility windows were analyzed: lag 0-9d, lag 10-14d, lag 70-90d and lag 0-90d. Pollutant joint effects on semen parameters were analyzed by Bayesian kernel machine regression. Mediating effect of semen parameters on the association between pollutants and infertility was analyzed. False-positive rate was controlled by Bonferroni correction. RESULTS: Single- and two-pollutant models showed SO2, O3, PMs and NO2 were negatively associated with progressive motility, total motility and sperm morphology, among which, each IQR increase in SO2 at lag 0-90d was associated with -4.13 %(95%CI:-6.25 %, -1.95 %, P < 0.001) change of normal morphology, and O3 at lag 0-90d was negatively associated with progressive motility and total motility (ß = -3.64 %, 95%CI:-5.63 %, -1.61 %; ß = -2.24 %, 95%CI:-3.38 %, -1.08 %, P < 0.001). Joint effect analysis showed a negative effect on sperm concentration and a suggestive effect on vitality. Mediating effect analysis showed sperm normal morphology had a substantial mediating effect in the association of SO2 with infertility (59.68 %, P < 0.001). CONCLUSION: Multiple air pollutants may introduce semen quality in the population at entire window of spermatogenesis, among which SO2 needs especial attention, as its damage on sperm morphology may increase risk of infertility.
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Poluentes Atmosféricos , Poluição do Ar , Infertilidade , Humanos , Masculino , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Sêmen , Estudos Prospectivos , Análise do Sêmen , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Dióxido de Nitrogênio/análise , Teorema de Bayes , Material Particulado/análise , China/epidemiologiaRESUMO
Fine particulate matter (PM2.5) has been reported to cause various types of damage to male reproductive system, but the research on the underlying mechanisms is still insufficient. This study attempted to explore the underlying mechanisms of this widely concerning environmental health problem through in vivo and in vitro exposure models. Significant pathological damage and abnormal mitochondria in spermatocytes were observed in the real-time PM2.5 exposure animal model. In addition, significant alterations in key biomarkers of iron metabolism and ferroptosis were found in testis tissues. Notably decreased cell viability was found in vitro. Moreover, the ferroptosis pathway was significantly enriched in the transcriptome enrichment analysis. Subsequent experiments showed that the two core events of ferroptosis, iron overload and lipid peroxidation, occurred in spermatocytes after PM2.5 treatment. Moreover, lipid metabolic genes (Acsl4 and Aloxe3) and the antioxidant gene Gpx4 were found to be key target genes of ferroptosis caused by PM2.5 in spermatocytes. Importantly, further studies showed that the damaging effect could be reversed by the iron chelator deferoxamine mesylate (DFOM) and the lipid peroxidation inhibitor ferrostatin-1 (Fer-1), which further confirmed the role of ferroptosis in PM2.5 toxicity. Our study revealed the vital role of ferroptosis in PM2.5-induced male reproductive damage, providing novel insights into the air pollution-induced decrease in male fertility.
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Ferroptose , Ferro , Animais , Masculino , Ferro/metabolismo , Ferroptose/genética , Espermatócitos/metabolismo , Oxirredução , Peroxidação de Lipídeos , Homeostase , Material Particulado/toxicidade , Material Particulado/metabolismoRESUMO
Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) leads to dysfunctions of human trophoblast cells and further induces miscarriage. In our previous study, we have found that lnc-HZ03 and miR-hz03 are upregulated in BPDE-exposed human trophoblast cells and in recurrent miscarriage tissues; and the upregulated miR-hz03 caused by lnc-HZ03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. However, how lnc-HZ03 upregulates miR-hz03 is completely unknown. In this study, we find that lnc-HZ03 upregulates the expression level of a transcription factor TFIID (a TATA-binding protein) and promotes TFIID-mediated transactivation response element RNA-binding protein (TRBP) transcription. Subsequently, the upregulated TRBP promotes the maturation of miR-hz03 by splicing its precursor pre-miR-hz03 in human trophoblast cells. In BPDE-exposed trophoblast cells or in recurrent miscarriage tissues, lnc-HZ03 was upregulated, which accelerates the TFIID-mediated TRBP transcription and thus promotes TRBP-mediated miR-HZ03 maturation. Subsequently, the upregulated miR-hz03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. This work provides new insights into the regulation of miRNA expression levels by lncRNAs in BPDE-exposed human trophoblast cells.
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Aborto Habitual , MicroRNAs , RNA Longo não Codificante , Gravidez , Feminino , Humanos , Trofoblastos/metabolismo , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , MicroRNAs/genética , MicroRNAs/metabolismo , Aborto Habitual/metabolismo , Fator de Transcrição TFIID/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
BACKGROUND: Chronic mTORC1 activation in skeletal muscle is linked with age-associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E-binding proteins (4EBPs). Whole-body knockout of S6K1 or muscle-specific over-expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1-mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1-mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear. METHODS: Mice with myofiber-specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1-mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt-TSC1mKO or S6K1-TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development. RESULTS: Here, we show that 4EBP1mt-TSC1mKO, but not S6K1-TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P < 0.001) and strength (36.8% increase compared with TSC1mKO, P < 0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two-fold reduction compared with TSC1mKO, P < 0.05) and restored autophagy flux without relieving mTORC1-mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5-fold reduction compared with TSC1mKO, P < 0.05) in muscle and restored mitochondrial homeostasis and function. CONCLUSIONS: We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia.
Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina , Sarcopenia , Animais , Camundongos , Modelos Animais de Doenças , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Sarcopenia/genética , Sarcopenia/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
Dietary restriction (DR) is known to promote autophagy to exert its longevity effect. While SAMS-1 (S-adenosyl methionine synthetase-1) has been shown to be a key mediator of the DR response, little is known about the roles of S-adenosyl methionine (SAM) and SAM-dependent methyltransferase in autophagy and DR-induced longevity. In this study, we show that DR and SAMS-1 repress the activity of SET-2, a histone H3K4 methyltransferase, by limiting the availability of SAM. Consequently, the reduced H3K4me3 levels promote the expression and activity of two transcription factors, HLH-30/TFEB and PHA-4/FOXA, which both regulate the transcription of autophagy-related genes. We then find that HLH-30/TFEB and PHA-4/FOXA act collaboratively on their common target genes to mediate the transcriptional response of autophagy-related genes and consequently the lifespan of the animals. Our study thus shows that the SAMS-1-SET-2 axis serves as a nutrient-sensing module to epigenetically coordinate the activation of HLH-30/TFEB and PHA-4/FOXA transcription factors to control macroautophagy/autophagy and longevity in response to DR.Abbreviations: ChIP: chromatin immunoprecipitation; ChIP-seq: chromatin immuno precipitation-sequencing; COMPASS: complex of proteins associated with Set1; DR: dietary restriction; GO: gene ontology; SAM: S-adenosyl methionine; SAMS-1: S-adenosyl methionine synthetase-1; TSS: transcription start site; WT: wild-type.
Assuntos
Proteínas de Caenorhabditis elegans , Longevidade , Animais , Longevidade/fisiologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Histonas/metabolismo , Metilação , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Autofagia/genética , Fatores de Transcrição/metabolismo , Metionina , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
Aim: Public concerns over the mental health problems of college students are rising. Previous research show that female tend to suffer more from mental health problems than males, with few studies focusing on males. This study sought to explore the association of lifestyle-related risk factors with the prevalence of mental health problems among male college students in China. Methods: The lifestyle information and mental health status of 686 male college students from Chongqing, China, were assessed in 2014, and 582 of them were followed up a year later. Participants completed a questionnaire assessing demographic and lifestyle factors which include sleep quality, computer usage, sedentariness, physical activity, smoking, current alcohol, coke, coffee, and milk tea drinking, and current tea/fried food/baked food consumption. Mental health problems were measured using the Depression Anxiety Stress Scale-21 (DASS-21). Results: Univariate analyses indicated that age, sleep latency, sleep duration, computer usage time, milk tea drinking, and fried food consumption were potential risk factors for mental health problems (p's < 0.05). Multivariate analysis further revealed that, either at baseline or during follow-up, participants with (i) more computer usage time were at a higher risk of having depression symptoms (p's < 0.05) and (ii) a higher frequency of fried food consumption were associated with a higher risk of having depression, anxiety, and stress symptoms (p's < 0.05). Additionally, the cross-lagged analysis showed that (i) computer usage time in 2014 is positively correlated with depression status (ß = 0.106, p < 0.05) but not anxiety (ß = 0.047, p > 0.05) and stress (ß = 0.019, p > 0.05) status a year later and (ii) fried food consumption in 2014 is positively correlated with depression (ß = 0.129, p < 0.01), anxiety (ß = 0.168, p < 0.001), and stress (ß = 0.113, p < 0.01) status a year later. Conclusions: Computer usage time and fried food consumption were lifestyle-related risk factors for mental health problems in male college students in Chongqing, China. These results might emphasize further preventive strategies for mental health problems, especially in male college students.