TFEB/LAMP2 contributes to PM0.2-induced autophagy-lysosome dysfunction and alpha-synuclein dysregulation in astrocytes.

Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM0.2) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM0.2-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM0.2. Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM0.2 toxicity.

ASC/Caspase-1-activated endothelial cells pyroptosis is involved in vascular injury induced by arsenic combined with high-fat diet.

Environmental arsenic (As) or high-fat diet (HFD) exposure alone are risk factors for the development of cardiovascular disease (CVDs). However, the effects and mechanisms of co-exposure to As and HFD on the cardiovascular system remain unclear. The current study aimed to investigate the combined effects of As and HFD on vascular injury and shed some light on the underlying mechanisms. The results showed that co-exposure to As and HFD resulted in a significant increase in serum lipid levels and significant lipid accumulation in the aorta of rats compared with exposure to As or HFD alone. Meanwhile, the combined exposure altered blood pressure and disrupted the morphological structure of the abdominal aorta in rats. Furthermore, As combined with HFD exposure upregulated the expression of vascular endothelial cells pyroptosis-related proteins (ASC, Pro-caspase-1, Caspase-1, IL-18, IL-1ß), as well as the expression of vascular endothelial adhesion factors (VCAM-1 and ICAM-1). More importantly, we found that with increasing exposure time, vascular injury-related indicators were significantly higher in the combined exposure group compared with exposure to As or HFD alone, and the vascular injury was more severe in female rats compared with male rats. Taken together, these results suggested that the combination of As and HFD induced vascular endothelial cells pyroptosis through activation of the ASC/Caspase-1 pathway. Therefore, vascular endothelial cells pyroptosis may be a potential molecular mechanism for vascular injury induced by As combined with HFD exposure.

Mitigation of maternal fecal microbiota transplantation on neurobehavioral deficits of offspring rats prenatally exposed to arsenic: Role of microbiota-gut-brain axis.

It is established that gut microbiota dysbiosis is implicated in arsenic (As)-induced neurotoxic process, however, the underlying mode of action remains largely unclear. Here, through remodeling gut microbiota on As-intoxicated pregnancy rats using fecal microbiota transplantation (FMT) from Control rats, neuronal loss and neurobehavioral deficits in offspring prenatally exposed to As were significantly alleviated after maternal FMT treatment. In prenatal As-challenged offspring after maternal FMT treatment, remarkably, suppressed expression of inflammatory cytokines in tissues (colon, serum, and striatum) were observed along with reversed mRNA and protein expression of tight junction related molecules in intestinal barrier and blood-brain barrier (BBB); Further, expression of serum lipopolysaccharide (LPS), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and nuclear transcription factor-κB (NF-κB) in colonic and striatal tissues were repressed with activation of astrocytes and microglia inhibited. In particular, tightly correlated and enriched microbiomes were identified such as higher-expressed g_Prevotella, g_UCG_005, and lower-expressed p_Desulfobacterota, g_Eubacterium_xylanophilum_group. Collectively, our results first demonstrated that reconstruction of normal gut microbiota by maternal FMT treatment alleviated prenatal As-induced overall inflammatory state and impairments of intestinal barrier and BBB integrity by impeding LPS-mediated TLR4/Myd88/NF-κB signaling pathway through microbiota-gut-brain axis, which provides a novel therapeutic avenue for developmental arsenic neurotoxicity.

Co-exposure to arsenic and fluoride to explore the interactive effect on oxidative stress and autophagy in myocardial tissue and cell.

Co-contamination of arsenic and fluoride is widely distributed in groundwater. However, little is known about the interactively influence of arsenic and fluoride, especially the combined mechanism in cardiotoxicity. Cellular and animal models exposure to arsenic and fluoride were established to assess the oxidative stress and autophagy mechanism of cardiotoxic damage using the factorial design, a widely used statistical method for assessing two factor interventions. In vivo, combined exposure to high arsenic (50 mg/L) and high fluoride (100 mg/L) induced myocardial injury. The damage is accompanied by accumulation of myocardial enzyme, mitochondrial disorder, and excessive oxidative stress. Further experiment identified that arsenic and fluoride induced the accumulation of autophagosome and increased expression level of autophagy related genes during the cardiotoxicity process. These findings were further demonstrated through the in vitro model of arsenic and fluoride-treated the H9c2 cells. Additionally, combined of arsenic-fluoride exposure possesses the interactively influence on oxidative stress and autophagy, contributing to the myocardial cell toxicity. In conclusion, our data suggest that oxidative stress and autophagy are involved in the process of cardiotoxic injury, and that these indicators showed interaction effect in response to the combined exposure of arsenic and fluoride.

Organic extracts in PM2.5 are the major triggers to induce ferroptosis in SH-SY5Y cells.

As a major air pollutant, PM2.5 can induce apoptosis of nerve cells, causing impairment of the learning and memory capabilities of humans and animals. Ferroptosis is a newly discovered way of programmed cell death. It is unclear whether the neurotoxicity induced by PM2.5 is related to the ferroptosis of nerve cells. In this study, we observed the changes in ferroptosis hallmarks of SH-SY5Y cells after exposure to various doses (40, 80, and 160 µg/mL PM2.5) for 24 h, exposure to 40 µg/mL PM2.5 for various times (24, 48, and 72 h), as well as exposure to various components (Po, organic extracts; Pw, water-soluble extracts; Pc, carbon core component). The results showed that PM2.5 reduced the cell viability, the content of GSH, and the activity of GSH-PX and SOD in SH-SY5Y cells with exposure dose and duration increasing. On the other hand, PM2.5 increased the content of iron, MDA, and the level of lipid ROS in SH-SY5Y cells with exposure dose and duration increasing. Additionally, PM2.5 reduced the expression levels of HO-1, NRF2, SLC7A11, and GPX4. The ferroptosis inhibitors Fer-1 and DFO significantly increase the cells viabilities and significantly reversed the changes of other above ferroptosis hallmarks. We also observed the different effects on ferroptosis hallmarks in the SH-SY5Y cells exposed to PM2.5 (160 µg/mL) and its various components (organic extracts, water-soluble extracts, and carbon core) for 24 h. We found that only the organic extracts shared similar results with PM2.5 (160 µg/mL). This study demonstrated that PM2.5 induced ferroptosis of SH-SY5Y cells, and organic extracts might be the primary component that caused ferroptosis.

Nano-Calcium Carbonate Affect the Respiratory and Function Through Inducing Oxidative Stress: A Cross-sectional Study Among Occupational Exposure of Workers and a Further Research for Underlying Mechanisms.

OBJECTIVE: The aim of the study is to investigate whether nano-calcium carbonate (nano-CaCO 3 ) occupational exposure could induce adverse health effects in workers. METHODS: A cross-sectional study was conducted in a nano-CaCO 3 manufacturing plant in China. Then, we have studied the dynamic distribution of nano-CaCO 3 in nude mice and examined the oxidative damage biomarkers of subchronic administrated nano-CaCO 3 on Sprague-Dawley rats. RESULTS: The forced vital capacity (%) and the ratio of FEV1 to FVC is the rate of one second of workers were significantly decreased than unexposed individuals. Dynamic imaging in mice of fluorescence labeled nano-CaCO 3 showed relatively high uptake and slow washout in lung. Similar to population data, the decline in serum glutathione level and elevation in serum MDA were observed in nano-CaCO 3 -infected Sprague-Dawley rats. CONCLUSIONS: We found that nano-CaCO 3 exposure may result in the poor pulmonary function in workers and lead to the changes of oxidative stress indexes.

Meta-analysis of TLR4 pathway-related protein alterations induced by arsenic exposure.

Arsenic is a toxic metal, which ultimately leads to cell apoptosis. TLR4 signaling pathway played a key role in immunomodulatory. Therefore, alterations in related proteins on the TLR4 signaling pathway induced by arsenic exposure was systematically reviewed and analyzed by meta-analysis. Some databases were searched including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and WANFANG MED ONLINE. The results of NF-κB, IKK, NF-κBp65, phospho-NF-κBp65, and TLR4 expressions were analyzed by Review Manage 5.3. In the arsenic intervention group, NF-κB, phospho-NF-κBp65, and TLR4 expression levels were higher than the control group, respectively. SMD and 95%CI were 11.29 (6.34, 16.24), 4.71(1.73, 7.68), and 5.79 (-4.22, 15.80). Compared to controls, in the exposed group, IKK levels were found to be 38.11-fold higher (Z = 0.97; P = 0.33); NF-κBp65 levels were found to be 0.92-fold higher (Z = 3.33; P = 0.0009) for normal cells and tissue, while IKK levels were found to be 5.18-fold lower (Z = 5.34; P < 0.0001); NF-κBp65 levels were found to be 2.01-fold lower (Z = 3.87; P = 0.0001) for abnormal cells. With comparing of low dose, high dose of arsenic exposure was found to reduce the expression of NF-κB, but increase the expression of NF-κBp65. This review supports the alterations in related proteins on the TLR4 signaling pathway induced by arsenic exposure, which is helpful to provide theoretical basis for the mechanism of toxicity of arsenic-induced immune system damage.

Advances in Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions.

As the use of herbs has become more popular worldwide, there are increasing reports of herb-drug interactions (HDIs) following the combination of herbs and drugs. The active components of herbs are complex and have a variety of pharmacological activities, which inevitably affect changes in the pharmacokinetics of chemical drugs in vivo. The absorption, distribution, metabolism, and excretion of drugs in vivo are closely related to the expression of drug transporters. When the active components of herbs inhibit or induce the expression of transporters, this can cause changes in substrate pharmacokinetics, resulting in changes in the efficacy and toxicity of drugs. In this article, the tissue distribution and physiological functions of drug transporters are summarized through literature retrieval, and the effects of herbs on drug transporters and the possible mechanism of HDIs are analyzed and discussed in order to provide ideas and a reference for further guiding of safe clinical drug use.

Energy metabolism disorders and oxidative stress in the SH-SY5Y cells following PM2.5 air pollution exposure.

Studies have shown that PM2.5 exposure can induce neuronal apoptosis and neurobehavioral changes in animal experiments due partly to the mitochondria-mediated oxidative damage. How does it affect the mitochondrial energy metabolism as well as the neuronal damage, however, remain unclear. This study aimed to investigate the molecular processes of energy metabolism and oxidative damage induced by ambient PM2.5 exposure in SH-SY5Y cells. SH-SY5Y cells were treated with PM2.5 to establish a cytotoxicity model. A Seahorse Extracellular Flux Analyzer (XFp) was performed to evaluate the cellular mitochondrial respiratory and glycolysis after exposure to PM2.5. The dose- and time-dependent effects of PM2.5 on oxidative damage and apoptosis were analyzed. To further explore the relationship among oxidative damage, energy metabolism and apoptosis, SH-SY5Y cells were co-cultured with BHA and PM2.5 for 24 h. The results demonstrated that the basic respiration and ATP production, the typical index of mitochondrial respiration as well as glycolysis, significantly reduced in SH-SY5Y cells with dose and time dependent. At the same time, the PM2.5 could significantly decrease the cell viability and Mn-SOD activity, and increase the ROS levels and apoptosis rate as the escalation of dose and the extension of time. Importantly, the application of BHA could synchronously recover the PM2.5 induced cell energy metabolism disorder, oxidative damage, and apoptosis. It seems that the abnormal cellular energy metabolism may be caused by oxidative damage following fine particles exposure, and further led to apoptosis.

Mechanism of subchronic vinyl chloride exposure combined with a high-fat diet on hepatic steatosis.

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3 ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 µM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 µM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.

Arsenic-fluoride co-exposure induced endoplasmic reticulum stress resulting in apoptosis in rat heart and H9c2 cells.

Exposure to arsenic (As) or fluoride (F) has been shown to cause cardiovascular disease (CVDs). However, evidence about the effects of co-exposure to As and F on myocardium and their mechanisms remain scarce. Our aim was to fill the gap by establishing rat and H9c2 cell exposure models. We determined the effects of As and/or F exposure on the survival rate, apoptosis rate, morphology and ultrastructure of H9c2 cells; in addition, we tested the related genes and proteins of endoplasmic reticulum stress (ERS) and apoptosis in H9c2 cells and rat heart tissues. The results showed that As and/or F exposure induced early apoptosis of H9c2 cells and caused endoplasmic reticulum expansion. Additionally, the mRNA and protein expression levels of GRP78, PERK and CHOP in H9c2 cells were higher in the exposure groups than in the control group, and could be inhibited by 4-PBA. Furthermore, we found that As and/or F exposure increased the expression level of GRP78 in rat heart tissues, but interestingly, the expression level of CHOP protein was increased in the F and As groups, while significantly decreased in the co-exposure group. Overall, our results suggested that ERS-induced apoptosis was involved in the damage of myocardium by As and/or F exposure. In addition, factorial analysis results showed that As and F mainly play antagonistic roles in inducing myocardial injury, initiating ERS and apoptosis after exposure.

Co-exposure to fluoride and arsenic disrupts intestinal flora balance and induces testicular autophagy in offspring rats.

While numerous studies have shown that fluoride or arsenic exposure may damage the reproductive system, there are few reports of co-exposure to fluoride and arsenic. In addition, the literature on autophagy and intestinal flora composition in reproductive toxicity studies of co-exposure to fluoride and arsenic is insufficient. In this study, we developed a rat model of fluoride and arsenic exposure via drinking water from pre-pregnancy to 90 days postnatal. Sprague-Dawley rats were randomly divided into sterile water control group, fluoride group (100 mg/L NaF), arsenic group (50 mg/L NaAsO2) and combined exposure group (100 mg/L NaF+50 mg/L NaAsO2). Our results showed that fluoride and arsenic exposure caused a reduction in testicular weight and significant pathological damage to tissue. We found that the levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were reduced to varying degrees. Meanwhile experiments showed that fluoride and arsenic exposure can modulate autophagic flux, causing increased levels of Beclin1 and LC3 expression and decreased p62 expression. Analogously, by performing 16S sequencing of rat feces, we found 24 enterobacterial genera that differed significantly among the groups. Furthermore, the flora associated with testicular injury were identified by correlation analysis of hormonal indices and autophagy alterations with intestinal flora composition at the genus level, respectively. In summary, our study shows that fluoride and arsenic co-exposure alters autophagic flux in the testis, causes testicular injury, and reveals an association between altered intestinal flora composition and testicular injury.

Proteomics and transcriptomics jointly identify the key role of oxidative phosphorylation in fluoride-induced myocardial mitochondrial dysfunction in rats.

The regulation of mitochondrial function, which is dominated by oxidative phosphorylation (OXPHOs), is important in fluoride induced cardiovascular disease. Based on the previous study of fluoride-induced mitochondrial structure and membrane potential abnormalities, this study integrated ITRAQ protein quantification and RNA-Seq methods to analyze the sequencing data of rat myocardial tissue under fluoride exposure (0, 30, 60 and 90 mg/L). A total of 22 differentially expressed genes associated with the OXPHOs pathway were screened by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) co-enrichment analysis, and were localizated by Interaction Network and calculated inter-genes and inter-omics correlations by Pearson correlation. In general, fluoride exposure can down-regulate genes related OXPHOs, particularly affecting the assembly of the complex I including Ndufa10, resulting in abnormal mitochondrial ATP synthesis and reduced myocardial energy supply. Most importantly, this study shows that the enriched information from the proteomics can explain the change process of energy production, but the specific molecules involved in energy supply cannot be obtained via transcriptomics information alone. Based on the results of transcriptional and protein analysis, our findings contribute to an innovative understanding of the pathways and molecular changes of myocardial injury induced by fluorosis.

Effects of arsenic exposure on lipid metabolism: a systematic review and meta-analysis.

Lipid metabolism dysfunction is a risk factor for cardiovascular diseases. Reportedly, arsenic exposure could affect lipid metabolism, but this finding remains controversial. Herein, we updated and reevaluated evidence regarding the relationship between arsenic exposure and lipid metabolism. Electronic and manual searches were performed to determine the effect of arsenic exposure on lipid metabolism from inception up to 30 November 2019. Overall, five studies were included in our meta-analysis. Two reviewers independently extracted information. Standardized mean difference (SMD) and 95% confidence intervals (CI) were used to analyze the combined effects of four indicators related to lipid metabolism (total cholesterol [TC], triglyceride [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL]). Afterwards, subgroup and sensitivity analyses were performed to explore the source of heterogeneity. Publication bias was tested using funnel plots and Begg's test. In this study, we observed that arsenic exposure can affect lipid metabolism by reducing serum HDL levels and increasing serum LDL levels. Following subgroup analysis, the arsenic concentration appeared to affect lipid metabolism. Funnel plot and Begg's test suggested no asymmetry. In conclusion, we recommend that potential influencing factors, including age, exposure time, and multiple concentration gradients, should be considered to further explore the relationship between arsenic exposure and lipid metabolism.

Fluoride Exposure and Blood Pressure: a Systematic Review and Meta-Analysis.

Fluoride exposure may cause changes in blood pressure, but this conclusion is controversial. Therefore, this meta-analysis aims to investigate the potential relationship between fluoride exposure and blood pressure or hypertension. PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), WANFANG MED ONLINE, and Chinese Scientific Journals Full-Text Databases (VIP) were searched; in addition, two related studies were added manually. In total, 7 observational studies were identified, the pooled odds ratios (ORs) for hypertension between high and reference fluoride exposure groups were calculated, and the pooled standardized weighted mean difference (SMD) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using an inverse-variance weighted random-effects model; next, sensitivity analysis and subgroup analysis were used to assess potential sources of heterogeneity; furthermore, publication bias was assessed using the Begg and Egger test. In brief, there were no statistical differences between exposure groups and control groups in terms of blood pressure or hypertension when all included studies considered. However, subgroup analysis indicated that blood pressure will rise with the increase of fluoride exposure concentrations in endemic fluorosis areas. The corresponding pooled SMD estimates were 0.31 (95% CI 0.11, 0.51) and 0.27 (95% CI 0.11, 0.43) for SBP and DBP. Funnel plots suggested no asymmetry. Our findings support the possibility of a positive correlation between fluoride exposure and blood pressure in endemic fluorosis areas. Additional evidence is needed to assess the dose-response relationship between fluoride exposure and blood pressure.

Sub-chronic administration of benzo[a]pyrene disrupts hippocampal long-term potentiation via inhibiting CaMK II/PKC/PKA-ERK-CREB signaling in rats.

Benzo[a]pyrene (B[a]P) is recognized as a neurotoxic pollutant to mammals, which could impair learning and memory function. Although there is some evidence to suggest that N-methyl-d-aspartate receptor (NMDAR), a glutamate receptor and ion channel protein in nerve cells, is involved into the B[a]P induced neurotoxicity, the exact molecular mechanisms remain to be elucidated, particularly the effects of B[a]P on the NMDAR downstream signaling transduction pathways. In the present study, we examined the neurotoxicity of sub-chronic administrated B[a]P on male Sprague-Dawley rats. Our data suggested that B[a]P exposure caused significant deficits in learning and memory function and the impairment of hippocampal LTP in rats. Further mechanistic studies indicate that B[a]P-induced learning and memory deficits are associated with the inhibition of NMDAR NR1 subunit transcription and protein phosphorylation. More importantly, the inactivation of CaMK II/PKC/PKA-ERK-CREB signaling pathways in hippocampus was detected at both the 2.5 and 6.25 mg/kg B[a]P-treated groups, indicating that multiple targets in NMDAR and downstream signaling pathways are involved in the B[a]P-induced neurotoxicity.

Deregulation of autophagy is involved in nephrotoxicity of arsenite and fluoride exposure during gestation to puberty in rat offspring.

Exposure to fluoride (F) or arsenite (As) through contaminated drinking water has been associated with chronic nephrotoxicity in humans. Autophagy is a regulated mechanism ubiquitous for the body in a toxic environment with F and As, but the underlying mechanisms of autophagy in the single or combined nephrotoxicity of F and As are unclear. In the present study, we established a rat model of prenatal and postnatal exposure to F and As with the aim of investigating the mechanism underlying nephrotoxicity of these pollutants in offspring. Rats were randomly divided into four groups that received NaF (100 mg/L), NaAsO2 (50 mg/L), or NaF (100 mg/L) with NaAsO2 (50 mg/L) in drinking water or clean water during pregnancy and lactation; after weaning, pups were exposed to the same treatment as their mothers until puberty. The results revealed that F and As exposure (alone or combined) led to significant increases of arsenic and fluoride levels in blood and bone, respectively. In this context, F and/or As disrupted histopathology and ultrastructure in the kidney, and also altered creatinine (CRE), urea nitrogen (BUN) and uric acid (UA) levels. Intriguingly, F and/or As uptake induced the formation of autophagosomes in kidney tissue and resulted in the upregulation of genes encoding autophagy-related proteins. Collectively, these results suggest that nephrotoxicity of F and As for offspring exposed to the pollutants from in utero to puberty is associated with deregulation of autophagy and there is an antagonism between F and As in the toxicity autophagy process.

Heat-shock protein 70 (HSP70) polymorphisms affect the risk of coke-oven emission-induced neurobehavioral damage.

OBJECTIVES: Epidemiology studies indicated that coke-oven workers with long-term exposure to polycyclic aromatic hydrocarbons (PAHs) often have some neurobehavioral abnormalities especially impairment for cognitive function, while the underlying mechanisms are not fully understood. Numerous studies have indicated the antioxidant and anti-apoptosis roles of heat shock protein 70 (Hsp70). The genetic polymorphisms in HSP70 genes are associated with multiple diseases including neurotoxicity. However, it is unclear whether HSP70 polymorphisms are related to the neurotoxicity of PAH. We, therefore, investigate the possible association between HSP70 polymorphisms and neurobehavioral abnormalities. METHODS: 188 coke-oven workers and 137 control workers were recruited in this study. Emotional and cognitive function was assessed using the WHO/NCTB. HSP70 polymorphisms (HSP70-1 G190C, HSP70-2 G1267 A and HSP70-hom T2437C) were checked by PCR-RFLP. RESULTS: The results indicated that HSP70-1 CC genotypes in coke-oven workers were associated with poor neurobehavioral performance such as the attention /response speed and visual perception/memory, while the HSP70-2 AA genotypes were associated with lower short-term auditory memory. CONCLUSIONS: HSP70-1 CC and HSP70-2 AA genotypes in coke-oven workers may increase the risk for neurobehavioral damage, especially attention, learning and memory.

Role of endoplasmic reticulum stress and oxidative stress in vinyl chloride-induced hepatic steatosis in mice.

Vinyl chloride (VC) is a common industrial organochlorine, shown to cause hepatic angiosarcoma and hepatic steatosis. However, the role of endoplasmic reticulum stress (ERS) and oxidative stress (OS) in hepatic steatosis after subchronic exposure to VC in mice, is unclear. Based on body weight, forty healthy SPF male C57BL/6 J mice were randomly divided into a control group and three VC exposure groups (57.3, 286.7, and 1433.6 ppm) (n = 10 each). VC was administered by static inhalation in a 50 L sealed plexiglass inhalation chamber for 2 h per day, five days per week for 16 weeks. Serum and liver tissues were analyzed for liver enzymes and lipids. Hepatic cytochrome P450 2E1 (CYP2E1) and OS related indicators malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured. The mRNA expressions of ERS downstream genes, including glycoregulatory protein-78 (GRP-78), sterol regulatory element binding protein-1 (SREBP-1), Acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were detected by real-time PCR (RT-PCR) and their protein levels examined by western blotting. The CYP2E1 levels increased after VC administration in a dose-dependent manner. MDA levels increased (P < .05) and SOD and GSH levels decreased (P < .05) in the liver of each group with the increase in the dose of VC. ERS and expressions of downstream genes (GRP-78, SREBP-1, ACC, and FAS) were enhanced after VC administration. These results suggested that OS and ERS could be induced by VC, which may lead to an increase in fatty acid synthesis in the liver, further aggravating hepatic steatosis.

Interaction of heat shock protein 70 (HSP70) polymorphisms and occupational hazards increases the risk of hypertension in coke oven workers.

OBJECTIVES: The interaction between genetic, epigenetic inheritance and environmental factors determines susceptibility to hypertension. Previous epidemiology studies have shown that coke oven workers who are frequently exposed to various occupational hazards have remarkable increase in the risk for hypertension. Among many genetic variants identified in hypertension, heat shock protein 70 (HSP70) was found to play important roles in the pathogenesis of hypertension and associated diseases. We therefore explore the possible role of HSP70 polymorphisms and their interaction with occupational environment in hypertension risk. METHODS: We carried out a case-control study among 367 coke oven workers in northwest China, focused on three common HSP70 polymorphisms (HSP70-1 G190C, HSP70-2 A1267G and HSP70-hom T2437C), and evaluated the association of HSP70 gene polymorphisms with work sites for high risk of hypertension. RESULTS: The results indicated that HSP70-1 GC and CC genotype had 2.73-fold and 4.26-fold increased relative risk (95% CI 1.33 to 5.55 and 1.17 to 15.53), respectively, comparing with HSP70-1 GG genotype. HSP70-2 AG and GG conferred a 47% and 36% reduced risk (95% CI 0.23 to 0.99 and 0.14 to 0.92) comparing with HSP70-2 AA genotype. Further analysis of the interaction of HSP70 polymorphisms with occupational environment indicated a strong positive interaction between HSP70 genotype (HSP70-1 GC+CC, HSP70-2 AA and HSP70-hom TC+CC) and oven top workplace. CONCLUSIONS: Collectively, these data indicate that HSP70 polymorphisms interact with occupational hazards might increase the risk of hypertension in coke oven workers.