Background Beyond occupational settings, environmental benzene exposure may pose respiratory risk, but few studies have linked long-term low-concentration exposure to the incidence of Chronic Obstructive Pulmonary Disease (COPD) in the general population. We aim to investigate the dose-response relationship and the modifying effects of polygenic risk scores (PRS). Methods This study included 285,338 UK Biobank participants. Cox models and restricted cubic splines were used to assess the exposure-response relationship between environmental benzene exposure and incident COPD risk. Biological aging (Phenotypic Age) was derived from baseline biomarker. Additive interactions with biological aging, telomere length, PRS and smoking were quantified using the Relative Excess Risk due to Interaction (RERI) and the Attributable Proportion (AP). Results Benzene exposure showed a clear dose-response relationship with COPD risk. Each 1µg/m³ increase in benzene concentration was associated with a hazard ratio (HR) of 1.40 (95% CI: 1.35, 1.45). Significant additive interactions emerged for biological aging, shortened telomeres, and smoking (RERI: 0.27, 0.09, and 0.92, respectively; all P < 0.05). Notably, individuals with high benzene exposure and high PRS faced the highest COPD risk (HR: 2.43, 95% CI: 2.16, 2.74), with significant additive interactions (RERI: 0.19, 95% CI: 0.05, 0.34) Conclusion Long-term low-concentration environmental benzene exposure is dose-responsively associated with increased COPD risk in the general population. Additive effects were observed with biological aging, shortened telomeres, smoking, and high genetic risk.

The possible protective effect of interleukin-32 (IL-32) in Mycobacterium tuberculosis (Mtb) infection has been indicated. However, few studies have been focused on IL-32 in tuberculosis patients. Additionally, the regulation of IL-32 production has rarely been reported. In the present study, the production, regulation, and role of IL-32 in tuberculous pleurisy (TBP) were investigated. We found that the content of IL-32 in tuberculous pleural effusion (TPE) was higher than the level in the malignant pleural effusion and transudative pleural effusion. The level of IL-32 mRNA in pleural fluid mononuclear cells (PFMCs) was higher than that in peripheral blood mononuclear cells (PBMCs) of patients with TBP, and this difference was mainly reflected in the splice variants of IL-32α, IL-32β, and IL-32γ. Compared with the PBMCs, PFMCs featured higher IL-32β/IL-32γ and IL-32α/IL-32γ ratios. In addition, lipopolysaccharide (LPS), Bacillus Calmette-Guérin (BCG), and H37Ra stimulation could induce IL-32 production in the PFMCs. IL-32 production was positively correlated with the TNF-α, IFN‐γ, and IL-1Ra levels in TPE, whereas IFN-γ, but not TNF-α or IL-1Ra, could induce the production of IL-32 in PFMCs. Furthermore, IL-32γ could induce the TNF-α production in PFMCs. Monocytes and macrophages were the main sources of IL-32 in PFMCs. Nevertheless, direct cell–cell contact between lymphocytes and monocytes/macrophages plays an important role in enhancing IL-32 production by monocyte/macrophage cells. Finally, compared with the non-tuberculous pleural effusion, the purified CD4+ and CD8+ T cells in TPE expressed higher levels of intracellular IL-32. Our results suggested that, as a potential biomarker, IL-32 may play an essential role in the protection against Mtb infection in patients with TBP. However, further studies need to be carried out to clarify the functions and mechanisms of the IFN-γ/IL-32/TNF-α axis in patients with TBP.

OBJECTIVE:To investigate the toxic effects and potential mechanisms of tri(1, 3-dichloro-2-propyl) phosphate(TDCIPP) exposure on the mouse testicular supporting cell line(TM4 cells). METHODS:TM4 cells were treated with different concentrations of TDCIPP(0, 12.5, 25 and 50 μmol/L), or 50 μmol/L TDCIPP combined with antioxidant N-acetylcysteine(NAC) for 24 h. Cell viability was assessed using the CCK8 assay, intracellular ROS levels were detected using the DCFH-DA probe, and the protein levels of oxeiptosis-related proteins, such as KEAP1, PGAM5, AIFM1 and phosphorylated AIFM1(p-AIFM1), were detected using Western blot. RESULTS:TDCIPP dose-dependently reduced TM4 cell viability(P&lt;0.05). ROS levels in TM4 cells treated with 12.5, 25 and 50 μmol/L TDCIPP were 9.44±1.42, 17.25±1.81 and 18.38±2.66, respectively, significantly higher than the control group&apos;s 5.08±0.90(P&lt;0.05). ROS levels in the 5 mmol/L NAC+50 μmol/L TDCIPP group were 14.70±0.50, significantly lower than the corresponding TDCIPP group&apos;s 26.44±0.73(P&lt;0.05). The activity of TM4 cells in KEAP1siRNA+TDCIPP group and PGAM5siRNA+TDCIPP group were 77.00±1.73 and 76.67±1.53, respectively, significantly higher than TDCIPP group 68.67±1.53(P&lt;0.05). The relative expression of KEAP1 protein in TM4 cells treated with 25 and 50 μmol/L TDCIPP were 0.77±0.04 and 0.82±0.02, respectively, significantly higher than the control group&apos;s 0.57±0.01(P&lt;0.05). The relative expression of PGAM5 protein in TDCIPP-treated TM4 cells were 1.17±0.04, 1.38±0.03 and 1.41±0.03, respectively, significantly higher than the control group&apos;s 0.81±0.02(P&lt;0.05). The relative expression of AIFM1 protein were 0.42±0.01, 0.63±0.01 and 0.68±0.02, respectively, significantly higher than the control group&apos;s 0.34±0.02(P&lt;0.05). The relative expression of p-AIFM1 protein were 1.73±0.02, 1.52±0.02 and 0.73±0.01, respectively, significantly lower than the control group&apos;s 2.25±0.02(P&lt;0.05). In the 5 mmol/L NAC+50 μmol/L TDCIPP group, the relative expression of KEAP1, PGAM5 and AIFM1 proteins in TM4 cells were 0.61±0.01, 0.58±0.01 and 0.48±0.03, respectively, significantly lower than the TDCIPP group&apos;s 0.86±0.12(P&lt;0.05), 0.74±0.02(P&lt;0.05) and 0.92±0.01(P&lt;0.05). The relative expression of p-AIFM1 protein in the 5 mmol/L NAC+50 μmol/L TDCIPP group was 0.45±0.11, significantly higher than the TDCIPP group&apos;s 0.23±0.01(P&lt;0.05). CONCLUSION:The reduction of TM4 cell viability induced by TDCIPP may be related to ROS-mediated regulation of the KEAP1/PGAM5/AIFM1 pathway, leading to oxeiptosis.

OBJECTIVE:To investigate the effects of bisphenol A(BPA) on the proliferation and apoptosis of mouse testicular sertoli cells(TM4 cells) and the role of PERK-eIF2α-ATF4-CHOP pathway.METHODS:TM4 cells were treated with different concentrations of BPA(0, 25, 50, 100 μmol/L) and 100 μmol/L BPA combined with protein kinase R-like ER kinase(PERK) inhibitor GSK2656157 for 24 h, and the apoptosis of TM4 cells was observed by TUNEL staining. The expression levels of Bax, Bcl-2, cleaved Caspase-3, GRP78 and PERK-eIF2α-ATF4-CHOP pathway-related proteins were detected by Western blot.RESULTS:The apoptosis rate of TM4 cells in 25, 50 and 100 μmol/L BPA exposed groups was increased to 3.31%±0.34%, 7.51%±1.10% and 14.58%±0.91%, respectively, which was significantly higher than that in control group(0.73%±0.03%, P&lt;0.05). Compared with the control group(1.00), cleaved Caspase-3 protein expression of TM4 cells in the 25, 50 and 100 μmol/L BPA exposed groups increased to 1.49±0.11, 1.59±0.12, 2.42±0.24, respectively; the ratio of Bax/Bcl-2 increased to 2.06±0.19, 3.94±0.034, 6.14±0.71, respectively; the protein expression of GRP78 increased to 1.29±0.06, 1.39±0.06, 1.92±0.17, respectively; the expression of p-PERK protein was increased to 1.64±0.03, 2.52±0.09, 2.80±0.11, respectively; the expression of p-eIF2α protein was increased to 1.79±0.05, 2.48±0.10, 4.77±0.32, respectively; ATF4 protein expression was increased to 2.51±0.03, 3.24±0.14 and 7.45±0.51, respectively; CHOP protein expression was increased to 1.44±0.01, 3.20±0.11 and 3.80±0.11, respectively, and all the differences were statistically significant(P&lt;0.05). Compared to 100 μmol/L BPA group, the expression level of p-PERK, p-eIF2α, ATF4, CHOP, cleaved Caspase-3 protein and the ratio of Bax/Bcl-2 in 100 μmol/L BPA+10 μmol/L GSK2656157 group were decreased to 2.17±0.11, 1.81±0.13, 1.71±0.23, 2.18±0.22, 1.43±0.03, 2.22±0.13, respectively; the apoptosis rate of TM4 cells was also decreased to 7.28%±0.47%, all the differences were statistically significant(P&lt;0.05).CONCLUSION:BPA can induce apoptosis of TM4 cells by activating endoplasmic reticulum stress and regulating PERK-eIF2α-ATF4-CHOP pathway.

Cadmium is one of the environmental and occupational pollutants and its potential adverse effects on human health have given rise to substantial concern. Cadmium causes damage to the male reproductive system via induction of germ-cell apoptosis; however, the underlying mechanism of cadmium-induced reproductive toxicity in Leydig cells remains unclear. In this study, twenty mice were divided randomly into four groups and exposed to CdCl2 at concentrations of 0, 0.5, 1.0 and 2.0 mg/kg/day for four consecutive weeks. Testicular injury, abnormal spermatogenesis and apoptosis of Leydig cells were observed in mice. In order to investigate the mechanism of cadmium-induced apoptosis of Leydig cells, a model of mouse Leydig cell line (i.e. TM3 cells) was subjected to treatment with various concentrations of CdCl2. It was found that mitochondrial function was disrupted by cadmium, which also caused a significant elevation in levels of mitochondrial superoxide and cellular ROS. Furthermore, while cadmium increased the expression of mitochondrial fission proteins (DRP1 and FIS1), it reduced the expression of mitochondrial fusion proteins (OPA1 and MFN1). This led to excessive mitochondrial fission, the release of cytochrome c and apoptosis. Conversely, cadmium-induced accumulation of mitochondrial superoxide was decreased by the inhibition of mitochondrial fission through the use of Mdivi-1 (an inhibitor of DRP1). Mdivi-1 also partially prevented the release of cytochrome c from mitochondria to cytosol and attenuated cell apoptosis. Finally, given the accumulation of LC3II and SQSTM1/p62 and the obstruction of Parkin recruitment into damaged mitochondria in TM3 cells, the autophagosome-lysosome fusion was probably inhibited by cadmium. Overall, these findings suggest that cadmium induces apoptosis of mouse Leydig cells via the induction of excessive mitochondrial fission and inhibition of mitophagy.

OBJECTIVE:To study the impact of cadmium (Cd) on the expressions of PIWI-interacting RNAs (piRNA) in the rat testis and its possible action mechanism.METHODS:Twelve 6-week-old SD rats were randomly divided into a Cd-exposure and a control group, the former gavaged with CdCl2 at 3 mg/kg/d and the latter with normal saline, all for 28 successive days. Then the testicular tissues were collected from the rats, sperm concentration and motility were obtained by computer-assisted sperm analysis (CASA), and piRNA sequencing was performed using the gene chip, followed by bioinformatics analysis of differentially expressed piRNAs.RESULTS:Compared with the controls, the rats in the Cd-exposure group showed significantly decreased sperm concentration and motility (P < 0.05). The expressions of 272 piRNAs were up-regulated and 402 down-regulated after 28 days of Cd exposure, and 4 of the up-regulated piRNAs were consistent with the results of gene chip verification. Bioinformatics analysis showed that the 4 up-regulated piRNA target genes were involved in 50 biological processes, such as negative regulation of apoptosis, positive regulation of gene expression and positive regulation of GTPase activity, and mainly concentrated in 13 signaling pathways including transcription dysregulation, calcium and mitogen-activated protein kinase signaling pathways in cancer. Among them, PIRNA-DQ765261 had a binding site with Bcl-2.CONCLUSION:Cadmium can induce changes in the expressions piRNAs in the rat testicular tissue, and some piRNAs may be involved in the autophagy and apoptosis of sperm. Bcl-2 may be the target of PIRNA-DQ765261.

目的 研究氧化应激在邻苯二甲酸单(2-乙基己基)酯(mono-2-ethylhexyl-phthalate,MEHP)诱导小鼠初级精母细胞(GC-2spd)毒性中的作用及机制.方法 将培养的GC-2spd细胞分为对照组(含0.1％二甲基亚砜的无血清培养基)、MEHP染毒组(1、10、100 μmol/L MEHP 3个不同剂量组)、N-乙酰半胱氨酸(N-acetylcysteine,NAC)预处理组(100 μmol/L NAC+100 μmol/L MEHP),MEHP 染毒24h,NAC预处理2h,NAC的预处理浓度(100 μmol/L)通过CCK-8实验确定.采用DCFH-DA探针法检测细胞内活性氧(reactive oxide species,ROS)水平,JC-1法检测线粒体膜电位,Western blot法检测细胞内线粒体凋亡通路相关蛋白和p-STAT3Tyr705、P53蛋白表达水平.结果 随着MEHP染毒剂量升高,细胞内代表活性氧水平的绿色荧光信号增多;不同剂量MEHP染毒组的线粒体膜电位均下降,表现为红绿荧光细胞比例比值减小,10和100μmol/L MEHP染毒组的红绿荧光细胞比例比值分别为5.15±1.68和4.09±1.72,明显低于对照组(7.91±1.24)(P＜0.05);促凋亡蛋白Bax与抗凋亡蛋白Bcl-2表达水平比值(Bax/Bcl-2)在1、10、100 μmol/L MEHP染毒组分别为 1.23±0.17、2.64±0.43和4.75±0.73,与对照组(0.52±0.11)相比明显增加(P＜0.05);cytochrome C 蛋白表达水平在 100 μmol/L MEHP 染毒组升高为0.83±0.09,cleaved caspase-9蛋白表达水平在10和100 μmol/L MEHP染毒组升高为0.41±0.03和0.52±0.09,cleaved caspase-3蛋白表达水平在 10和 100 μmol/L MEHP 染毒组升高为0.60±0.12和0.84±0.17,与对照组相比差异均具有统计学意义(P＜0.05);STAT3/p53通路中,p-STAT3Tyr705蛋白表达水平在10和100 μmol/L MEHP染毒组分别下降为0.70±0.14和0.41±0.04,P53蛋白表达水平在10和100 μmol/L MEHP染毒组分别升高为1.32±0.05和1.66±0.22,与对照组相比差异均具有统计学意义(P＜0.05);NAC预处理后,与100 μmol/L MEHP组相比,NAC预处理组ROS生成减少,线粒体膜电位升高为5.92±1.64,Bax/Bcl-2下降为 1.92±0.06,cytochrome C、cleaved caspase-9和 cleaved caspase-3蛋白表达水平分别下降为0.57±0.07、0.35±0.04和0.53±0.06,p-STAT3Tyr705蛋白表达水平升高为0.86±0.07,P53蛋白表达水平下降为1.01±0.06,差异均有统计学意义(P＜0.05).结论 MEHP诱导GC-2spd细胞凋亡可能与ROS介导的STAT3/p53通路调控线粒体凋亡通路有关.

To investigate the potential associations between household renovation and allergic diseases among preschool children in Wuhan, we conducted a large cross-sectional questionnaire survey among 9455 preschool children aged 3-6 years in Wuhan during November to December 2019. Data on demographics, health status, and home decoration conditions were analysed based on a questionnaire. Compared with tiles/stone/cement floor covering, the use of composite floor significantly increased the risk of diagnosed rhinitis and eczema among children (rhinitis: AOR, 95% CI: 1.36, 1.06-1.73; eczema: AOR, 95% CI: 1.47, 1.17-1.85). Household renovation had significant associations with diagnosed eczema (within 1 year before pregnancy: AOR, 95% CI: 1.34, 1.20-1.50; during pregnancy: AOR, 95% CI: 1.25, 1.08-1.44). This study suggests that use of artificial synthetic materials in home renovation during early childhood and pregnancy may be potential risk factors for childhood asthma, allergic rhinitis, and eczema.

Cadmium (Cd) is a heavy metal that is widely present in modern industrial production. It is a known, highly toxic environmental endocrine disruptor. Long-term exposure to Cd can cause varying degrees of damage to the liver, kidney, and reproductive system of organisms, especially the male reproductive system. This study aimed to explore the mechanism of Cd toxicity in the male reproductive system during puberty. Eighteen healthy 6-week-old male Sprague-Dawley rats were randomly divided into three groups (control group, low-dose group, and high-dose group) according to their body weight, with six in each group. Cd (0, 1, and 3 mg/kg/day) was given by gavage for 28 consecutive days. The results showed that Cd exposure to each dose group caused a decrease in the testicular organ coefficient and sperm count, compared with the control group. Cd exposure resulted in significant changes in testicular morphology in the 3 mg/kg/day Cd group. In the 1 and 3 mg/kg/day Cd groups, serum testosterone decreased and apoptosis of testicular cells increased significantly (p < 0.05). In addition, compared with the control group, the activity of glutathione peroxidase and superoxide dismutase in each Cd exposure dose group decreased, but the content of malondialdehyde in the high-dose, 3 mg/kg/day Cd treatment group significantly increased (p < 0.05). Although Cd exposure caused an increase in the messenger RNA (mRNA) levels of Bcl-2, Caspase-3 and Caspase-9 in the testicular tissues (p < 0.05), Bcl-2 expression was unchanged (p > 0.05). The expression level of Akt mRNA in testicular tissue of rats in the high-dose 3 mg/kg/day Cd group was increased (p < 0.05). Our data suggest that Cd affected testosterone levels, and apoptosis was observed in spermatids.

Background: Emerging research suggested an association of early-life particulate air pollution exposure with development of asthma in childhood. However, the potentially differential effects of submicron particulate matter (PM; PM with aerodynamic diameter <= 1 mm [PM1]) remain largely unknown. Objective: This study primarily aimed to investigate associations of childhood asthma and wheezing with in utero and first-year exposures to size-specific particles. Methods: We conducted a large cross-sectional survey among 5788 preschool children aged 3 to 5 years in central China. In utero and first-year exposures to ambient PM1, PM with aerodynamic diameter less than or equal to 2.5 mu m, and PM with aerodynamic diameter less than or equal to 10 mu m at 1 x 1-km resolution were assessed using machine learning- based spatiotemporal models. A time-to-event analysis was performed to examine associations between residential PM exposures and childhood onset of asthma and wheezing. Results: Early-life size-specific PM exposures, particularly during pregnancy, were significantly associated with increased risk of asthma, whereas no evident PM-wheezing associations were observed. Each 10-mu g/m(3) increase in in utero and first-year PM1 exposure was accordingly associated with an asthma's hazard ratio in childhood of 1.618 (95% CI, 1.159-2.258; P = .005) and 1.543 (0.822-2.896; P = .177). Subgroup analyses suggest that short breast-feeding duration may aggravate PM associated risk of childhood asthma. Each 10-mu g/m(3) increase in in utero exposure to PM1, for instance, was associated with a hazard ratio of 2.260 (1.393-3.666) among children with 0 to 5 months' breast-feeding and 1.156 (0.721-1.853) among those longer breast-fed. Conclusions: Our study added comparative evidence for increased risk of childhood asthma in relation to early-life PM exposures, highlighting stronger associations with ambient PM1 than with PM with aerodynamic diameter less than or equal to 2.5 mu m and PM with aerodynamic diameter less than or equal to 10 mu m.

目的 探讨STAT3/p53在邻苯二甲酸二(2-乙基)己酯(di-2-ethylhexyl phthalate,DEHP)诱导大鼠睾丸损伤中的作用.方法 将24只6周龄SD雄性大鼠随机分为对照(玉米油)组及50、100、200 mg/mlDEHP染毒组,每组6只.每日早晨9点,采用灌胃方式进行染毒,每天1次,连续28 d.检测睾丸组织中丙二醛(MDA)含量、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活力和细胞凋亡水平及Bax、Bcl-2、细胞色素C(Cyt C)、caspase-9、caspase-3的mRNA表达水平以及p53、p-STAT3蛋白的表达水平.结果 与对照组相比,各剂量DEHP染毒组大鼠睾丸组织GSH-Px活力及500、1 000 mg/kg DEHP染毒组大鼠SOD活力均降低,差异均有统计学意义(P＜0.05);而各剂量DEHP染毒组大鼠睾丸组织MDA的含量均无明显改变;且随着DEHP暴露剂量的升高,大鼠睾丸组织MDA含量呈上升趋势,而SOD、GSH-Px活力均呈下降趋势.与对照组相比,500、1 000 mg/kg DEHP染毒组大鼠睾丸细胞的凋亡指数较高,差异有统计学意义(P＜0.05);且随着DEHP暴露剂量的升高,大鼠睾丸的细胞凋亡指数呈上升趋势.与对照组相比,500、1 000 mg/kg DEHP染毒组大鼠睾丸组织Bax、Cyt C、caspase-9、caspase-3 mRNA的表达水平及250 mg/kg DEHP染毒组大鼠睾丸组织Bcl-2 mRNA的表达水平均较高,而1 000 mg/kg DEHP染毒组大鼠睾丸组织Bcl-2 mRNA的表达水平较低,差异均有统计学意义(P＜0.05);且随着DEHP暴露剂量的升高,大鼠睾丸组织Bax、Cyt C、caspase-9、caspase-3 mRNA的表达水平均呈上升趋势,而Bcl-2 mRNA的表达水平呈下降趋势.与对照组相比,500、1 000 mg/kg DEHP染毒组大鼠睾丸组织p53蛋白的表达水平均较高,而各剂量DEHP染毒组大鼠睾丸组织p-STAT3蛋白的表达水平均较低,差异均有统计学意义(P＜0.05);且随着DEHP暴露剂量的升高,大鼠睾丸组织p53蛋白的表达水平呈上升趋势,而p-STAT3蛋白的表达水平呈下降趋势.结论 DEHP可诱导大鼠睾丸组织发生氧化应激,影响STAT3-p53调控的线粒体途径,诱导大鼠睾丸细胞凋亡,引起睾丸损伤.

目的 探索邻苯二甲酸二(2-乙基己基)酯(di-2-ethylhexyl phthalate,DEHP)和镉联合暴露对青春期雄性大鼠的生殖毒性.方法 采用3×3析因设计,将54只健康6周龄清洁级雄性SD大鼠按体重随机分为9组,分别为对照(0 mg/kg DEHP+0 mg/kg氯化镉)组和250、1000mg/kgDEHP染毒组及1、3 mg/kg氯化镉染毒组以及DEHP(250、1000 mg/kg)+氯化镉(1、3 mg/kg)染毒组,每组6只.采用灌胃方式进行染毒,染毒容量均各为5 ml/kg,连续染毒28 d.收集附睾尾部精子,采用CASA精子分析系统记录精子活力及密度;采用TUNEL法检测睾丸细胞的凋亡情况.结果 与对照组相比,仅1000 mg/kg DEHP+3 mg/kg氯化镉染毒组大鼠的精子活力降低,250 mg/kg DEHP+3 mg/kg氯化镉联合染毒组以及1000mg/kg DEHP+1、3 mg/kg氯化镉联合染毒组大鼠的精子密度和活动精子密度也降低,差异均有统计学意义(P＜0.05).与对照组相比,各染毒组的睾丸细胞凋亡指数均增高,除250 mg/kg DEHP染毒组外,差异均有统计学意义(P＜0.05);联合染毒组的睾丸细胞凋亡指数均低于相同浓度的DEHP染毒组,差异有统计学意义(P＜0.05);250、1000 mg/kg DEHP+3 mg/kg氯化镉染毒组的睾丸细胞凋亡指数均低于3 mg/kg氯化镉染毒组,差异有统计学意义(P＜0.05).250、1000 mg/kg DEHP+3 mg/kg氯化镉染毒对大鼠睾丸细胞凋亡率的影响有交互作用(P＜0.05),表现为为拮抗作用.结论 DEHP和镉联合染毒可以造成青春期雄性大鼠睾丸损伤,其具体作用机制有待进一步研究.

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism that is indispensable for the formation and maintenance of cilia and flagella; however, the implications and functions of IFT81 remain unknown. In this study, we disrupted IFT81 expression in male germ cells starting from the spermatocyte stage. As a result, homozygous mutant males were completely infertile and displayed abnormal sperm parameters. In addition to oligozoospermia, spermatozoa presented dysmorphic and nonfunctional flagella. Histological examination of testes from homozygous mutant mice revealed abnormal spermiogenesis associated with sloughing of germ cells and the presence of numerous multinucleated giant germ cells (symblasts) in the lumen of seminiferous tubules and epididymis. Moreover, only few elongated spermatids and spermatozoa were seen in analyzed cross sections. Transmission electron microscopy showed a complete disorganization of the axoneme and para-axonemal structures such as the mitochondrial sheath, fibrous sheath, and outer dense fibers. In addition, numerous vesicles that contain unassembled microtubules were observed within developing spermatids. Acrosome structure analysis showed normal appearance, thus excluding a crucial role of IFT81 in acrosome biogenesis. These observations showed that IFT81 is an important member of the IFT process during spermatogenesis and that its absence is associated with abnormal flagellum formation leading to male infertility. The expression levels of several IFT components in testes, including IFT20, IFT25, IFT27, IFT57, IFT74, and IFT88, but not IFT140, were significantly reduced in homozygous mutant mice. Overall, our study demonstrates that IFT81 plays an essential role during spermatogenesis by modulating the assembly and elongation of the sperm flagella.

Di (2-ethylhexyl) phthalate (DEHP) is a known environmental endocrine disruptor that impairs development of testis and spermatogenesis. This study aims to explore the effects of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat. 24 6-week-old male Sprague-Dawley rats were randomly divided into 4 groups (Control, low-dose, middle-dose and high-dose group) and were treated with increasing concentration of DEHP (0, 250, 500, 1000 mg/kg/day) respectively for 28 consecutive days by intragastric administration. Our results showed that DEHP exposure induced obvious morphological changes of testis, decreased organ coefficient of testis and sperm count, and increased testicular cell apoptosis in the 500 and 1000 mg/kg/day DEHP groups (p < .05). The serum testosterone decreased in a dose-dependent manner after treatment with DEHP. Furthermore, the exposure of DEHP elevated the levels of oxidative stress accompanied by upregulated expression of p53 and reduced expression of STAT3. In addition, compared with the control group, the expression of PI3K, p-Akt and p-mTOR proteins significantly decreased, whereas the downstream autophagy-related proteins phosphorylated ULK1, Beclin-1, Atg7, LC3-II obviously increased in the 250 mg/kg/day DEHP group (p < .05). The expression of p62 was reduced in DEHP-treated groups. Our data indicated that autophagy could be activated to protect testes from DEHP-induced reproductive damage by inhibiting PI3K-Akt-mTOR signaling pathway in the 250 mg/kg/day DEHP group. STAT3/p53-mediated mitochondrial apoptosis pathway might play a major role to cause testis injury and reproductive dysfunction in the 500 and 1000 mg/kg/day DEHP groups.

目的 研究双酚A(bisphenol A,BPA)与壬基酚(nonylphenol,NP)联合作用对子代大鼠睾丸组织氧化应激的影响.方法 采用2×2析因设计,将48只清洁级21日龄SD大鼠随机分为4组,分别为对照组、NP(5 mg/kg)染毒组、BPA(0.5 mg/kg)染毒组和NP(5 mg/kg)+BPA(0.5 mg/kg)染毒组,每组12只(雄雌比为1:3).采用经口灌胃方式染毒至大鼠55日龄,妊娠期和哺乳期(出生21 d)仅对母鼠染毒,隔天一次.每组随机选取6只雄性仔鼠,饲养至60日龄,测定睾丸组织中丙二醛(MDA)含量和总超氧化物歧化酶(T-SOD)、谷胱甘肽过氧化物酶(GSH-Px)活力.结果 与对照组相比,BPA染毒组仔鼠睾丸组织GSH-Px、T-SOD的活力均较低;NP+BPA染毒组T-SOD活力降低,而MDA含量升高,差异均有统计学意义(P<0.05);而NP染毒组仔鼠睾丸组织GSH-Px、T-SOD的活力及MDA含量均无明显改变.与NP+BPA染毒组比较,NP染毒组睾丸组织T-SOD活力较高,而MDA含量降低;BPA染毒组睾丸组织GSH-Px活力较高,而MDA含量降低,差异均有统计学意义(P<0.05).析因分析结果显示,NP和BPA联合染毒对子鼠睾丸组织GSH-Px活力和MDA含量的影响存在交互作用(P<0.05),分别表现为拮抗效应和协同效应;而对T-SOD活力的影响不存在交互作用(P>0.05).结论 NP和BPA联合染毒可造成雄性子代大鼠睾丸组织氧化损伤,其具体作用机制有待进一步研究.

Fluoride is an essential trace element for human beings and animals; however, high level of fluoride in drinking water is harmful to the living system. Chronic fluoride intoxication causes damages to osseous tissue (teeth and bone) and soft tissues (liver, kidney, brain, etc.). Liver and kidney are the target organs markedly attacked by excessive amount of fluoride. High doses of fluoride intake lead to changes of structure, function, and metabolism in liver and kidney.

BPA and NP are both typical endocrine disruptors, the exposed populations are widespread, and the health risks mustn't be ignored. However, the interactions between them on spermatogenesis are rarely mentioned. And the underlying mechanism is unclear yet. In the present study, prepubertal SD rats were exposed to different low doses of BPA and NP separately or jointly for 4 weeks. The results indicate that the joint exposure induced excessive apoptosis and autophagy in the testes, as proved by a series of characteristics such as chromatin condensation and autophagosomes formation. Besides, endocrine disorders and oxidative stress were also caused by the exposure. Apoptosis was mediated by the mitochondrial apoptosis pathway, since the Bax and Caspase-3 gene expressions significantly increased with a prominent decrease of Bcl-2. While autophagy was caused by the inhibition of the Akt/mTOR pathway, as the expressions of the downstream genes Beclin-1, Atg5, Atg12 and the split of LC3 protein increased altogether. Worse yet, autophagy and apoptosis might reinforce each other and make the situation more severe in the joint group. What's more, remarkable histopathological changes such as spermatogenic epithelium atrophy, germ cell loss, and various ultrastructural modifications were strongly related to the apoptosis and autophagy. In aggregate, this study shows the enormous risk on male reproductive system brought by the interactions between BPA and NP. The findings provide a broader vision to understand the roles of apoptosis and autophagy induced by the joint exposure in the aggravation of spermatogenesis impairment, which could be a reference for the situation of complex EDCs exposure-induced male reproductive toxicity, and possibly inspire us to find new ideas for preventive and therapeutic treatments.

Objective: To explore the effects of BPA on the expression of N-cadherin, Vimentin and FSHR in rat Sertoli cells. Methods: Primary Sertoli cells collected from prepuberty rats (18-21 d) were cultured for 48 h, and then they were treated with 0, 30, 50, 70 μmol/L BPA respectively for 24 h. The methods of MTT, real-time quantitative PCR and Western blotting were utilized to measure the cell ability of Sertoli cells, the mRNA and protein expression levels of N-cadherin, Vimentin and FSHR respectively. Results: Compared with control, the cell abilities of Sertoli cells in 50 μmol/L BPA group and 70 μmol/L BPA group increased significantly (P<0.05) . The cell abilities of Sertoli cells decreased with the increases of exposure doses of BPA. Compared with control, the expression of N-cadherin mRNA only increased in 30 μmol/L BPA group (P<0.05) , the expression of Vimentin mRNA decreased significantly in all doses group of BPA (P<0.05) , the expression of FSHR mRNA increased in all doses group of BPA (P<0.05) . Compared with the control, the protein levels of N-cadherin increased significantly in 50 μmol/L BPA group (P<0.05) , the protein levels of Vimentin decreased significantly in all doses group of BPA (P<0.05) , the protein levels of FSHR decreased significantly in 50 μmol/L BPA group and 70 μmol/L BPA group (P<0.05) . Conclusion: The mechanism of testicular toxicity from BPA might be the alterations of N-cadherin, Vimentin and FSHR by disturbing normal spermatogenesis.