Role of the RIP3-PGAM5-Drp1 pathway in aluminum-induced PC12 cells necroptosis.

Epidemiological studies from diverse global regions suggest a correlation between the accumulation of aluminum in the brain and the onset of various neurodegenerative diseases, including Alzheimer's disease, of which, neuronal cells death happen. Our previous research has found the potential of aluminum to induce neuronal cell death. A comprehensive exploration of the regulatory pathways influenced by aluminum in neuronal cell death could contribute to the development of strategies aimed at preventing the detrimental impact of aluminum on neuronal cells. This study is dedicated to exploring the impact of aluminum on mitochondrial homeostasis through the RIP3-PGAM5-Drp1 pathway, with a specific focus on its potential role in necroptosis. We observed that the inhibition of RIP3 function and the reduction in PGAM5 protein expression both mitigate aluminum-induced necroptosis in PC12 cells and enhance mitochondrial function. However, the inhibition of PGAM5 protein expression does not exert an impact on the expression of RIP3 and MLKL proteins. In summary, our study posits that aluminum can induce necroptosis in PC12 cells through the RIP3-PGAM5-Drp1 pathway.

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris.

Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure-activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure-activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics.

Molecular mechanism of the carboxyl terminus of Hsc70-interacting protein in TAU hyperphosphorylation induced by AlCl3 in N2a cells.

Aluminum (Al) is recognized as a neurotoxin. Studies have confirmed that the neurotoxicity induced by Al may be related to tau hyperphosphorylation. Phosphorylated tau is degraded through the ubiquitin-proteasome pathway (UPP), in which the carboxyl terminus of Hsc70-interacting protein (CHIP) plays an important role. However, whether the CHIP plays a role in regulating tau hyperphosphorylation induced by Al is yet to be determined. The purpose of this study was to explore the molecular mechanism of the CHIP in tau hyperphosphorylation induced by AlCl3 in N2a cells. Mouse neuroblastoma cells (N2a) were exposed to different concentrations of AlCl3 (0, 0.5, 1, and 2 mM) and treated with CHIP/CHIP shRNA/CHIP (ΔU-box)/CHIP (ΔTPR) plasmid transfection. The cell viability was determined by the CCK-8 kit. Protein expression was detected by Western blot. The interaction between CHIP and AlCl3 exposure on the proteins was analyzed by factorial design ANOVA. The results showed that Al can cause tau hyperphosphorylation, mainly affecting the pThr231, pSer262, and pSer396 sites of tau in N2a cells. UPP is involved in the degradation of tau hyperphosphorylation induced by Al in N2a cells, of which CHIP may be the main regulatory target. Both the U-box and TPR domains of CHIP are indispensable and play an important role in the regulation of tau hyperphosphorylation induced by AlCl3 in N2a cells.

ANXA2 and Rac1 negatively regulates autophagy and osteogenic differentiation in osteosarcoma cells to confer CDDP resistance.

BACKGROUND: Cisplatin (CDDP) is a mainstay chemotherapeutic agent for OS treatment, but drug resistance has become a hurdle to limit its clinical effect. Autophagy plays an important role in CDDP resistance in OS, and in the present study we explored the role of ANXA2 and Rac1 in dictating CDDP sensitivity in OS cells. METHODS: ANXA2 and Rac1 expression levels were examined by Western blot and autophagy induction was detected by transmission electron miscroscope (TEM) in the clinical samples and OS cell lines. CDDP resistant cells were established by exposing OS cells to increasing doses of CDDP. The effects of ANXA2 and Rac1 knockdown on CDDP sensitivity were evaluated in the cell and animal models. RESULTS: Reduced autophagy was associated with the increased expression of ANXA2 and Rac1 in CDDP resistant OS tumor samples and cells. Autophagy suppression promoted CDDP resistance and inducing autophagy re-sensitized the resistant cells to CDDP treatment in vitro and in vivo. Further, knocking down ANXA2 or Rac1 re-activated autophagy and attenuated CDDP resistance in OS cells. We further demonstrated that CDDP resistant OS cells displayed a poorer osteogenic differentiation state when compared to the parental cell lines, which was significantly reversed by autophagy re-activation and ANXA2 or Rac1 silencing. CONCLUSION: Our findings revealed a complicated interplay of ANXA2/Rac1, autophagy induction, and osteogenic differentiation in dictating CDDP resistance in OS cells, suggesting ANXA2 and Rac1 as promising targets to modulate autophagy and overcome CDDP resistance in OS cells.

Interaction between aluminum exposure and ApoEε4 gene on cognitive function of in-service workers.

The occurrence and development of cognitive impairment, the early stage of AD, may be affected both by factors of environmental (aluminum exposure) and genetic (ApoEε4 gene). But whether there is an interaction between the two factors on cognitive function is still unknown. To explore the interaction between the two factors on cognitive function of in-service workers. A total of 1121 in-service workers in a large aluminum factory were investigated in Shanxi Province. Cognitive function was assessed by the Mini-mental State Examination (MMSE), the clock-drawing test (CDT), the Digit Span Test (DST, including DSFT and DSBT), the fuld object memory evaluation (FOM), and the verbal fluency task (VFT). The plasma-Al (p-Al) concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) as an internal exposure indicator, and the participants were divided into four Al exposure groups according to the quartile of p-Al concentrations, namely Q1, Q2, Q3, and Q4. ApoE genotype was determined by Ligase Detection Reaction (LDR). The multiplicative model was fitted using non-conditional logistic regression and additive model was fitted using crossover analysis to analyze the interaction between p-Al concentrations and the ApoEε4 gene. Finally, a dose-response relationship between p-Al concentrations and cognitive impairment was observed, with the p-Al concentrations increased, cognitive function performance gradually becomes worse (Ptrend＜0.05), and the risk of cognitive impairment gradually increases (Ptrend＜0.05), mainly in executive/visuospatial impairment, auditory memory impairment (particularly the working memory impairment). And ApoEε4 gene may be a risk factor for cognitive impairment, while no association between the ApoEε2 gene and cognitive impairment is observed. Additionally, an additive but no multiplicative interaction between p-Al concentrations and ApoEε4 gene is observed, and when the two factors work together, the risk of cognitive impairment further increased, of which 44.2% can be attributed to the interaction effect.

Forecasting and analysis of the effect of lifestyle on cognitive dysfunction induced by occupational aluminum exposure based on Bayesian networks.

OBJECTIVES: To evaluate the risk of cognitive impairment in workers with plasma aluminum concentrations and lifestyles using a Bayesian network (BN). METHODS: In 2019, 476 male workers in the Shanxi Aluminum factory were investigated. We measured plasma aluminum concentrations in workers by inductive coupled plasma mass spectrometry (ICPMS) and tested workers' cognitive function by the MoCA scale. We collected the data of lifestyle by the occupational Workers' Health questionnaire and express the influence of lifestyle on cognition by the OR value (95 %CI) of logistic regression. A Bayesian network model was used to predict the risk of cognitive dysfunction. RESULTS: The subjects were divided into a cognitively normal group and cognitively impaired group according to MoCA scores. There were statistically significant differences in age, education level, alcohol consumption, physical exercise, reading, aluminum length of service and blood aluminum concentration between the two groups (P < 0.05). The plasma aluminum concentration in the cognitive impairment group was 1.68 times higher than that in the cognitive normal group. Four groups were established according to the quartile of blood aluminum concentration of the subjects, namely, Group Q1 (<14.95 µg/L), Q2 group (14.95-32.96 µg/L), Q3 group (32.96-56.62 µg/L), and Q4 group (>56.62 µg/L). Binary logistic regression analysis showed that in the adjustment variable Model2, drinking, short sleep, long sleep, and mobile phone use increased the risk of cognitive impairment by 1.505(0.99,2.289), 1.269(0.702,2.295), 1.125(0.711,1.781) and 1.19(0.779,1.82), respectively, compared with their reference values. The risk of cognitive impairment from reading and exercise was 0.7(0.398,1.232) and 0.787(0.51,1.217), respectively, compared with those of no reading and no exercise. The risk of cognitive impairment of blood aluminum concentration in the Q2, Q3, and Q4 groups was 2.103(1.092,4.051), 1.866(0.955,3.644) and 3.679(1.928,7.020), respectively, compared with that in the Q1 group. Compared with age <40 , the risk of cognitive impairment of age ≥40 was 2.515(1.508,4.193) (P < 0.05). Bayesian network model results showed that if all participants had plasma aluminum concentrations higher than Q4, the prevalence of cognitive impairment was 54.5 %. The prevalence of cognitive impairment was 75.0 % if all participants had plasma aluminum levels above Q4, were older than 40, smoked, drank alcohol, used a cell phone for more than 2 h, slept for more than 8 h, did not exercise, and did not read. CONCLUSIONS: Our findings suggest that both poor lifestyle and occupational aluminum exposure may affect cognitive function. Workers must maintain a reasonable lifestyle and reduce aluminum exposure, which can control the occurrence of cognitive impairment.

Effects of H19/SAHH/DNMT1 on the oxidative DNA damage related to benzo[a]pyrene exposure.

The mechanisms that long noncoding RNA (lncRNA) H19 binding to S-adenosylhomocysteine hydrolase (SAHH) interacted with DNA methyltransferase 1 (DNMT1) and then regulated DNA damage caused by polycyclic aromatic hydrocarbons (PAHs) remain unclear. A total of 146 occupational workers in a Chinese coke-oven plant in 2014 were included in the final analyses. We used high-performance liquid chromatography mass spectrometry (HPLC-MS) equipped to detect urine biomarkers of PAHs exposure, including 2-hydroxynaphthalene (2-NAP), 2-hydroxyfluorene (2-FLU), 9-hydroxyphenanthrene (9-PHE) and 1-hydroxypyrene (1-OHP). The levels of SAM and SAH in plasma were detected by HPLC-ultraviolet. By constructing various BEAS-2B cell models exposed to 16 µM benzo[a]pyrene (BaP) for 24 h, toxicological parameters reflecting distinct mechanisms were evaluated. We documented that urinary 1-hydroxypyrene (1-OHP) levels were positively associated with blood H19 RNA expression (OR: 1.51, 95% CI: 1.03-2.19), but opposite to plasma SAHH activity (OR: 0.63, 95% CI: 0.41-0.98) in coke oven workers. Moreover, by constructing various BEAS-2B cell models exposed to benzo[a]pyrene (BaP), we investigated that H19 binding to SAHH exaggerated DNMT1 expressions and activity. Suppression of H19 enhanced the interaction of SAHH and DNMT1 in BaP-treated cells, decreased eight-oxoguanine DNA glycosylase 1 (OGG1) methylation, reduced oxidative DNA damage and lessened S phase arrest. However, SAHH or DNMT1 single knockdown and SAHH/DNMT1 double knockdown showed the opposite trend. A H19/SAHH/DNMT1 axis was involved in OGG1 methylation, oxidative DNA damage and cell cycle arrest by carcinogen BaP.

The interaction effects of secondhand smoke exposure and overweight on the prevalence of hypertension in Chinese coke oven workers and NHANES participants (2013-2016).

BACKGROUND: The prevalence of hypertension may be affected by environmental pollution and personal behavior. OBJECTIVES: We aimed to evaluate the interaction effects of secondhand smoke exposure and overweight on hypertension. METHODS: In this cross-sectional study, a total of 627 workers from a coking plant in China and 1011 individuals from the NHANES database in the United States from 2013 to 2016 were selected as the research participants. The concentrations of 11 urinary polycyclic aromatic hydrocarbons (PAHs) metabolites and 3 tobacco metabolites were measured. An interaction effect was tested in the modified Poisson regression models. RESULTS: For smokers among Chinese coke oven workers, the only statistically significant positive association was with hypertension in the highest tertile of nicotine metabolized ratio (NMR) (PR: 1.539, 95% CI: 1.013-2.337). Nonsmoking Chinese workers with 3rd tertile urinary nicotine levels were associated with a 114.8% significantly increased prevalence of hypertension (PR: 2.148, 95% CI: 1.025-4.500) compared to nonsmokers 1st tertile with nicotine levels. Association between tobacco exposure and hypertension is possibly modified by PAHs exposure (PR: 2.335, 95% CI: 0.933-5.841). Nonsmokers in the NHANES database with high urinary nicotine levels were associated with a 17.3% significantly increased prevalence of hypertension (PR: 1.173, 95% CI: 1.028-1.338) compared to those with low nicotine levels. We observed that overweight people with high nicotine levels had a significantly higher likelihood of hypertension than no overweight people with low nicotine levels among nonsmoking Chinese coke oven workers and NHANES participants (PR = 4.686, 95% CI: 1.488-14.754; PR = 1.251, 95% CI: 1.039-1.506). CONCLUSIONS: Tobacco exposure and overweight are important risk factors for hypertension, and secondhand smoke exposure and overweight have an interactive effect on the incidence of hypertension in nonsmoking Chinese coke oven workers and NHANES participants.

Blood glucose mediated the effects of cognitive function impairment related to aluminum exposure in Chinese aluminum smelting workers.

OBJECT: To explore the effects of occupational aluminum exposure on workers' cognitive function and blood glucose concentration, and to analyze whether blood glucose concentration can mediate the cognitive changes caused by aluminum. METHOD: Our study recruited 375 workers from an aluminum factory in northern China. We collected the fasting elbow venous blood of the workers, measured their fasting blood glucose concentration (FBG), and used ICP-MS to determine plasma aluminum concentration (P-Al) as an indicator of internal exposure. The Montreal Cognitive Assessment (MoCA), was used to assess the cognitive function of workers. Generalized linear model was used to analyze the association of P-Al with cognitive function and blood glucose concentration, and the restricted cubic spline model was used to fit the dose-response relationship. We also conducted a mediation effect analysis. RESULT: We observed the dose-response relationship, that is, as the P-Al increased, sum of MoCA, visuospatial/executive, naming, language, and abstraction scores decreased, and the blood glucose concentration increased. For every e-fold increase in P-Al, sum of MoCA, visuospatial/executive, naming, language, and abstraction scores decreased by 0.328 points, 0.120 points, 0.059 points, 0.060 points, and 0.083 points, respectively, and FBG rose by 0.109 mmol/L. FBG has a significant mediating effect between P-Al and sum of MoCA (P for mediator=0.042), and it could explain 10.7% of the effect of cognitive level related to P-Al. CONCLUSION: Occupational aluminum exposure negatively affected the cognitive function of workers and positively affected FBG. FBG may partially explain the impact of occupational aluminum exposure on workers' cognitive function.

Interaction of polycyclic aromatic hydrocarbon exposure and high-fasting plasma glucose on lung function decline in coke oven workers: a cross-lagged panel analysis.

Individuals with abnormal fasting plasma glucose (FPG) may be more susceptible to lung diseases associated with environmental pollutants. A cross-sectional survey of 629 workers in 2017 and a panel study of 304 workers from 2014 to 2019 were performed in China. The results showed that elevated total hydroxylated polycyclic aromatic hydrocarbon (ΣOH-PAH) concentration was associated with lower the percentage of predicted forced vital capacity (FVC%) among high-FPG workers (ß for the cross-sectional analysis: -1.78%, 95%CI: -2.92%, -0.64%; ß for the panel study: -1.10%, 95%CI: -2.19%, -0.02%). The absolute value of the cross-lagged path coefficient from FPG to FVC% (ß2 = -0.096) was significantly greater than that from FVC% to FPG (ß1 = 0.037). Our results suggest that FPG abnormalities may precede the lung function decline induced by PAH exposure and that high-FPG and high ΣOH-PAH levels have an interactive effect on lung function decline.

Mechanism by Which Aluminum Regulates the Abnormal Phosphorylation of the Tau Protein in Different Cell Lines.

Aluminum (Al) is an environmental neurotoxin to which humans are extensively exposed; however, the molecular mechanism of aluminum toxicity is unclear. Several studies have indicated that exposure to aluminum can cause abnormal phosphorylation of the tau protein. The purpose of this study was to investigate respectively the special molecular mechanism of abnormal regulation on synthesis and degradation of the tau protein induced by AlCl3 in cells of different species. The results of tau protein showed that the sites of abnormal tau phosphorylation induced by AlCl3 are Thr231, Ser262, and Ser396 in N2a cells. Meanwhile, the expressions of Thr181, Thr231, and Ser262 increased abnormally in SH-SY5Y cells. The result of the study showed that PP2A expression was high in N2a cells, while GSK-3ß and PP2A in SH-SY5Y cells were involved in the synthesis process of abnormal tau phosphorylation induced by AlCl3. In N2a cells, the ubiquitin-proteasome pathway (UPP) mainly regulated tau phosphorylation at Ser262 and Ser396. Meanwhile, in SH-SY5Y cells, the UPP mainly regulated tau phosphorylation at Thr231 and Ser396. In summary, the UPP is involved in the degradation of Tau that is abnormally phosphorylated induced by AlCl3, but this process is site-specific and differs in cells of different species.

miR-29a/b1 Regulates BACE1 in Aluminum-Induced Aß Deposition in Vitro.

Aluminum is an environmental neurotoxin that comes extensively in contact with human beings. Animal and human studies demonstrated that aluminum exposure increases the deposition of beta amyloid proteins in the brain as it was observed in Alzheimer's disease. The purpose of this study was to investigate whether miR-29a/b1 affected the expression of beta-secrete enzymes (BACE1) in the process of amyloid ß-protein (Aß) deposition caused by aluminum exposure. The study was performed using two different cell lines. Our results showed that after rat primary cortical neurons were exposed to aluminum, BACE1 gene and protein levels increased to different degrees, and the expression level of Aß1-42 increased. In aluminum-exposed groups, the expression of miR-29a and miR-29b1 decreased, while the expression of amyloid protein Aß1-42 and BACE1 increased. In miRs transfection groups, the expression of amyloid protein Aß1-42 and BACE1 decreased. Aluminum may affect the expression of BACE1 by lowering miR-29a and miR-29b1. AEK293 cells were utilized in this research since they present elevated levels of miR-29a and miR-29b1. After HEK293 cells were exposed to aluminum alone, BACE1 mRNA and BACE1 protein expression levels increased with the increase of aluminum exposure dose (p < 0.05), and the level of Aß1-42 also increased (p < 0.05). Compared with the group exposed to aluminum alone at the same doses, the expression levels of BACE1 mRNA and BACE1 protein in the miRs transfected plus aluminum-exposed groups significantly decreased (p < 0.05), and the level of Aß1-42 also decreased (p < 0.05). This result is consistent with the investigation in rat primary neurons. The results of two types of cells showed that aluminum may cause abnormal down-regulation of the expressions of miR-29a and miR-29b1, thus negatively regulating the increase of BACE1 expression and finally leading to the increase of Aß.

Telomere length mediates the association between polycyclic aromatic hydrocarbons exposure and abnormal glucose level among Chinese coke oven plant workers.

INTRODUCTION: Diabetes is a chronic and complex disease determined by environmental and genetic factors. This study aimed to investigate the association between polycyclic aromatic hydrocarbons (PAHs) exposure and fasting blood glucose levels and telomere length among coke-oven plant workers, to explore potential role of telomere length (TL) in the association between PAHs exposure and abnormal glucose level. METHODS: The cross-sectional survey was conducted in 2017. The high-performance liquid chromatography mass spectrometry (HPLC-MS) was used to detect 11 urine biomarkers of PAHs exposure. TL was measured using the Real-time quantitative polymerase chain reaction (RT-qPCR) method. Logistic regression model, the modified Poisson regression models, and mediation analysis were used to evaluate the associations between PAHs exposure, TL, and abnormal glucose. RESULTS: The results showed that the urinary 1-hydroxypyrene (1-PYR) was positively related to abnormal glucose in a dose-dependent manner (Ptrend = 0.007), the prevalence ratio of abnormal glucose was 8% (95% CI: 1.01-1.16) higher in 3rd tertile of urinary 1-PYR levels. Urinary 1-PYR in the 2nd tertile and 3rd tertile were associated with a 53% (OR = 0.47, 95% CI: 0.28-0.79) and 59% (OR = 0.41, 95% CI: 0.23-0.76) higher risk of shortening TL. And there was a negatively association between 1-PYR and TL in a dose-dependent manner (Ptrend = 0.045). We observed that the association between 1-PYR and abnormal glucose was more significantly positive among participants with median TL level (Ptrend = 0.006). In addition, mediation analysis showed the TL could explain 11.7% of the effect of abnormal glucose related to PAHs exposure. CONCLUSIONS: Our findings suggested the effect of abnormal glucose related to PAHs exposure was mediated by telomere length in coke oven plant workers.

Urinary polycyclic aromatic hydrocarbon metabolites, peripheral blood mitochondrial DNA copy number, and neurobehavioral function in coke oven workers.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are the risk factors for workers' neurological performance, which were widely exist in the occupational environment. OBJECTIVE: We aimed to investigate the dose-response relationship between various PAH metabolites and workers' neurobehavioral changes and to explore whether mitochondrial DNA copy number (mtDNAcn) can be used as a potential biomarker to reflect changes in neurobehavioral behavior. METHOD: A total of 697 workers were recruited from a coke oven plant. The concentrations of eleven PAHs metabolites were determined by HPLC-MS/MS. Peripheral blood mtDNAcn was measured using QPCR. Neurobehavioral function was measured by NCTB questionnaire. The dose-response relationships were evaluated using restricted cubic spline models. Mediation analysis was also carried out. RESULTS: We found dose-response relationships between urinary 2-hydroxynaphthalene (2-OH Nap), sum of PAH metabolites (Æ© -OH PAHs) and total digit span (DSP), backward digit span (DSPB), forward digit span (DSPF) and mtDNAcn. Each one-unit increase in ln-transformed of 2-OH Nap or Æ© -OH PAHs was associated with a 2.64 or 3.22 decrease in DSP, a 1.20 or 1.58 decrease in DSPF, a 1.44 or 1.62 decrease in DSPB and a 0.13 or 0.12 decrease in mtDNAcn. However, we did not find a significant mediation effect of mtDNAcn between PAHs metabolites and DSP, DSPF, or DSPB. CONCLUSION: Our data indicated that workers urinary 2-hydroxynaphthalene and sum of PAH metabolites levels were inversely associated with mtDNAcn and neurobehavior, especially their auditory memory. However, there was no significant mediation effect of mtDNAcn between urinary PAHs metabolites and neurobehavior.

Role of mGluR 1 in synaptic plasticity impairment induced by maltol aluminium in rats.

The main symptoms of Alzheimer's disease (AD) is the loss of learning and memory ability, of which biological basis is synaptic plasticity. Aluminium has been found to cause changes in synaptic plasticity, but its molecular mechanism was unclear. In this study, Sprague-Dawley rats were injected with aluminium maltol (Al(mal)3) through the lateral ventricle to establish an AD-like model. Y-maze, electrophysiological measurements, Golgi staining, scanning electron microscopy, quantitative real-time polymerase chain reaction, and western blot techniques were used to investigate regulation of the metabolic glutamate receptor 1 (mGluR1) in synaptic plasticity impairment induced by Al(mal)3. The results showed that Al(mal)3 inhibited the induction and maintenance of long-term potentiation in the hippocampal CA1 region. During this process, the expression of mGluR1 was up-regulated and it inhibited the expression and phosphorylation of the N-methyl-D-aspartic acid receptors (NMDARs). This mainly affected NMDAR1 and NMDAR2B but did not affect protein kinase C expression.

Relationship between occupational aluminium exposure and histone lysine modification through methylation.

BACKGROUND: Aluminium is an environmental neurotoxin to which human beings are extensively exposed. However, the molecular mechanism of aluminium toxicity remains unclear. METHODS: The changes in cognitive function of aluminum exposed workers under long-term occupational exposure were evaluated, and the relationship between cognitive changes, plasma memory related BDNF and EGR1 protein expression, and variations of epigenetic markers H3K4me3, H3K9me2, H3K27me3 expression levels in blood was explored. RESULTS: MMSE, DSFT, DST scores in cognitive function and the levels of plasma BDNF and EGR1 protein expression decreased with the increase of blood aluminum level. H3K4me3, H3K9me2, H3K27me3 expression levels in peripheral blood lymphocytes of aluminum exposed workers were statistically different (all P<0.05). H3K4me3, H3K9me2 and H3K27me3 expression levels in lymphocytes were correlated with blood aluminum level. BDNF, EGR1 protein level and H3K4me3, H3K9me2, H3K27me3 expression levels have different degrees of correlation. There was a linear regression relationship between plasma BDNF, H3K4me3 and H3K9me2. H3K9me2 had a greater effect on BDNF than H3K4me3. There is a linear regression relationship between EGR1, H3K4me3 and H3K27me3, and the influence of H3K4me3 on EGR1 is greater than that of H3K27me3 on EGR1. CONCLUSION: Alummnum may regulate the expression of BDNF and EGR1 by regulating H3K4me3, H3K27me3 and H3K9me2, and affect the cognitive function of workers by affecting the expression of BDNF and EGR1.

Toxicity of alumina nanoparticles in the immune system of mice.

Aim: Alumina nanoparticles (AlNPs) exert toxic effects in several organs. This study aimed to investigate the toxicity of AlNPs to the immune system. Materials & methods: AlNPs distribution was assessed using CRi in vivo fluorescence imaging. Inductively coupled plasma atomic emission spectrometry was used to detect the content of aluminum in the spleen. Cytokines expression was detected in the immune organs and blood of mice. Results & conclusion: AlNPs can accumulate in mice spleen. Superoxide dismutase and glutathione levels decreased, whereas the level of malondialdehyde increased with decreasing particle size. AlNPs exposure caused cytokine level changes in the spleen, thymus and serum, besides causing damage to immune organs and dysfunction of immune cells, leading to abnormal immune-related cytokine expression.

Reduction of mitochondrial DNA copy number in peripheral blood is related to polycyclic aromatic hydrocarbons exposure in coke oven workers: Bayesian kernel machine regression.

Although association between polycyclic aromatic hydrocarbons (PAHs) exposure and mitochondrial DNA copy number (mtDNAcn) was researched by traditional linear model extensively, most of these studies analyzed independent effect of each PAHs metabolite and adjust for the confounding other metabolites concomitantly, without considering others interactions. As a complex organic pollutant, a reasonable statistical method is needed to study toxic effects of PAHs. Therefore, we aimed to conduct a novel statistical approach, Bayesian Kernel Machine Regression (BKMR), to explore the effect of PAHs exposure on mtDNAcn among coke oven workers. In this cross-sectional study, the concentrations urinary of PAHs metabolites were measured using high performance liquid chromatography mass spectrometry (HPLC-MS). The mtDNAcn was measured using real-time quantitative polymerase chain reaction (RT-PCR) in peripheral blood of 696 Chinese coke oven workers. The relationship of urinary of PAHs metabolites and mtDNAcn were evaluated by BKMR model. And the results showed a significant negative effect of PAHs metabolites on mtDNAcn when PAHs metabolites concentrations were all above 35th percentile compared to the median and the statistically significant negative single-exposure effect of 2-OHNAP and 2-OHPHE on mtDNAcn when all of the other PAHs are fixed at a particular threshold (25th, 50th, 75th percentile). The changes in log 2-OHNAP and 2-OHPHE from the 25th to the 75th percentile when other PAHs metabolites were at the 50th percentile were associated with change in mtDNAcn of -0.082 (-0.021, -0.124) and -0.048 (-0.021, -0.090) respectively. And evidence of a linear effect of urinary 2-OHNAP and 2-OHPHE were found. Finally, our findings suggested that PAHs cumulative exposures and particularly single-exposure of 2-OHNAP and 2-OHPHE might compromise mitochondrial function by decreasing mtDNAcn in Chinese coke oven workers.