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To study the associations between pubertal timing and semen quality and reproductive hormones, 680 volunteers were recruited from universities in Chongqing, China. Pubertal timing was obtained using a questionnaire. The main measurements were five routine semen parameters and six reproductive hormones. After adjusting for potential confounders, we found that early pubertal timing was associated with lower sperm concentration. An one-year increase in age of peak height velocity was associated with a 4.7% (95% confidence interval [CI] = 1.0 to 8.6) increase in sperm concentration. An one-year increase in age of first spermatorrhea was associated with a 6.4% increase in sperm concentration and a 2.9% decrease in semen volume (95% CI = 1.7 to 11.3, −5.5 to −0.3; respectively). Regarding reproductive hormones, an one-year increase in age of height spurt and peak height velocity was associated with a 6.5% and a 6.7% decrease in estrogen (95% CI = −9.8 to −3.0, −10.4 to −2.8; respectively). While an one-year increase in age of height spurt was associated with higher follicle-stimulating hormone (% change = 2.6, 95% CI = 0.2 to 4.7). This was the first report that has suggested that early pubertal timing is associated with lower sperm concentration. However, further study is still needed to validate this association and fully elucidate the mechanism behind it.

Studies have shown that the effects of ambient particulate matter (PM) may be related to particle's size. However, results on the relationships between different PM and reproductive health are controversial. To explore the impacts of various PM fractions on male reproductive health, a total of 796 eligible subjects recruited in 2013 baseline investigation. In addition, there were 656 (82.4%) and 568 (71.3%) subjects participated follow-up surveys in 2014 and 2015, respectively. We used multivariable regression analysis and mixed-effect model to investigate the associations between air pollutants PM10, PM10-2.5, and PM2.5 exposures and semen quality, sperm DNA fragmentation and serum reproductive hormones of subjects. In the preliminary regression analysis, PM10, PM10-2.5, and PM2.5 exposure all associated with sperm concentration, morphology, sperm high DNA stainability (HDS), serum estradiol and testosterone levels. However, in mixed models, we only found that PM10 exposure were negatively associated with sperm normal morphology (95% CI: -14.13, -24.47) but positively associated with sperm progressive motility (95% CI: 23.00, 8.49), and PM10-2.5 exposure was inversely associated with sperm concentration (95% CI: -9.06, -27.31) after multiplicity adjustment. Our results provide the evidence that air PM10 and PM10-2.5 exposures, not PM2.5, are risk factors of semen quality.

// Yong-Sheng Huang 1, * , Wen-Bin Liu 1, * , Fei Han 1 , Jun-Tang Yang 1 , Xiang-Lin Hao 1 , Hong-Qiang Chen 1 , Xiao Jiang 1 , Li Yin 1 , Lin Ao 1 , Zhi-Hong Cui 1 , Jia Cao 1 and Jin-Yi Liu 1 1 Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, PR China * These authors have contributed equally to this work Correspondence to: Jin-Yi Liu, email: jinyiliutmmu@163.com Jia Cao, email: caojia1962@126.com Keywords: MPDZ, CNV, ccRCC, prognosis Received: December 15, 2016 Accepted: July 12, 2017 Published: August 12, 2017 ABSTRACT The vital copy number variation (CNV) plays a crucial role in clear cell renal cell carcinoma (ccRCC). MPDZ inhibit cell polarity associate with osmotic pressure response and cancer-related biological processes. In order to clarify the role of the CNV of MPDZ in the progression of ccRCC, we analyzed the CNV and expression of MPDZ and prognosis in ccRCC patients from The Cancer Genome Atlas data portal. Notably, we found that the deletion of MPDZ was the common CNV, which was present in 28.65% of ccRCC patients. With the development of tumors, the percentage of MPDZ deletion increased significantly (19.38% in stage I; 20.00% in stage II; 40.94% in stage III; and 45.00% in stage IV). The deletion of MPDZ significantly increased ccRCC risk (P=0.0025). Low MPDZ expression associated with its deletion was significantly associated with adverse outcomes in ccRCC patients (P=0.0342). Furthermore, immunohistochemical analysis by tissue microarray showed that MPDZ was expressed at lower levels in tumor tissues compared with adjacent tissues (P

Background: Environment-Protection-Agency Reference Doses (EPA RfDs) for phthalate intakes are based on limited evidence, especially regarding low-dose male-reproductive toxicity. This study investigates the association between phthalate exposure and semen parameters and reproductive hormones in a general population with low phthalate exposure compared to the EPA RfDs. Methods: The MARHCS (Male-Reproductive-Health-in-Chongqing-College-Students) cohort recruited 796 male students, who experienced a relocation of campuses and shifting environmental exposure. Urine, semen and blood before and after the relocation was collected and investigated for: (1) the associations between 13 urinary phthalate metabolites and 11 semen/hormone outcomes (five semen parameters including semen volume, sperm concentration, total sperm number, progressive motility, normal morphology) and six serum reproductive hormones including estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, testosterone; (2) re-analysis of the metabolite-outcome associations in the subjects with estimated phthalate intakes below the RfDs; (3) a change in phthalate metabolites and change in semen/hormone outcomes after the relocation; (4) the association between these changes. Results: (1) All but two semen/hormone outcomes were associated with at least one phthalate metabolite, e.g., each quartile monoethyl phthalate was associated with a 5.3%, 5.7% and 2.6% decrease of sperm concentration, total sperm number and progressive motility respectively. (2) In the subjects with phthalate intakes below the RfDs, these metabolite-outcome associations remained significant. (3) All metabolites except mono(2-ethylhexyl) phthalate declined after relocation (P

Strand displacement DNA synthesis is essential for DNA replication. Gp90, the sole DNA polymerase of Pseudomonas aeruginosa phage 1, can bypass multiply DNA lesions. However, whether it can perform strand displacement synthesis is still unknown. In this work, we found that gp90 exo

Three new monoterpenoid indole alkaloids (MIAs), hunterines A-C (

The negative association between psychological stress and male fertility has been known for many years. This study was aimed at (i) identifying spermatogenesis impairment induced by psychological stress in rats and (ii) exploring the role of glucocorticoid receptor (GR) signaling in these adverse effects (if they exist). Male Sprague Dawley rats were exposed to a six-week period of unpredictable chronic mild stress (uCMS) along with cotreatment of GR antagonist RU486 (1 mg/kg/day). Testicular damage was assessed by testicular pathological evaluation, epididymal sperm concentration, serum testosterone levels, testicular apoptotic cell measurements, and cell cycle progression analyses. Rats in the uCMS group had decreased levels of serum testosterone and decreased epididymal sperm concentration. The uCMS-treated rats also had decreased numbers of spermatids and increased levels of apoptotic seminiferous tubules, additionally, cell cycle progression of spermatogonia was arrested at the G0/G1 phase. Furthermore, uCMS exposure caused an increase in serum corticosterone level and activated GR signaling in the testes including upregulated GR expression. RU486 treatment suppressed GR signaling and alleviated the damaging effects of stress, resulting in an increased epididymal sperm concentration. Overall, this work demonstrated for the first time that the activation of GR signaling mediates stress-induced spermatogenesis impairment and that this outcome is related to cell apoptosis and cell cycle arrest in germ cells.

Background High rates of recurrence and metastasis are the major cause of the poor outcomes for patients with lung cancer. In previous research, we have demonstrated that Tac2-N promotes tumor growth by suppressing p53 signaling in lung cancer. Beyond that, other biological functions and clinical significance of Tac2-N in lung cancer progression are still unknown. Methods Tissue microarrays of 272 lung cancer patients were constructed to assess the association of Tac2-N expression and prognosis of lung cancer patients with different clinical stages. The protein expression of Tac2-N in metastatic and non-metastatic specimens were detected by IHC. In vitro migration and invasion and in vivo nude mice metastasis model were used to evaluate the effect of Tac2-N ectopic expression on metastasis capability of lung cancer cells. The downstream signaling pathway of Tac2-N was explored using luciferase reporter assays and WB. Results The expression of Tac2-N was associated with advanced stages, but not with early stages (P = 0.513). Tac2-N expression is sharply overexpressed in metastatic tumors compared with non-metastatic tumors. In vitro and in vivo assays suggested that Tac2-N facilitated migration and invasion of lung cancer cells in vitro and promoted tumor metastasis in vivo. Mechanistically, Tac2-N increased the degradation of IκB by promoting its phosphorylation, and subsequently activated NF-κB activity by facilitating the nuclear translocation of NF-κB and stimulating the transcription of targets, MMP7 and MMP9. Notably, the C2B domain of Tac2-N was crucial for Tac2-N to activate NF-κB signal. Blockage of NF-κB by shRNA or inhibitor attenuates the function of Tac2-N in the promotion of metastasis. Conclusions Our study provided proof of principle to show that Tac2-N serves as a novel oncogene gene and plays an important role in the progression and metastasis of lung cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1316-7) contains supplementary material, which is available to authorized users.

Although TC2N has proven to be an oncogene in lung cancer, its biological function and molecular mechanisms in other cancer still remains unclear. Here, we investigate in breast cancer that TC2N expression is sharply overexpressed in breast cancer specimens compared with normal breast specimens, and the low TC2N expression was associated with advanced stage, lymphatic metastasis, larger tumors and shorter survival time. Upregulation of TC2N significantly restrains breast cancer cell proliferation in vitro and tumor growth in vivo. Mechanistically, TC2N blocks AKT signaling in a PI3K dependent and independent way through weakening the interaction between ALK and p55γ or inhibiting the binding of EBP1 and AKT. To sum up, these results unmask an ambivalent role of TC2N in cancer, providing a promising inhibitor for PI3K-AKT signaling.

Male reproductive damage in the general population comprises different disorders in various biomarkers, which could be respectively caused by a number of exposure factors. However, researchers considering the environmental/behavioral/psychological exposures together to evaluate their contribution to male reproductive damage are still lacking. The present study investigated the comprehensive association between 138 environmental/behavioral/psychological exposures and 32 male reproductive biomarkers in 796 young Chinese men using graph-guided fused lasso (GFLASSO) and hierarchical clustering methods. All biomarkers were found to be associated with various exposures. A combination of these exposures not only predicted the levels of single biomarkers in another test dataset, but also identified the comprehensive reproductive features by clustering the men into five subgroups with distinct damages representing disrupted spermatogenesis with abnormal sperm morphology, low sperm motility with DNA fragmentation, chromatin immaturity, aberrant endocrine, or DNA strand breakage. The findings can be used to suggest a novel way to identify the males with a high risk of reproductive damage and develop personalized preventive strategies.

Parkinson's disease is a common neurodegenerative disease in the elderly, and mitochondrial defects underlie the pathogenesis of PD. Impairment of mitochondrial homeostasis results in reactive oxygen species formation, which in turn can potentiate the accumulation of dysfunctional mitochondria, forming a vicious cycle in the neuron. Mitochondrial fission/fusion and biogenesis play important roles in maintaining mitochondrial homeostasis. It has been reported that PGC-1α is a powerful transcription factor that is widely involved in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. Therefore, we explored mitochondrial biogenesis, mitochondrial fission/fusion, and especially PGC-1α as the key point in the signaling mechanism of their interaction in rotenone-induced dopamine neurotoxicity. The results showed that mitochondrial number and mass were reduced significantly, accompanied by alterations in proteins known to regulate mitochondrial fission/fusion (MFN2, OPA1, Drp1, and Fis1) and mitochondrial biogenesis (PGC-1α and mtTFA). Further experiments proved that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity and also promotes mitochondrial biogenesis. By establishing cell models of PGC-1α overexpression and reduced expression, we found that PGC-1α can regulate MFN2 and Drp1 protein expression and phosphorylation to influence mitochondrial fission/fusion. In summary, it can be concluded that PGC-1α-mediated cross talk between mitochondrial biogenesis and fission/fusion contributes to rotenone-induced dopaminergic neurodegeneration.

Epidemiological and experimental evidence for detrimental effects of cell phone use on semen quality is still equivocal. And that recruiting participants from infertility clinic not from general population may raise the possibility of a selection bias. To investigate effects of cell phone use on semen parameters in a general population,We screened and documented the cell phone use information of 794 young men from the Male Reproductive Health in Chongqing College students (MARHCS) cohort study in 2013, followed by 666 and 568 in 2014 and 2015, respectively. In the univariate regression analyses, we found that the daily duration of talking on the cell phone was significantly associated with decreased semen parameters, including sperm concentration [β coefficient = −6.32% per unit daily duration of talking on the cell phone (h); 95% confidence interval (CI), −11.94, −0.34] and total sperm count (−8.23; 95% CI, −14.38, −1.63) in 2013; semen volume (−8.37; 95% CI, −15.93, −0.13) and total sperm count (−16.59; 95% CI, −29.91, −0.73) in 2015]. Internet use via cellular networks was also associated with decreased sperm concentration and total sperm counts in 2013 and decreased semen volume in 2015. Multivariate analyses were used to adjust for the effects of potential confounders, and significant negative associations between internet use and semen parameters remained. Consistent but nonsignificant negative associations between talking on the cell phone and semen parameters persisted throughout the three study years, and the negative association was statistically significant in a mixed model that considered all three years of data on talking on the cell phone and semen quality. Our results showed that certain aspects of cell phone use may negatively affect sperm quality in men by decreasing the semen volume, sperm concentration, or sperm count, thus impairing male fertility. Keywords: Cell phone, Talking, Internet use, Sperm parameters

Glucocorticoids are commonly used in clinic, but the immunosuppression seriously hinders their usage. Herein, immunomodulatory effect of artesunate (AS) on hydrocortisone (HC)-induced immunosuppression was investigated. HC-induced immunosuppression mice (HC mice) were established by intramuscular administration with HC (20 mg/kg) once a day for 5 consecutive days. The results showed HC mice challenged with Escherichia coli on the sixth day presented a lower ability to clear bacteria, decreased TNF-α in blood, decreased spleen index and thymus index. Significantly, AS (20 mg/kg) treatment not only enhanced the ability of HC mice to clear bacteria, but also increased spleen index, the levels of pro-inflammatory cytokines from 78.7 ± 12.1 ng/ml (TNF-α) and 48.7 ± 8.6 pg/ml (IL-6) to 174.0 ± 90.5 ng/ml and 783.3 ± 90.5 pg/ml, number of white blood cells in blood, and sIgA in colon. Subsequently, HC-induced immunosuppression peritoneal macrophages model (HC cells) was established via addition of HC (0.5 μg/ml) for 0.5 h, and then LPS (100 ng/ml) was added to clarify the functional status of the cells. The results showed HC inhibited TNF-α and IL-6 mRNA expressions and their release, but AS (2.5 μg/ml) could increase TNF-α and IL-6 mRNA expressions and their release. AS inhibited GILZ mRNA up-regulated by HC and increases TLR4/NF-κB p65 expressions down-regulated by HC. Our findings revealed that AS's effect is closely related to the improvement of the TLR4/NF-κB signal transduction pathway via inhibiting the up-regulation of GILZ mRNA, demonstrating AS does possess immunomodulatory effects and is worth further investigation in the future.

Background 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. Method 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. Results 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. Conclusion 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.

Poor sleep quality and mental health problems are common in college students. The objective of this study is to examine whether sleep quality predicts the risk of future mental health problems, and vice versa.The sleep quality and mental health status of 686 male college students were estimated, and 582 of them were followed up a year later. Subjective sleep quality and mental health problems were measured with the Pittsburgh Sleep Quality Index (PSQI) and the Depression Anxiety Stress Scale-21 (DASS-21), respectively.Either at baseline or during follow-up, the PSQI global score was positively associated with scores for depression, anxiety, and stress on the DASS-21 (p's 0.001). Longitudinal analyses revealed that DASS-21 total score increased in line with increased of PSQI global score during the year (p .001). More importantly, the cross-lagged analysis showed that (i) PSQI global score at baseline was positively related to depression (β = 0.261), anxiety (β = 0.321), and stress (β = 0.311) scores a year later (p's 0.001) and (ii) depression (β = 0.259), stress (β = 0.245) and anxiety (β = 0.292) scores at baseline were related to PSQI global score a year later (p's 0.001). Finally, we further found that among those without mental health problems at baseline, poorer baseline sleep quality predicted a higher risk of anxiety symptoms a year later (RR 3.07, 95% CI 1.36-6.97, p = .007).These data may suggest a bidirectionally relationship between sleep quality and mental health problems.

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.

Interleukin 23 receptor (IL23R) is a signaling protein normally implicated in gut T cell development, but which has also been correlated with poor cancer prognoses. Previous studies have found that interfering with this pathway results in improved cancer outcomes in mice. These studies found that blocking IL23R was more effective than neutralizing IL23, suggesting that an IL23R-expressing cell was responsible for the tumor-protective effects observed in targeting IL23R. Here, we show that Treg-specific targeting of IL23R provides potent tumor immunity that explains previous successes with anti-IL23R therapy in cancer. We show that there is indeed a tumor-infiltrating Treg subset, marked by IL23R expression, that is enriched for markers of potent suppressive activity. Moreover, we find that targeting their IL23R expression is correlated with Treg conversion and increased IFNγ expression on tumor-infiltrating CD8 T cells. Preliminary results suggest that this Treg conversion is associated with enhanced IL12 sensitivity as a result of targeting the IL23R chain. In keeping with the tumor-specific expression pattern of IL23R, we did not find these changes in systemic T cells in the tumor-bearing mice. Ultimately, these Treg-specific IL23R-deleted mice do not display overt autoimmune disease at even advanced ages, suggesting this approach could represent a safe avenue of cancer immunotherapeutic research.

Objectives. To study the associations between kisspeptin levels in seminal plasma and blood plasma and semen quality. Materials and Methods. We conducted a male reproductive health survey in June 2014. A total of 666 volunteers were recruited from colleges in Chongqing, China. All volunteers completed a questionnaire including information on domestic characteristics and some potential confounders. We tested the kisspeptin levels in both blood and seminal plasma. Total seminal kisspeptin was calculated as the concentration of kisspeptin in seminal plasma multiplied by semen volume. Semen samples were tested according to the 2010 World Health Organization’s (WHO) guidelines. Spearman correlation and multivariate linear regression were used to explore the association between kisspeptin concentrations in seminal plasma and blood plasma and semen quality. Potential confounders that were adjusted for included age, abstinence time, body mass index (BMI), grade, and smoking. Results. The median of kisspeptin levels in seminal plasma was 60,000 times higher than kisspeptin in blood plasma (28.0 × 106 pg/ml versus 448.9 pg/ml). Each interquartile range (IQR) of kisspeptin in seminal plasma was associated with a 4.6% (95% confidence interval [CI]: 1.6%–7.6%) increase in sperm concentration. Each IQR of total kisspeptin was associated with a 7.7% (95% CI: 4.4%–11.0%) increase in total sperm number and a 7.8% (95% CI: 4.0%–11.7%) increase in total motile sperm count. Kisspeptin levels were further classified into quartiles and Q1 was set as the reference level. Subjects in the high total kisspeptin group had 57.5% (95% CI: 33.2%–86.2%) higher total sperm number than the reference group. Conclusion. The positive association between kisspeptin levels in seminal plasma and semen quality supported an important role for the KISS1/GPR54 system in male reproductive health. Kisspeptin may be a potential marker of male reproductive health and an alternative strategy for treating infertility.

Social jetlag (SJ), discrepancy from inner clock for work and non-work-related reasons, is prevalent worldwide and has been associated with decreased fertility in women, but not in men. In the current study, we firstly extracted the national rate of rotating shift work (RSW) in men of reproductive age (15-49 years) from 35 European countries from the European Working Conditions Survey. Regression analysis revealed an inverse correlation between RSW and the national fertility rate (as reported by the World Bank; P < 0.001). For every 10% increase in RSW rate, fertility rate decreased by 0.114 (equivalent to 11.4 fewer births per 100 women). Then we compared 16 semen/reproductive-hormone parameters of RSW workers against day workers in 1346 reproductive-age Chinese men. RSW was associated with 1.26 (95%CI 1.05-1.52) fold risk of low sperm count. The SJ-sperm correlation was also observed in a cohort of 796 unemployed reproductive-age Chinese undergraduates: each hour non-work-related SJ between school days and days off was associated with 1.16 (95%CI 1.02-1.31) fold risk, and sperm count increased during follow up in men who reduced SJ after baseline. At last, a mouse model subjected to photoperiod shifting was established to simulate SJ and the related sperm decrease. Apoptosis analysis suggested the damage originated in spermatogenic cells in seminiferous tubules. Differentially expressed gene analysis showed that photoperiod shifting down-regulated marker genes of post-spermatocyte stage cells. The most enriched functional pathway was homologous recombination, which happened in spermatocytes during meiosis. Our study suggests that SJ is associated with male reproductive damage.

Objective Psychosocial factors have been associated with a decline of the quality of semen. The study was aimed at (i) estimating the association between work stress and semen quality and (ii) exploring the moderating effect of social support in semen parameters among Chinese male workers. Methods Data were obtained from 384 adult male workers recruited from April 2014 to December 2015 in Chongqing, China. Participants completed a questionnaire assessing demographic and life-style factors. Work stress and social support was measured by the Chinese version of a 22-item Job Content Questionnaire (JCQ). They underwent a physical examination and provided a semen sample. Results Subjects with high work stress were associated with a higher risk of being classified below WHO's thresholds for “normal,” defined by sperm concentration (OR 2.14, 95% CI 1.24–3.68, p = .006) or total sperm count (OR 1.95, 95% CI 1.13–3.36, p = .02) criteria than subjects with low work stress were. However, these adverse associations were not observed among subjects with high social support (p = .80 for sperm concentration, and p = .39 for total sperm count). Interaction effects between social support and work stress on sperm concentration (p = .002) and total sperm count (p = .02) were detected. Conclusion Work stress is associated with lower levels of semen quality. Social support attenuates the negative association between work stress and semen quality, which may have implications for reproductive health.

Stated preference method is usually used to evaluate the non-market value of environmental goods which includes contingent valuation method (CVM) and choice experiments (CE). In this paper, stated preference method was adopted to evaluate the non-market value of Sanjiang Plain wetland. A willingness to pay (WTP) evaluation model of stated preference method was constructed based on the random utility theory. The average WTP of CVM and CE was obtained, respectively. The average WTP elicited by CE was 379 yuan per year, and the marginal WTPs of different selection properties including water conservation, wetland area, natural landscape and biodiversity were114.00, 72.55, 59.55 and 37.09 yuan per year, respectively. Meanwhile, the average WTP elicited by CVM was 134 yuan per year. The influence of factors on WTP was analyzed and reasons for protest responses were discussed. Results showed that the respondents' WTP elicited by CE was signi-ficantly higher than that by CVM, and respondents' socio-economic attitudes such as level of education and personal annual income had a significant positive impact on respondents' WTP. There were no significant difference in the reasons of protest responses between CVM and CE. Besides, respondents' multiple attributes and multiple levels analysis could be carried out by CE and the WTP of wetland's selection attributes could be calculated. Therefore, CE had the better ability of revealing respondents' preference information than CVM and its assessment results were more close to the actual value.陈述性偏好法是当前用于评估环境物品非市场价值的主要方法,包括条件价值评估法(CVM)和选择实验(CE).本文利用陈述性偏好法对三江平原湿地的生态保护价值进行评估,基于随机效用理论构建陈述性偏好方法的支付意愿评价模型,求出基于CVM与CE的三江平原湿地生态保护价值的支付意愿(WTP).结果表明: 基于CE的平均支付意愿为每年379元,不同选择属性的边际支付意愿分别是水源涵养为每年114.00元,湿地面积为每年72.55元,自然景观为每年59.55元,生物多样性为每年37.09元;CVM的平均支付意愿为每年134元.分析支付意愿的影响因素,并对受访者拒绝支付原因进行探讨.CE方法得到受访者的支付意愿显著高于CVM方法,社会经济属性中受教育程度和个人平均年收入与受访者的支付意愿呈显著正相关,而拒绝支付原因没有显著差异.CE可以进行多属性、多水平分析,求出湿地各选择属性的支付意愿,因此CE比CVM更能揭示受访者的偏好信息,其评估结果更接近于实际.

Study question In addition to sperm motility, which major biological characteristics of sperm fertility potential are associated with mitochondrial functionality? Summary answer Sperm fertilization capacities, including acrosin activity, acrosome reaction (AR) capability and chromatin integrity, are related to the mitochondria functionality as evaluated by the mitochondrial membrane potential (MMP). What is known already Correlative studies suggest a potential role of sperm MMP in predicting sperm fertilization ability and ensuring sperm motility. However, researches characterizing other determinants of sperm fertility potential according to MMP are lacking. Study design, size, duration The sperm MMP was examined in 627 young college students in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Among these participants, acrosin activity and chromatin integrity were measured in 378 and 604 subjects, respectively. These two determinants of sperm fertility potential were first compared among high-, moderate- and low-MMP groups in the college population. The effects of MMP collapse caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on acrosin activity, AR, DNA fragmentation, reactive oxygen species (ROS) production, and ATP content in human spermatozoa were evaluated in vitro. Participants/materials, setting, methods The sperm MMP was evaluated by using JC-1 staining, acrosin activity was measured using a N-α-benzoyl-dl-arginine-para-nitroanilide HCl (BAPNA) substrate method, the integrity of chromatin represented by DNA fragmentation index (DFI) was measured by sperm chromatin structure assay (SCSA), AR was evaluated with chlortetracycline staining, and intracellular ROS production was evaluated with dihydroethidium. ATP concentration was determined with luciferase. Measurements were performed by spectrophotometry or flow cytometry. Main results and the role of chance Nonparametric analysis revealed significantly higher acrosin activity and a lower DFI in subjects with moderate or high MMP compared to those with low MMP. After adjustment for potential confounders, increases of 7.9 and 44.4% in sperm acrosin activity and deceases of 12.0 and 25.2% in the sperm DFI were found in the moderate- and high-MMP groups, respectively. The MMP dissipation induced by CCCP caused significant declines in acrosin activity and AR capacity and increased DFI in human spermatozoa. Moreover, sperm MMP dissipation induced ROS overproduction and decreased ATP content. Limitations, reasons for caution We cannot exclude a contribution of leukocytes to ROS production and no size gating was used to exclude these cells from the FACS measurements. No simultaneous live-dead staining was done and a contribution of dead sperm to the MMP and acrosome assays cannot be excluded. Wider implications of the findings Mitochondrial functionality might be necessary to maintain sperm acrosin activity, AR and chromatin integrity. Tests of mitochondrial functionality should be developed and used independently of or in addition to conventional semen parameters in infertility diagnosis or risk-assessment processes. Study funding/competing interest(s) This study was supported by the Key Program of the National Natural Science Foundation of China (No. 81630087) and the National Natural Science Foundation of China (No. 81703254). None of the authors have any competing interests to declare.

The increasing prevalence of extremely low frequency electromagnetic fields (ELF-EMFs) exposure has raised considerable public concern regarding the potential hazardous effects of ELF-EMFs on male reproductive function. Increasing evidence indicates that miRNAs are necessary for spermatogenesis and male fertility. However, the regulation of miRNA expression and the roles of miRNAs in response to ELF-EMFs remain unclear. In our study, mouse spermatocyte-derived GC-2 cells were intermittently exposed to a 50 Hz ELF-EMF for 72 h (5 min on/10 min off) at magnetic field intensities of 1 mT, 2 mT and 3 mT. MiR-26b-5p was differentially expressed in response to different magnetic field intensities of ELF-EMFs. The host gene CTDSP1 showed an unmethylation status in GC-2 cells at different magnetic field intensities of ELF-EMF exposure. MiR-26b-5p had no significant, obvious influence on the cell viability, apoptosis or cell cycle of GC-2 cells. However, the overexpression of miR-26b-5p significantly decreased the percentage of G0/G1 phase cells and slightly increased the percentage of S phase cells compared to the sham group that was exposed to a 50 Hz ELF-EMF. Computational algorithms identified Cyclin D2 (CCND2) as a direct target of miR-26b-5p. MiR-26b-5p and a 50 Hz ELF-EMF altered the expression of CCND2 at both the mRNA and protein levels. Overexpressed miR-26b-5p in GC-2 cells can change the mRNA expression of CCND2 following 50 Hz ELF-EMF at 3 mT. These findings demonstrate that miR-26b-5p could serve as a potential biomarker following 50 Hz ELF-EMF exposure, and miR-26b-5p-CCND2-mediated cell cycle regulation might play a pivotal role in the biological effects of ELF-EMFs.

Studies have shown that the effects of ambient particulate matter (PM) may be related to particle's size. However, results on the relationships between different PM and reproductive health are controversial. To explore the impacts of various PM fractions on male reproductive health, a total of 796 eligible subjects recruited in 2013 baseline investigation. In addition, there were 656 (82.4%) and 568 (71.3%) subjects participated follow-up surveys in 2014 and 2015, respectively. We used multivariable regression analysis and mixed-effect model to investigate the associations between air pollutants PM

We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

1,2:3,4-Diepoxybutane (DEB) is a major carcinogenic metabolite of 1,3-butadiene (BD), which has been shown to cause DNA strand breaks in cells through its potential genotoxicity. The adverse effect of DEB on male reproductive cells in response to DNA damage has not been thoroughly studied, and the related mechanism is yet to be elucidated. Using mouse spermatocyte-derived GC-2 cells, we demonstrated in the present study that DEB caused the proliferation inhibition and marked cell cycle arrest at the G2 phase but not apoptosis. DEB also induced DNA damage as evidenced by γ-H2AX expression, the comet assay, and the cytokinesis-block micronucleus assay. Meanwhile, DEB triggered the Chk1/Cdc25c/Cdc2 signal pathway, which could be abated in the presence of UCN-01 or Chk1 siRNA. GC-2 cells exposed to DEB experienced ROS generation and pretreatment of N-acetyl-l-cysteine, partly attenuated DEB-induced DNA damage, and G2 arrest. Furthermore, measurement of testicular cells showed an increased proportion of tetraploid cells in mice administrated with DEB, alongside the enhanced expression of p-Chk1. Also, the defective reproductive phenotypes, including reduced sperm motility, increased sperm malformation, and histological abnormality of testes, were observed. In conclusion, these results suggest DEB induces DNA damage and G2 cell cycle arrest by activating the Chk1-dependent pathway, while oxidative stress may be associated with eliciting toxicity in male reproductive cells.

The aim of the study was to examine the association between polymorphisms of DNA repair genes and chromosomal damage of 1,3-butadiene- (BD-) exposed workers. The study was conducted in 45 pairs of occupationally exposed workers in a BD product workshop and matched control workers in an administrative office and a circulatory water workshop in China. Newly developed biomarkers (micronuclei, MNi; nucleoplasmic bridges, NPBs; nuclear buds, NBUDs) in the cytokinesis-blocked micronucleus (CBMN) cytome assay were adopted to detect chromosomal damage. PCR and PCR-restriction fragment length polymorphism (RFLP) are adopted to analyze polymorphisms of DNA repair genes, such as X-ray repair cross-complementing Group 1 (XRCC1), O6-methylguanine-DNA methyltransferase (MGMT), poly (adenosine diphosphate-ribose) polymerases (ADPRT), and apurinic/apyrimidinic endonucleases (APE1). The BD-exposed workers exhibited increased frequencies of MNi and NPBs when compared to subjects in the control group. The results also show that the BD-exposed workers carryingXRCC1diplotypesTCGA-CCGG(4.25±2.06‰) (FR=2.10, 95% CI: 1.03–4.28) andTCGG-TCGA(5.80±3.56‰) (FR=2.75, 95% CI: 0.76–2.65) had statistically higher NBUD frequencies than those who carried diplotypeTCGG-TCGG(1.89±1.27‰). Our study suggests that polymorphisms ofXRCC1gene may influence chromosomal damage in BD-exposed workers.

The aims of this study were to explore the associations between negative life events and anxiety, depressive, and stress symptoms among male senior college students who experience negative life events in daily life. Data were obtained from 582 male senior college students recruited from universities in Chongqing China. Participants completed the Adolescent Self-rating Life Events Checklist (ASLEC), and the Depression, Anxiety, and Stress Scale-21 (DASS-21). Socio-demographic information, lifestyle information, and a blood sample were acquired. 39 (6.7%), 74 (12.7%), and 39 (6.7%) subjects were depressed, anxious, and stressed, respectively. The results confirmed that negative life events were positively related to mental health problems. Different types of negative life events had their specific associations with being depressed, anxious, or stressed. With respect to different types of negative life events, subjects with more “interpersonal relationship” related problems had a higher probability of being anxious and stressed; whereas, subjects with more “change for adaptation” related problems had a higher probability of being depressed and anxious. These results indicate that more concerns over the events with both high occurrence rate and severity might be helpful to mental health prevention and promotion for senior college students.

Summary This study explores whether sleep duration is associated with sperm chromatin integrity. To do so, we conducted a three-phase panel study of 796 male volunteers from colleges in Chongqing (China) from 2013 to 2015. Sleep duration was measured using a modified Munich Chronotype Questionnaire. Sperm DNA integrity was examined via Sperm Chromatin Structure Assay and Comet assay. Setting 7–7.5 h day−1 of sleep duration as a reference, either longer or shorter sleep duration was associated negatively with high DNA stainability (HDS) (P = 0.009), which reflected the immaturity of sperm chromatin. The volunteers with > 9.0 h day−1 sleep and those with ≤ 6.5 h day−1 sleep had 40.7 and 30.3% lower HDS than did volunteers with 7–7.5 h day−1 sleep. No association was found between sleep duration and DNA fragmentation index or Comet assay parameters. This study suggests that sleep duration is associated with sperm chromatin integrity. Further studies are required to validate these findings and investigate the mechanism underlying this association.

The aim of the present study was to assess the oxidative stress level and chromosomal damage induced by occupational exposure to low dose ionizing radiation (LDIR). Two hundred and eighteen hospital workers occupationally exposed to LDIR were included in this study, along with 118 healthy age- and gender-comparable controls. Occupational dosimetry records were collected over the last year and revealed that the accumulated annual dose for each hospital worker was below the permissible limit of the International Commission on Radiological Protection (ICRP). The individuals' oxidative and antioxidative status were determined by measuring the activities of copper zinc-superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), catalase (CAT) enzymes, and the levels of malondialdehyde (MDA) in erythrocytes. The effect of radiation on chromosomal integrity was measured by the frequency of micronuclei (MN) formation using the cytokinesis block technique. Our results showed that the activities of CuZn-SOD and CAT enzymes and MDA levels observed in the hospital workers were higher than those in the controls (p 0.05). We did not find significant difference in GSH-Px enzyme activity between the two groups (p = 0.247). A higher frequency of MN was found in exposed groups than in the controls [3(1-5) ‰ versus 2(0.75-4) ‰; p0.001]. The difference was significant for males (p = 0.012), but not females (p = 0.14). Multiple linear regression analysis showed differences in the oxidant activities and MN frequency between hospital workers and controls adjusted for age, gender, smoking status and drinking status. Correlation analysis indicated that the frequency of MN was positively associated with MDA levels (p 0.05). Altogether, these results support the detrimental effects of chronic low dose radiation in humans, which involves the induction of oxidative stress and chromosomal damage.

Smoke inhalation injury is the main cause of fatalities for fire victims. Understanding in the pathophysiology of the injury has not been fully explored in recent years. To further explore the pathophysiological mechanism, a dynamic and controllable animal model is necessary.To develop a rat model of smoke inhalation injury to simulate human victims in air-restricted vehicle cabin fires.Smoke concentration, including CO, O2, VOCs and smoke temperature under different combustion conditions, were detected. Levels of COHb, respiratory function, lung wet-to-dry weight ratio and protein concentration in BALF and blood were measured. Pathological evaluations of lung in tissues were conducted at 1, 6, 24 and 48 h post-exposure.Smoke concentration rose with the increase of combustion temperature and decrease of oxygen flow. Further, 215 kinds of VOCs in the smoke were detected, and the concentrations of benzene, methylbenzene, ethylbenzene, dimethylbenzene, phenylethylene and trimethylbenzene was 32.93, 402.06, 764.03, 113.73, 1006.61 and 89.28 mg/m(3), respectively. Significant hypoxemia and CO poisoning occurred in rats. The FCOHb after exposure for 14 min immediately rose to (44.2 ± 12.3) % and then gradually decrease to a normal level at 300 min post-exposure. At 24 h post-exposure, Penh increased significantly (p 0.05), and high pulmonary vascular permeability and significant lung edema (p 0.05) were observed in the smoke inhalation group.In summary, the novel rat model of smoke inhalation injury system used in the study is dynamic and controllable, and appropriate for use in smoke inhalation injury studies of air-restricted cabins in vehicles.

The increasing exposure to radiofrequency (RF) radiation emitted from mobile phone use has raised public concern regarding the biological effects of RF exposure on the male reproductive system. Autophagy contributes to maintaining intracellular homeostasis under environmental stress. To clarify whether RF exposure could induce autophagy in the spermatocyte, mouse spermatocyte-derived cells (GC-2) were exposed to 1800MHz Global System for Mobile Communication (GSM) signals in GSM-Talk mode at specific absorption rate (SAR) values of 1w/kg, 2w/kg or 4w/kg for 24h, respectively. The results indicated that the expression of LC3-II increased in a dose- and time-dependent manner with RF exposure, and showed a significant change at the SAR value of 4w/kg. The autophagosome formation and the occurrence of autophagy were further confirmed by GFP-LC3 transient transfection assay and transmission electron microscopy (TEM) analysis. Furthermore, the conversion of LC3-I to LC3-II was enhanced by co-treatment with Chloroquine (CQ), indicating autophagic flux could be enhanced by RF exposure. Intracellular ROS levels significantly increased in a dose- and time-dependent manner after cells were exposed to RF. Pretreatment with anti-oxidative NAC obviously decreased the conversion of LC3-I to LC3-II and attenuated the degradation of p62 induced by RF exposure. Meanwhile, phosphorylated extracellular-signal-regulated kinase (ERK) significantly increased after RF exposure at the SAR value of 2w/kg and 4w/kg. Moreover, we observed that RF exposure did not increase the percentage of apoptotic cells, but inhibition of autophagy could increase the percentage of apoptotic cells. These findings suggested that autophagy flux could be enhanced by 1800MHz GSM exposure (4w/kg), which is mediated by ROS generation. Autophagy may play an important role in preventing cells from apoptotic cell death under RF exposure stress.

Possible hazardous health effects of radiofrequency electromagnetic radiations emitted from mobile phone on the reproductive system have raised public concern in recent years. This systemic review and meta-analysis was prepared following standard procedures of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and checklist. Relevant studies published up to May 2013 were identified from five major international and Chinese literature databases: Medline/PubMed, EMBASE, CNKI, the VIP database and the Cochrane Central Register of Controlled Trials in the Cochrane Library. Eighteen studies with 3947 men and 186 rats were included in the systemic review, of which 12 studies (four human studies, four in vitro studies and four animal studies) with 1533 men and 97 rats were used in the meta-analyses. Systemic review showed that results of most of the human studies and in vitro laboratory studies indicated mobile phone use or radiofrequency exposure had negative effects on the various semen parameters studied. However, meta-analysis indicated that mobile phone use had no adverse effects on semen parameters in human studies. In the in vitro studies, meta-analysis indicated that radiofrequency radiation had detrimental effect on sperm motility and viability in vitro [pooled mean difference (MDs) (95% CI): -4.11 (-8.08, -0.13), -3.82 (-7.00, -0.65) for sperm motility and viability respectively]. As for animal studies, radiofrequency exposure had harmful effects on sperm concentration and motility [pooled MDs (95% CI): -8.75 (-17.37, -0.12), -17.72 (-32.79, -2.65) for sperm concentration and motility respectively]. Evidence from current studies suggests potential harmful effects of mobile phone use on semen parameters. A further multicentred and standardized study is needed to assess the risk of mobile phone use on the reproductive system.

To investigate the association and effects of air pollution level on male semen quality in urban and rural areas, this study examines the outdoor concentrations of particulate matter (PM10), sulfur dioxide (SO2), nitrous dioxide (NO2) and semen quality outcomes for 1346 volunteers in both urban and rural areas in Chongqing, China. We found the urban area has a higher pollution level than the rural area, contrasted with better semen quality in the rural residents, especially for sperm morphology and computer assistant semen analysis (CASA) motility parameters. A multivariate linear regression analysis demonstrates that concentrations of PM10, SO2, and NO2 significantly and negatively are associated with normal sperm morphology percentage (P

Ethnopharmacological relevance Tripterygium hypoglaucum (levl.) Hutch ( Celastraceae ) (THH) root is a traditional Chinese medicinal herb commonly used for treating autoimmune diseases and cancer. Alkaloid is one of the most bioactive components of THH extract. To evaluate the in vitro and in vivo antitumor properties of the total alkaloids of THH (THHta). Materials and methods THHta was extracted in pilot-scale. HCT116 cells were chose to establish human colon cancer xenograft model. The in vitro anti-tumor activity of THHta was tested by Cell malignant transformation test, Soft agar colony formation assay and MTT assay. The in vivo anti-tumor effect of THHta was confirmed by xenograft mouse model. THHta-induced apoptosis was examined by flow cytometry. The levels of apoptosis-related proteins were investigated by Western blot. Results TPA-induced cell transformation was significantly inhibited by THHta in JB6 Cl41 cells. THHta inhibits the growth of colon cancer cells in vitro in a significant dose-dependent manner. Compared to the control set, i.p. administration of THHta to xenograft mice significantly reduced both tumor weight and volume. Apoptosis induction of THHta was mediated by activation of caspase-3, PARP and inhibiting of Bcl-2, Bcl-xL and XIAP. Conclusion THHta was effective in inhibiting tumor growth both in vitro and in vivo at less toxic concentrations by inducing apoptosis which suggested it could be developed as a potential anticancer agent.