Association between short-term exposure to particulate matter air pollution and cause-specific mortality in Changzhou, China.

BACKGROUND: Extensive studies have linked ambient particulate matter (PM) to an increased mortality burden from a wide range of causes. However, the effects of PM on mortality rates from specific causes were unclear. This study aimed to estimate the detrimental effects of PM on cause specific deaths in Changzhou, China. METHOD: Data representing daily mortality rates, weather conditions and particulate air pollution levels were obtained from government-controlled agencies of Changzhou, from January 1, 2015 to December 31, 2016. An inverse distance weighting method was used to assess the population exposure to PM and a time-series was performed to detect the detrimental effects of PM. RESULTS: Positive associations were identified between PMs and daily mortality rates from non-accidental, circulatory, hypertensive, respiratory and chronic lower respiratory causes at a lag of 0-3 days. The effects of PMs were strongest on hypertensive mortality, with an increase of 5.27% (95% confidence interval (CI): 2.43-8.19%) and 3.52% (95% CI: 1.55-5.53%), per 10 µg/m3 increment in PM2.5 and PM10 respectively. The elderly exhibited a higher mortality risk with PMs exposure. Females were more vulnerable to circulatory, hypertensive and respiratory death while males were more sensitive to chronic lower respiratory and neurodegenerative mortality. The effects were stronger in warm seasons for circulatory mortality and stronger in cold seasons for respiratory mortality. CONCLUSION: These findings indicate that PM could exert adverse influences on the outcomes of several pathological processes, especially for women and the elderly with hypertension disease.

High-fat diet aggravates 2,2',4,4'-tetrabromodiphenyl ether-inhibited testosterone production via DAX-1 in Leydig cells in rats.

Growing evidence has revealed that a high-fat diet (HFD) could lead to disorders of glycolipid metabolism and insulin-resistant states, and HFDs have been associated with the inhibition of testicular steroidogenesis. Our previous study demonstrated that 2,2',4,4'-tetrabromodiphenyl ether (BDE47) could increase the risk of diabetes in humans and reduce testosterone production in rats. However, whether the HFD affects BDE47-inhibited testosterone production by elevating insulin levels and inducing related pathways remains unknown. In male rats treated with BDE47 by gavage for 12 weeks, the HFD significantly increased the BDE47 content of the liver and testis and increased the weight of the adipose tissue; increased macrovesicular steatosis in the liver and the levels of triglycerides, fasting glucose and insulin; further aggravated the disruption of the seminiferous epithelium; and lowered the level of testosterone, resulting in fewer sperm in the epididymis. Of note, the HFD enhanced BDE47-induced DAX-1 expression and decreased the expression levels of StAR and 3ß-HSD in the testicular interstitial compartments in rats. In isolated primary Leydig cells from rats, BDE47 or insulin increased DAX-1 expression, decreased the expression of StAR and 3ß-HSD, and reduced testosterone production, which was nearly reversed by knocking down DAX-1. These results indicated that the HFD aggravates BDE47-inhibited testosterone production through hyperinsulinemia, and the accumulation of testicular BDE47 that induces the up-regulation of DAX-1 and the subsequent down-regulation of steroidogenic proteins, i.e., StAR and 3ß-HSD, in Leydig cells.

BCL2 Ala43Thr is a functional variant associated with protection against azoospermia in a Han-Chinese population.

Apoptosis is very common during various stages of mammalian germ cell development and differentiation, and the BCL2 gene is one of the most important apoptotic regulators. Although its genetic variants are reported to be involved in cancers and autoimmune diseases, little information is available regarding BCL2 polymorphisms in male spermatogenesis. In the present study, single nucleotide polymorphisms (SNPs) in coding regions of the BCL2 gene were examined in a hospital-based, case-control study including 198 infertile patients with idiopathic azoospermia and 183 fertile controls. Subsequently, a functional study was conducted for comparison of paclitaxel-induced cytotoxicity and apoptosis between the BCL2 variant and the wild type in vitro. Three SNPs were found in exon 2--A21G (rs1801018), G127A (rs1800477), and C300T (rs61733416)--with the latter first reported in the Han-Chinese population. The frequency of G127A (GA+AA) genotype was significantly lower in azoospermic, infertile men compared to the age-matched controls (P = 0.01). This genotype may confer a lower risk of azoospermia (adjusted odd ratio [OR] = 0.448, 95% confidence interval = 0.226-0.889). In addition, HeLa cells expressing the BCL2 Ala43Thr (G127A), similar to the control cells, were more sensitive to paclitaxel-induced cytotoxicity and apoptosis than those expressing wild-type BCL2. Consistently, the cleaved PARP and p-BCL2 proteins were subsequently increased after paclitaxel treatment, as also predicted by the bioinformatics analysis. Considering the decreased antiapoptotic function of BCL2, these results suggest that the Ala43Thr variant is associated with protection against azoospermia in the Han-Chinese population.

Polysaccharide SAFP from Sarcodon aspratus attenuates oxidative stress-induced cell damage and bleomycin-induced pulmonary fibrosis.

Sarcodon aspratus, a popular edible fungus for its tasty flavour and can be used as a dietary supplement for its functional substances. Our study is conducted to evaluate the protective effect of Sarcodon aspratus polysaccharides (SAFP) on oxidative stress damage and pulmonary fibrosis (PF), and further explore the signaling pathways in vitro and in vivo. Results indicated that SAFP could enhance the A549 cells viability, prevent cell apoptosis and inhibit H2O2 induced oxidative damage via attenuation of MDA and ROS levels. SAFP could also activate Nrf2 by inducing the translocation of Nrf2 from cytoplasm to nucleus as well as the level of HO-1. Pretreatment with SAFP could reduce bleomycin-induced pathological changes and collagen deposition in mice. Furthermore, SAFP could significantly upregulate antioxidase activities and downregulate fibrosis-associated indices including marker proteins, proinflammatory cytokines and profibrogenic cytokines. These findings indicated that SAFP could effectively attenuate H2O2-induced cellular oxidative stress through Nrf2/MAPK signaling pathway and delay progression of PF by reducing oxidative damage and inflammation through NF-κB/TGF-ß1/MAPK pathway. Therefore, SAFP could be explored as a natural potential candidate drug for pulmonary fibrosis and other fibrosis-related diseases.

Cordyceps cicadae polysaccharides ameliorated renal interstitial fibrosis in diabetic nephropathy rats by repressing inflammation and modulating gut microbiota dysbiosis.

Diabetic nephropathy (DN), a complication of diabetes mellitus, has been the leading cause of death in people with chronic kidney disease. This study was conducted to examine the potential health benefits of Cordyceps cicadae polysaccharides (CCP) on kidney injury and renal interstitial fibrosis that occur in DN rats. First, a DN model was established using SD rats fed with a high-fat diet for 8 weeks, then injected with STZ (35 mg/kg) intraperitoneally. The rats were then supplemented with CCP (75, 150 and 300 mg/kg) for 4 weeks. The results indicated that CCP improve insulin resistance and glucose tolerance in DN rats. Furthermore, CCP intervention significantly suppressed the inflammation, renal pathological changes and renal dysfunction, slowing down the progression of renal interstitial fibrosis. Moreover, high-throughput pyrosequencing of 16S rRNA suggested that CCP modulated the dysbiosis of gut microbiota by enhancing the relative abundance and proliferation capacity of probiotics. In vitro, CCP can markedly decrease LPS-induced inflammatory cytokine levels and TGF-ß1-induced fibroblast activation. In summary, the results provided evidence that CCP exerted a beneficial effect on tubulointerstitial fibrosis in DN rats by possibly suppressing the inflammatory response and modulating gut microbiota dysbiosis, via blocking the TLR4/NF-κB and TGF-ß1/Smad signaling pathway.

Short-term effects of ambient air pollutants and myocardial infarction in Changzhou, China.

Ambient air pollution had been shown strongly associated with cardiovascular diseases. However, the association between air pollution and myocardial infarction (MI) is inconsistent. In the present study, we conducted a time-series study to investigate the association between air pollution and MI. Daily air pollutants, weather data, and MI data were collected from January 2015 to December 2016 in Changzhou, China. Generalized linear model (GLM) was used to assess the immediate effects of air pollutants (PM2.5, PM10, NO2, SO2, and O3) on MI. We identified a total of 5545 cases for MI, and a 10-µg/m3 increment in concentrations of PM2.5 and PM10 was associated with respective increases of 1.636% (95% confidence interval [CI] 0.537-2.740%) and 0.805% (95% CI 0.037-1.574%) for daily MI with 2-day cumulative effects. The associations were more robust among males and in the warm season versus the cold one. No significant effect was found in SO2, NO2, or O3. This study suggested that short-term exposure to PM2.5 and PM10 was associated with the increased MI risks. Our results might be useful for the primary prevention of MI exacerbated by air pollutants.

Acute effects of air pollution on ischaemic stroke onset and deaths: a time-series study in Changzhou, China.

OBJECTIVE: To investigate the acute effect of air pollutants on ischaemic stroke (IS) and IS-related death. SETTING: Five urban districts in Changzhou, China, between 9 January 2015 and 31 December 2016. PARTICIPANTS: A total of 32 840 IS cases and 4028 IS deaths were enrolled. MAIN OUTCOME MEASURES: A time-series design, generalised additive model and multivariable regression model were used to examine the percentage change (95% CI) in daily IS counts and deaths with an IQR increase in air pollutant levels for different single or multiple lag days in single-pollutant and two-pollutant models. RESULTS: Daily IS counts increased 0.208% (95% CI 0.036% to 0.381%) with an IQR increment in the levels of nitrogen dioxide (NO2). The estimated risk of NO2 was more robust in males and in the cold season. For daily IS counts, the estimated effects of NO2 and sulfur dioxide (SO2) were more significant when adjusted for particulate matter with aerodynamic diameters <2.5 µm (PM2.5) and PM10. An IQR increment in the concentration of PM10, SO2 and NO2 significantly increased IS deaths with 6 days of cumulative effects (0.268%, 95% CI 0.007% to 1.528%; 0.34%, 0.088% to 0.592%; and 0.263%, 0.004% to 0.522%, respectively). Young individuals (<65 years old) had a higher IS mortality risk for PM2.5, PM10, NO2 and CO. For IS death, the effect estimates of SO2 in the elderly, females and the cold season were more pronounced; statistical significance was also identified for SO2 when adjusted for carbon monoxide (CO). CONCLUSIONS: This study suggested that short-term exposure to ambient NO2 was associated with increased IS risk. In addition, SO2 was associated with increased IS onset and death.

Protective Effects of Ambient Ozone on Incidence and Outcomes of Ischemic Stroke in Changzhou, China: A Time-Series Study.

The potential beneficial effect of ozone (O3) on stroke had been identified experimentally and clinically, but these effects remain controversial in population-based studies. This study aimed to explore the epidemiological association between O3 and risk of ischemic stroke. Ischemic stroke related health data and air pollution data were obtained from the Center for Disease Control and Prevention and Environmental Monitoring Center in Changzhou between 2015 and 2016, respectively. The associations between the short-term exposure to O3 and daily ischemic stroke onsets and deaths were examined based on time-series generalized additive Poisson model. During the study period, daily ischemic stroke onsets and deaths decreased 0.340% (95% confidence interval (CI) -0.559% to -0.120%) and 0.697% (95% CI -1.103% to -0.290%) with an interquartile range (IQR) (41.1 µg/m³) increase in levels of ambient O3, respectively. The protective effects of O3 were more significant in men and elders and in the cool season than those in women and young people and in the warm season, respectively. The negative association was independent of PM2.5, PM10, SO2, NO2 or CO exposure. Acute O3 exposure was associated with decreased risk of ischemic stroke. These findings will help provide new insights into the relationship between ischemic stroke and ambient O3 concentrations.

Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.

BACKGROUND: 2,2',4,4'-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. It has been reported to be metabolized by cytochrome P450 (CYP) enzymes. Still, the effects of BDE47 on spermatogenesis failure are attracting an increasing amount of attention. However, it is unclear whether CYP-mediated metabolism contributes to BDE47-induced reproductive toxicity. METHODOLOGY AND PRINCIPAL FINDINGS: The role of cytochrome P450 3A1 (CYP3A1) in the formation of oxidative metabolites of BDE47 and its induced spermatogenesis failure was investigated in SD rats. BDE47 significantly increased the expression and activity of CYP3A1 in rat liver, and 3-OH-BDE47, the major oxidative metabolite of BDE47, dose-dependently increased in rat liver, serum, and testis, which was aggravated by dexamethasone (DEX), an inducer of CYP3A1. Additionally, testicular 3-OH-BDE47 and reactive oxygen species (ROS) in seminiferous tubules increased especially when BDE47 was administered in combination with DEX, which was confirmed in GC-1 and GC-2 cells that 3-OH-BDE47 induced more ROS production and cell apoptosis via the upregulation of FAS/FASL, p-p53 and caspase 3. As a result, daily sperm production dose-dependently decreased, consistent with histological observations in giant cells and vacuolar spaces and increase in TUNEL-positive apoptotic germ cells. CONCLUSION: CYP3A1-mediated metabolic activation of BDE47 and the active metabolite 3-OH-BDE47 and consequent ROS played an important role in reduction of spermatogenesis by germ cell apoptosis. Our study helps provide new insights into the mechanism of reproductive toxicity of environmental chemicals.

Effects of di-n-butyl phthalate on male rat reproduction following pubertal exposure.

Di-n-butyl phthalate (DBP) is an endocrine-disrupting chemical that has the potential to affect male reproduction. However, the reproductive effects of low-dose DBP are still not well known, especially at the molecular level. In the present study, pubertal male Sprague-Dawley rats were orally administered DBP at a wide range of doses (0.1, 1.0, 10, 100 and 500 mg kg⁻¹ day⁻¹) for 30 days. The selected end points included reproductive organ weights, testicular histopathology and serum hormonal levels. Additionally, proteomic analysis was performed to identify proteins that are differentially expressed as a result of exposure to DBP at low doses (0.1, 1.0 and 10 mg kg⁻¹ day⁻¹). Toxic effects were observed in the high-dose groups, including anomalous development of testes and epididymides, severe atrophy of seminiferous tubules, loss of spermatogenesis and abnormal levels of serum hormones. Treatment with low doses of DBP seemed to exert a 'stimulative effect' on the serum hormones. Proteomics analysis of rat testes showed 20 differentially expressed proteins. Among these proteins, alterations in the expression of HnRNPA2/B1, vimentin and superoxide dismutase 1 (SOD1) were further confirmed by Western blot and immunohistochemistry. Taken together, we conclude that high doses of DBP led to testicular toxicity, and low doses of DBP led to changes in the expression of proteins involved in spermatogenesis as well as changes in the number and function of Sertoli and Leydig cells, although no obvious morphological changes appeared. The identification of these differentially expressed proteins provides important information about the mechanisms underlying the effects of DBP on male rat reproduction.

Identification of the metabolites of polybrominated diphenyl ether 99 and its related cytochrome P450s.

OBJECTIVE: To investigate the metabolites of polybrominated diphenyl ether 99 (BDE-99) and its related cytochrome P450s in an in vitro system. METHODS: Rat primary hepatocytes were isolated and treated with BDE-99 for 24-72 h. Metabolites were then extracted from the hepatocytes and media, and detected by GC/MS. Several mRNAs of metabolic enzymes were also extracted from the same cells and the gene expression levels were determined using quantitative real-time PCR. In addition, selected recombinant cytochrome P450s (CYPs) were expressed in a bacurovirus/sf9 system, and these were further used to explore the metabolism of BDE-99 in vitro. The parent depletion approach was used for screening the ability of CYPs to eliminate BDE-99. RESULTS: A reductively debrominated metabolite, BDE-47, and three oxidative metabolites, 2, 4, 5-tribromophenol, 5-OH-BDE-47, and 5'-OH-BDE-99, were identified from the BDE-99-treated rat hepatocytes, whereas no MeO metabolite was detected in the system. RT-PCR analysis showed that CYP 3A23/3A1, 1A2, and 2B1/2 were induced by BDE-99. Furthermore, using the heterological expressed CYP proteins in in vitro BDE-99 metabolism experiments we found that CYP1A2 and CYP3A4 showed the highest metabolic efficiency for BDE-99, with the metabolic clearance rates of CYP1A2 and CYP3A4 being 30.3% and 27.7%, respectively. CYP1A1 and CYP2A6 displayed relatively low clearance rates, while CYP2E1 seemed not to be associated with the BDE-99 metabolism. CONCLUSIONS: In our in vitro rat primary hepatocyte metabolism system, four metabolites of BDE-99 were identified, and CYP3A4 and CYP1A2 were demonstrated to be involved in the BDE-99 metabolism.