The mitochondria-targeted antioxidant MitoQ ameliorates inorganic arsenic-induced DCs/Th1/Th2/Th17/Treg differentiation partially by activating PINK1-mediated mitophagy in murine liver.

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H2O2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H2O2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.

Effects of PM2.5 and high-fat diet interaction on blood glucose metabolism in adolescent male Wistar rats: A serum metabolomics analysis based on ultra-high performance liquid chromatography/mass spectrometry.

Fine particulate matter (PM2.5) and high-fat diet (HFD) are known to contribute to blood glucose metabolic disorders. However, limited research has investigated the combined impact of PM2.5 and HFD on blood glucose metabolism. This study aimed to explore the joint effects of PM2.5 and HFD on blood glucose metabolism in rats using serum metabolomics and to identify involved metabolites and metabolic pathways. The 32 male Wistar rats were exposed to filtered air (FA) or PM2.5 (real-world inhaled, concentrated PM2.5, 8 times the ambient level, ranging from 131.42 to 773.44 µg/m3) and fed normal diet (ND) or HFD for 8 weeks. The rats were divided into four groups (n = 8/group): ND-FA, ND-PM2.5, HFD-FA and HFD-PM2.5 groups. Blood samples were collected to determine fasting glucose (FBG), plasma insulin and glucose tolerance test and HOMA Insulin Resistance (HOMA-IR) index was calculated. Finally, the serum metabolism of rats was analyzed by ultra-high performance liquid chromatography/mass spectrometry (UHPLC-MS). Then we constructed the partial least squares discriminant analysis (PLS-DA) model to screen the differential metabolites, and performed pathway analysis to screen the main metabolic pathways. Results showed that combined effect of PM2.5 and HFD caused changes in glucose tolerance, increased FBG levels and HOMA-IR in rats and there were interactions between PM2.5 and HFD in FBG and insulin. By metabonomic analysis, the serum differential metabolites pregnenolone and progesterone, which involved in steroid hormone biosynthesis, were two different metabolites in the ND groups. In the HFD groups, the serum differential metabolites were L-tyrosine and phosphorylcholine, which involved in glycerophospholipid metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. When PM2.5 and HFD coexist, they may lead to more severe and complex effects on glucose metabolism by affecting lipid metabolism and amino acid metabolism. Therefore, reducing PM2.5 exposure and controlling dietary structure are important measures for preventing and reducing glucose metabolism disorders.

Lactobacillus rhamnosus GG ameliorates noise-induced cognitive deficits and systemic inflammation in rats by modulating the gut-brain axis.

Background: Environmental noise exposure is linked to neuroinflammation and imbalance of the gut microbiota. Promoting gut microbiota homeostasis may be a key factor in relieving the deleterious non-auditory effects of noise. This study aimed to investigate the effect of Lactobacillus rhamnosus GG (LGG) intervention on noise-induced cognitive deficits and systemic inflammation in rats. Methods: Learning and memory were assessed using the Morris water maze, while 16S rRNA sequencing and gas chromatography-mass spectrometry were used to analyze the gut microbiota and short-chain fatty acid (SCFA) content. Endothelial tight junction proteins and serum inflammatory mediators were assessed to explore the underlying pathological mechanisms. Results: The results indicated that Lactobacillus rhamnosus GG intervention ameliorated noise-induced memory deterioration, promoted the proliferation of beneficial bacteria, inhibited the growth of harmful bacteria, improved dysregulation of SCFA-producing bacteria, and regulated SCFA levels. Mechanistically, noise exposure led to a decrease in tight junction proteins in the gut and hippocampus and an increase in serum inflammatory mediators, which were significantly alleviated by Lactobacillus rhamnosus GG intervention. Conclusion: Taken together, Lactobacillus rhamnosus GG intervention reduced gut bacterial translocation, restored gut and blood-brain barrier functions, and improved gut bacterial balance in rats exposed to chronic noise, thereby protecting against cognitive deficits and systemic inflammation by modulating the gut-brain axis.

PINK1/Parkin-Mediated Mitophagy Partially Protects against Inorganic Arsenic-Induced Hepatic Macrophage Polarization in Acute Arsenic-Exposed Mice.

Inorganic arsenic is a well-known environmental toxicant and carcinogen, and there is overwhelming evidence for an association between this metalloid poisoning and hepatic diseases. However, the biological mechanism involved is not well characterized. In the present study, we probed how inorganic arsenic modulates the hepatic polarization of macrophages, as well as roles of PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy participates in regulating the metalloid-mediated macrophage polarization. Our results indicate that acute arsenic exposure induced macrophage polarization with up-regulated gene expression of inducible nitric oxide synthase (Inos) and arginase-1 (Arg1), monocyte chemotactic protein-1 (Mcp-1) and macrophage inflammatory protein-2 (Mip-2), tumor necrosis factor (Tnf)-α, interleukin (Il)-1ß and Il-6, as well as anti-inflammatory factors Il-4 and Il-10. In parallel, we demonstrated the disrupted hepatic redox balance typically characterized by the up-regulation of hydrogen peroxide (H2O2) and glutathione (GSH), and activation of PINK1/Parkin-mediated mitophagy in the livers of acute arsenic-exposed mice. In addition, our results demonstrate that it might be the PINK1/Parkin-mediated mitophagy that renders hepatic macrophage refractory to arsenic-induced up-regulation of the genes Inos, Mcp-1, Mip-2, Tnf-α, Il-1ß, Il-6 and Il-4. In this regard, this is the first time the protective effects of PINK1/Parkin-mediated mitophagy in inorganic arsenic-induced hepatic macrophage polarization in vivo have been reported. These findings add novel insights into the arsenical immunotoxicity and provide a basis for the preve.ntive and therapeutic potential of PINK1/Parkin-mediated mitophagy in arsenic poisoning.

Effect of ACE, ACE2 and CYP11B2 gene polymorphisms and noise on essential hypertension among steelworkers in China: a case-control study.

BACKGROUND: Previous studies on the relationship between ACE I/D, ACE2 G8790A and CYP11B2-344T/C gene polymorphisms and essential hypertension (EH) were inconsistent. Moreover, few studies have reported the combined effect of these gene polymorphisms and noise exposure on EH. The purpose of this study was to explore the combined and separate effects of ACE I/D, ACE2 G8790A and CYP11B2-344T/C gene polymorphisms and noise on EH among steelworkers. METHODS: A case-control study was conducted on 725 male workers between March 2014 and July 2014 in the Tangsteel Company, China. The noise exposure of the workers were measured. Logistic regression and crossover analysis were used to analyse the effects of the interactions on the EH among steelworkers. GMDR was used to determine the best combination model of gene-noise interactions. RESULTS: Multivariate logistic regression showed that noise exposure increased the odds of EH, and the OR is 1.52 (95% CI 1.04-2.22). The risk of having EH for ACE I/D DD genotype carriers was 1.99 times that for II genotype carriers (95% CI 1.14-3.51). There was a negative additive interaction between ACE2 G8790A and CYP11B2-344T/C on EH (U3 = - 2.221, P = 0.026, and S = 0.128) and a positive multiplicative interaction between ACE I/D and CYP11B2-344T/C on essential hypertension (P = 0.041). In addition, there was no significant gene-noise interaction model through the GMDR method after adjusting the confounders. CONCLUSIONS: The ACE DD genotype may make men susceptible to EH. Simultaneously carrying the DD genotype of ACE I/D and the TC genotype of CYP11B2-344T/C increased the risk of EH.

[Effects of fine particulate matter on cognitive function and gut microbiota in adult male mice].

OBJECTIVE: To study the effects of fine particulate matter(PM_(2.5))exposure to cognitive function and intestinal flora abundance and diversity in adult male mice. METHODS: The SPF grade male C57 BL/6 J mice with 8 weeks old were randomly divided into control group(NS group), PM_(2.5) exposure group(PM_(2.5) group), probiotic group(VSL#3 group) and PM_(2.5) + VSL#3 group(PMV group), with 8 mice in each group. The PM_(2.5) group and PMV group mice were exposed to PM_(2.5) using animal exposure system equipped with real-time PM_(2.5) concentration, and concentrated 6 times the outdoor PM_(2.5) concentration, 8 h every day, 5 d every week for 4 weeks. The VSL#3 group and PMV group mice were given VSL#3, 0.5 mL, 2×10~9 CFU/mL. After four weeks of exposure, feces from mice were collected for 16 s rRNA high-throughput sequencing, and the cognitive function was evaluated using Morris water maze and object recognition experiments. RESULTS: The escape latency of PM_(2.5) group in four-day training [(54.99±6.77) s, (41.21±9.98) s, (36.27±13.11) s, (30.01±14.80) s] were higher than that of NS group [(32.19±4.59) s, (20.50±6.77) s, (19.93±7.30) s, (16.94±9.91) s], and the difference were statistically significant(P<0.05). The escape latency of PMV group on the first and second day of training [(39.02±6.23) s, (28.83±9.53) s] were lower than that of PM_(2.5) group(P<0.05). The target quadrant residence time of mice in PM_(2.5) group [(18.30± 8.88) s] was lower than that in NS group and PMV group [(30.53±9.10) s, (30.00±10.61) s]. Compared with NS group(6.09±0.40), the shannon index of PM_(2.5) group and PMV group(5.05±0.65 and 5.46±0.52) were significantly reduced(P<0.05). The target quadrant time was positively correlated with the relative abundance of Actinomyces(r=0.576, P<0.05), and the recognition index was positively correlated with the relative abundance of Firmicutes(r=0.612, P<0.05). CONCLUSION: PM_(2.5) could lead to cognitive dysfunction in mice, which is related to diversity and abundance of the intestinal flora. Probiotic can improve cognitive function.

Real-world particulate matters induce lung toxicity in rats fed with a high-fat diet: Evidence of histone modifications.

Exposure to ambient particulate matters (PMs) has been associated with a variety of lung diseases, and high-fat diet (HFD) was reported to exacerbate PM-induced lung dysfunction. However, the underlying mechanisms for the combined effects of HFD and PM on lung functions remain poorly unraveled. By performing a comparative proteomic analysis, the current study investigated the global changes of histone post-translational modifications (PTMs) in rat lung exposed to long-term, real-world PMs. In result, after PM exposure the abundance of four individual histone PTMs (1 down-regulated and 3 up-regulated) and six combinatorial PTMs (1 down-regulated and 5 up-regulated) were significantly altered in HFD-fed rats while only one individual PTM was changed in rats with normal diet (ND) feeding. Histones H3K18ac, H4K8ac and H4K12ac were reported to be associated with DNA damage response, and we found that these PTMs were enhanced by PM in HFD-fed rats. Together with the elevated DNA damage levels in rat lungs following PM and HFD co-exposure, we demonstrate that PM exposure combined with HFD could induce lung injury through altering more histone modifications accompanied by DNA damage. Overall, these findings will augment our knowledge of the epigenetic mechanisms for pulmonary toxicity caused by ambient PM and HFD exposure.

[Effects of PM_(2. 5) exposure on synaptic plasticity and Wnt/ß-catenin pathway in rat hippocampus].

OBJECTIVE: To investigate the effects of PM_(2. 5) exposure on the development of synaptic plasticity and Wnt/ß-catenin pathway in hippocampus of offspring rats. METHODS: Healthy 7-week-old SPF SD rats(n=36) mated with a male to female ratio of 2∶1. Pregnant rats were randomly divided into three groups, including control group, low PM_(2. 5) group, and high PM_(2. 5) group, with eight rats in each group. The low and high PM_(2. 5) concentrations in dynamic exposure cabinet were approximately two times and four times higher than the annual average PM_(2. 5) concentration in Tangshan city respectively. The exposure started from pregnant day 0, until postnatal day 21(PND21) of offspring rats. After weaning, the offspring rats continued to be exposed to PM_(2. 5) until PND42. PND21 and PND42 pups were subjected to Morris water maze and new object recognition experiments. Western blot was used to detect post synaptic density-95(PSD-95), synaptophysin(SYN), growth associated protein(GAP-43), glycogen synthase kinase 3ß(GSK-3ß), ß-catenin protein levels and phosphorylation levels of GSK-3ß and ß-catenin in the hippocampus of offspring rats. RESULTS: Compared with the control group, the learning and memory abilities of the pups of each PM_(2. 5) group were significantly decreased with a dose dependent manner. Compared with the control group, the protein level of SYN, GAP-43 and PSD-95 in hippocampus of PND0 rats of each PM_(2. 5)groups were decreased(P<0. 05), and the protein level of SYN of each PM_(2. 5)group and PSD-95 of high PM_(2. 5) group in PND21 and PND42 were decreased(P<0. 05), and the level of GAP-43 of low PM_(2. 5) group in PND42 were decreased(P<0. 05). Compared with the low PM_(2. 5) group, the level of PSD-95 of high PM_(2. 5) group in PND0 and PND21, the level of PSD-95 of high PM_(2. 5) group in PND0 and PND42 were decreased(P<0. 05). Compared with the control group, the level of p-GSK-3ß in hippocampus of each PM_(2. 5)group in PND0, PND21 and PND42 was decreased(P<0. 05), and with the increase of PM_(2. 5) exposure dose, the trend is more obvious. The protein level of p-ß-catenin in hippocampus of high PM_(2. 5) group in PND0 and PND42 was significantly increased(P<0. 05). The level of p-ß-catenin in high-dose PND21 pups compared with the control group was significantly reduced(P<0. 05). CONCLUSION: Exposure to PM_(2. 5) in early life can damage the synaptic plasticity and decrease the protein levels of ß-catenin and p-GSK-3ß in the Wnt/ß-catenin pathway of hippocampus in offspring rats.

Silica dust exposure induces autophagy in alveolar macrophages through switching Beclin1 affinity from Bcl-2 to PIK3C3.

Increased deposition of silica dust in pulmonary interstitial tissues leads to silicosis, in which autophagy plays a defensive role in silica dust-associated stress response and cell death. Our previous studies revealed that silica dust exposure contributed to autophagy in pulmonary macrophages in vivo, while the specific regulatory mechanism is still unclear. This study aimed to figure out the regulatory mechanism as well as the role of autophagy in the pathogenesis of experimental silicosis. We used 3-methyladenine (3-MA) and ABT-737 to suppress the expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and B cell leukemia/lymphoma 2 (Bcl-2), two critical initiators of autophagy, and detected and evaluated the autophagy in NR8383 cells with or without silica dust exposure. We found that exposure of silica dust increased autophagy in NR8383 cells and elevated the expression of Beclin1 and PIK3C3, but it reduced the expression of Bcl-2. The relationship among Beclin1, PIK3C3, and Bcl-2 were then investigated using immunoprecipitation analysis, and we found that suppression of PIK3C3 and/or Bcl-2 using 3-MA and/or ABT-737 could alter the autophagy induced by silica dust in NR8383 cells, and the complexes of Beclin1/PIK3C3 and Beclin1/Bcl-2 were both downregulated, which may be that inhibition of PIK3C3 and Bcl-2 altered the affinity of Beclin1 with PIK3C3 and Bcl-2 and lead to the silence of PIK3C3 signaling. These findings indicate that silica dust exposure induces autophagy via changing the connectivity of Beclin1 from Bcl-2 to PIK3C3.

Potential lung carcinogenicity induced by chronic exposure to PM2.5 in the rat.

Exposure to fine particulate matter (PM2.5) may increase lung cancer risk, but the underlying mechanisms are poorly understood. This study explored the potential carcinogenicity in rat lung induced by chronic exposure to PM2.5. Adult male rats (200-220 g) were treated with PM2.5 (10 mg/kg body weight) by tracheal perfusion once per week for 1 year; the rats were killed, and expression of tumor markers (carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), squamous cell carcinoma antigen (SCCA)), cancer-related genes, and pathological changes were detected. Chronic treatment with PM2.5 significantly increased SCCA and NSE expression in rat lung tissue and serum. Damaged lung tissue structure was observed by hematoxylin and eosin staining. Although no evidence of tumors was detected, the Wnt/ß-catenin signaling, epithelial-mesenchymal transition, vascular endothelial growth factor, and epidermal growth factor receptor pathways were all activated or overexpressed and likely involved in the potential carcinogenicity in the rat model. Additionally, abnormal expression of the proto-oncogenes c-Myc and K-Ras and tumor suppressor p53 can be seen in lung tissue induced by PM2.5 exposure. Chronic exposure to PM2.5 has the potential to be carcinogenic in rat lung.

Comprehensive pulmonary metabolome responses to intratracheal instillation of airborne fine particulate matter in rats.

Airborne fine particulate matter (PM2.5) has been closely related with a variety of lung diseases. Although some modes of action (e.g. oxidative stress, inflammations) have been proposed, but the pulmonary toxicological mechanism remains obscure. In this paper, in order to understand the comprehensive pulmonary response to PM2.5 stress, a non-targeted high-throughput metabolomics strategy was adopted to characterize the overall metabolic changes and relevant toxicological pathways. PM2.5 samples were collected from Tangshan, one of the most polluted cities in China. Adult male rats were treated with PM2.5 suspension once a week at the dose of 1mg/kg/week through intratracheal instillation in three months. Aqueous and organic metabolite extracts of the lung tissues were subjected to metabolomics analysis using ultra-high performance liquid chromatograph/mass spectrometry. Along with a significant increase of oxidative stress, significant metabolome alterations were observed in the lung tissues of the treated rats. Nineteen metabolites were found decreased and 31 metabolites increased, which are mainly involved in lipid and nucleotide metabolism. Integrated pathway analysis suggests that PM2.5 can induce pulmonary toxicity through disturbing pro-oxidant/antioxidant balance, which may further correlate with metabolism changes of phospholipid, glycerophospholipid, sphingolipid and purine. These findings improve our understanding of the toxicological pathways of PM2.5 exposure.

Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats.

Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.

The preferential accumulation of heavy metals in different tissues following frequent respiratory exposure to PM2.5 in rats.

This study aimed to explore the pattern of accumulation of some of main heavy metals in blood and various organs of rats after exposed to the atmospheric fine particulate matter (PM2.5). Rats were randomly divided into control and three treatment groups (tracheal perfusion with 10 mg/kg, 20 mg/kg and 40 mg/kg of PM2.5 suspension liquid, respectively). Whole blood and the lung, liver, kidney, and cerebral cortex were harvested after rats were treated and sacrificed. The used heavy metals were detected using inductively coupled plasma-mass spectrometry (ICP-MS) instrument. As results, Lead was increased in the liver, lung and cerebral cortex and the level of manganese was significantly elevated in the liver and cerebral cortex in PM2.5 treated rats. Besides, arsenic was prominently enriched both in cerebral cortex and in blood, and so did the aluminum in the cerebral cortex and the copper in the liver. However, cadmium, chromium and nickel have shown no difference between the control group and the three PM2.5 treated groups. Following the exposure of PM2.5, different heavy metals are preferentially accumulated in different body tissues.

[Investigation on psychological stress of mine emergency rescue personnel].

OBJECTIVE: To investigate psychological stress and influence factors on the mine emergency rescue personnel. METHOD: 564 mine emergency rescue personnel from a rescue group were select as subjects, and 60 designers from a steel design institute were as controls. Self-made questionnaire and general job stress questionnaire were used to investigate the basic information, rescue history, psychosomatic symptoms, depression symptoms, daily job stress and negative emotions of emergency rescue personnel. SPSS17.0 software was used to analysis the psychological stress on the mine rescue personnel and its influence factors. RESULTS: The detection rate (41.94%) of depression symptoms in rescue team was higher than that of controls (24.90%). The score of daily job stress was higher than that of logistical support. The older age group with higher negative emotional and daily job stress than the younger. The highest negative emotion was in age group of more than 40 years old. The highest score of daily job stress was in ≤30 years old. The score of depression and psychosomatic symptoms were higher than those of the college and the above. The scores of depression in group of duration of rescue <10 years was higher than that of duration≥10 years. The score of daily job stress is the lowest in rescue for 1 to 2 times per year and the highest in group of simulation training once a week. The score of daily job stress and depressive symptoms were getting higher with the extension of combat duty time. Age, hours of combat duty, training times a week, education and life events were the main affecting fectors on mental health of mine rescuers. CONCLUSIONS: Mine rescuers have more psychological stress than generic population. The psychological stress of the mine crew is related to age, education, life events, training and combat readiness duty time.

Fluoride and arsenic exposure impairs learning and memory and decreases mGluR5 expression in the hippocampus and cortex in rats.

Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus.

[Effects of lead exposure on copper and copper transporters in choroid plexus of rats].

OBJECTIVE: To investigate the effects of lead exposure on the copper concentration in the brain and serum and the expression of copper transporters in the choroid plexus among rats. METHODS: Sixty specific pathogen-free Sprague-Dawley rats were randomly divided into a control group and three lead-exposed groups, with 8 mice in each group. The lead-exposed groups were orally administrated with 500 (low-dose group)), 1 000 (middle-dose group), and 2 000 mg/L (high-dose group) lead acetate in drinking water for eight weeks. And the rats in control group were given 2 000 mg/L sodium acetate in drinking water. The content of lead and copper in the serum, hippocampus, cortex, choroid plexus, bones, and cerebrospinal fluid (CSF) was determined by inductively coupled plasma-mass spectrometry (ICP-MS). Confocal and real-time PCR methods were applied to measure the expression of copper transporters including copper transporter 1 (Ctr1), antioxidant protein 1 (ATX1), and Cu ATPase (ATP7A). RESULTS: Compared with the control group, the lead-exposed groups showed significantly higher lead concentrations in the serum, cortex, hippocampus, choroid plexus, CSF, and bones (P < 0.05) and significantly higher copper concentrations in the CSF, choroid plexus, serum, and hippocampus (P < 0.05). Confocal images showed that Ctr1 protein was expressed in the cytoplasm and cell membrane of choroid plexus in control group. However, Ctr1 migrated to CSF surface microvilli after lead exposure. Ctr1 fluorescence intensity gradually increased with increasing dose of lead, except that the middle-dose group had a higher Ctr1 fluorescence intensity than the high-dose group. In addition, the middle- and high-dose groups showed a lower ATX1 fluorescence intensity compared with the control group. Real-time PCR data indicated that the three lead-exposed groups showed significantly higher mRNA levels of Ctr1 and ATP7A compared with the control group (P < 0.05). CONCLUSION: Copper homeostasis in the choroid plexus is affected by lead exposure to induce copper homeostasis disorders in brain tissue, which may be one of the mechanisms of lead neurotoxicity.

[Application of urinary proteomics in early diagnosis of bladder urothelial carcinoma].

OBJECTIVE: To investigate the difference in urinary proteome between patients with bladder urothelial carcinoma (BUC) and healthy volunteers and to provide a basis for the early diagnosis of BUC. METHODS: The urine samples from BUC patients and healthy volunteers (controls) were treated by 25% ethanol precipitation and two-dimensional gel electrophoresis (2-DE), and the obtained urinary proteins were subjected to Coomassie brilliant blue staining and analysis by PDQuest 8.0 (2-DE image analysis software); the differentially expressed proteins were sequenced by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry and identified using the Swiss-Prot database; the differential expression of these proteins was verified by western blot. RESULTS: High-resolution and high-reproducibility 2-DE images were obtained from the urine samples of BUC patients and controls, with 789 ± 18 and 762 ± 14 protein spots, respectively. Compared with the control group, the BUC grouP had significantly decreased expression of 6 protein spots and significantly increased expression of 11 protein spots. The mass spectrometry revealed five proteins with increased expression in the BUC group, including fibrinogen, lactate dehydrogenase B, apolipoprotein A1, clusterin, and haptoglobin, and the results were confirmed by western blot. CONCLUSION: There is significant difference in urinary proteome between BUC patients and healthy volunteers; the identification of differentially expressed proteins in urine lays the foundation for identifying potential molecular markers in early diagnosis of BUC.

Genomic damages in peripheral blood lymphocytes and association with polymorphisms of three glutathione S-transferases in workers exposed to formaldehyde.

DNA and chromosome damages in peripheral blood lymphocytes were evaluated in 151 workers occupationally exposed to formaldehyde (FA) and 112 non-FA exposed controls. The effects of polymorphisms in three glutathione-S-transferase (GSTs) genes on the DNA and chromosome damages were assessed as well. Alkaline comet assay and cytokinesis-block micronucleus (CBMN) assay were used to determine DNA and chromosome damages, respectively. The genotypes of GSTP1 (Ile105Val), GSTT1, and GSTM1 were assayed. The mean 8-h time-weighted average (TWA) concentrations of FA in two plywood factories were 0.83ppm (range: 0.08-6.30ppm). FA-exposed workers had higher olive tail moment (TM) and CBMN frequency compared with controls (Olive TM, 3.54, 95%CI=3.19-3.93 vs. 0.93, 95%CI=0.78-1.10, P<0.01; CBMN frequency, 5.51+/-3.37 vs. 2.67+/-1.32, P<0.01). Olive TM and the CBMN frequency also had a dose-dependent relation with the personal FA exposure. Significant association between FA exposure history and olive TM and CBMN frequency were also identified. The level of olive TM was slightly higher in FA-exposed workers with GSTM1 null genotype than those with non-null genotype (3.86, 95%CI=3.31-4.50 vs. 3.27, 95%CI=2.83-3.78, P=0.07) with adjustment of covariates. We also found that FA-exposed workers carrying GSTP1 Val allele had a slightly higher CBMN frequency compared with workers carrying only the wild-type allele (6.32+/-3.78 vs. 5.01+/-2.98, P=0.05). Our results suggest that the FA exposure in this occupational population increased DNA and chromosome damages and polymorphisms in GSTs genes may modulate the genotoxic effects of FA exposure.

[A case-control study on serum organochlorines residues, genetic polymorphisms of glutathione S-transferase T1 and the risks of breast cancer].

OBJECTIVE: To study the potential effect of gene-environment interaction between glutathione S-transferase T1 (GSTT1) and serum organochlorines residues on the risk of breast cancer in women, in China. METHODS: 70 newly diagnosed female breast cancer patients and 30 controls from September 2006 to October 2007 were interviewed using the same questionnaire to obtain information regarding exposure to those risks. Organochlorine residues level in serum was measured by gas chromatography (GC). Genotypes of GSTT1 polymorphisms were analyzed by multiplex allele-specific polymerase chain reaction (PCR). Interaction indexes (gamma) were calculated to determine the type of gene-environment interaction. RESULTS: After adjusting the confounding factors, results showed that interaction existed in genetic polymorphisms of GSTT1 and dichlorodiphenyltrichloroethane (DDT)/hexachlorocyclohexane (HCH) residues, with interaction indexes (gamma) value as 1.352 and 1.528. CONCLUSION: Genetic and environmental hazard factors had a co-effect on the development of breast cancer while genetic polymorphisms of GSTT1 and DDT/HCH expressed an interaction to breast cancer.