Erratum: Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al.

[This corrects the article DOI: 10.1016/j.omtn.2021.11.010.].

Predictive Value of Smoking Index Combined with NT-proBNP for Patients with Pulmonary Hypertension Due to Chronic Lung Disease: A Retrospective Study.

Purpose: Smoking is a major risk factor for the group 3 PH. NT-proBNP is a biomarker for risk stratification in PH. This study aims to investigate the effects of smoking status and smoking index (SI) on group 3 PH and to evaluate the value of SI and SI combined with NT-proBNP in early diagnosis and prediction of disease severity. Patients and Methods: Four hundred patients with group 3 PH at the First Hospital of Shanxi Medical University between January 2020 and December 2021 were enrolled and divided into two groups: mild (30 mmHg ≤ pulmonary artery systolic pressure (PASP)≤50 mmHg) and non-mild (PASP >50 mmHg). The effect of smoking on group 3 PH was analyzed using univariate analysis, and logistic analysis was conducted to evaluate the risk of group 3 PH according to smoking status and SI. Spearman correlation coefficient was used to test the correlation between SI and the index of group 3 PH severity. The predictive value of SI was evaluated using a receiver operating characteristic (ROC) curve. Results: Correlation and logistic analyses showed that SI was associated with PH severity. Smoking status (P=0.009) and SI (P=0.039) were independent risk factors for non-mild group 3 PH, and ROC showed that the predictive value of SI (AUC:0.596) for non-mild PH was better than that of the recognized pro-brain natriuretic peptide (NT-proBNP) (AUC:0.586). SI can be used as a single predictive marker. SI and NT-proBNP can be formulated as prediction models for screening non-mild clinical cases (AUC:0.628). Conclusion: SI is a potentially ideal non-invasive predictive marker for group 3 PH. SI and NT-proBNP could be used to develop a prediction model for screening non-mild PH cases. This can greatly improve the predictive specificity of the established PH marker, NT-proBNP.

Fabrication of a ß-CD-functionalized magnetic microporous organic network for effective enrichment and detection of fluoroquinolone antibiotics in water samples.

Fluoroquinolone (FQ) antibiotics, one of the leading environmental pollutants, have ecotoxic effects that can accumulate through ecosystems and harm human health. The determination of FQs is still difficult due to the complex matrix, many interfering factors, and low concentration. Hence, a magnetic microporous organic network (MON) composite denoted as Fe3O4@MON-NH2@CM-ß-CD with excellent FQ adsorption performance was prepared by ß-CD covalent modification of a MON. Based on the existence of π-π packing, hydrophobic interaction, and hydrogen bonding between Fe3O4@MON-NH2@CM-ß-CD and FQs, a new magnetic solid phase extraction (MSPE) method for the enrichment of FQs was developed. Under optimized MSPE conditions, five FQs were detected by HPLC-UV with good linearity (R2 ≥ 0.9989) in the range of 0.02-1 µg mL-1, and detection limits (S/N = 3) in the range of 0.0014-0.0023 µg mL-1. The satisfactory recoveries ranged from 93.1 to 116.2% with RSDs lower than 8.39% when applied to actual environmental water samples. These results revealed that Fe3O4@MON-NH2@CM-ß-CD as an adsorbent for MSPE had excellent performance for FQ extraction from real samples, and the MON material types were expanded through the functionalization of MONs, which would have great potential for further application in various analytical methods.

Associations between prenatal exposure to polycyclic aromatic hydrocarbons and thyroid hormones in umbilical cord blood.

We explored the association between maternal urinary polycyclic aromatic hydrocarbon (PAH) metabolites and thyroid hormones in umbilical cord blood in 120 pairs of pregnant women and newborns. Maternal urinary PAH metabolites were measured using high-performance liquid chromatography with tandem mass spectrometry. Thyroid hormones were measured using a flow fluorescence assay. The dose-response relationship between PAH metabolites and thyroid hormones was analyzed using the generalized linear model and restricted cubic spline model. Results showed that Æ©OH PAHs in maternal urine had a negative effect on triiodothyronine (T3). Associations between maternal urinary PAH metabolites and thyroid hormones in umbilical cord blood plasma were observed. Prenatal exposure to PAHs could affect neonatal thyroid hormones, thereby disrupting neonatal thyroid function.

Association of polycyclic aromatic hydrocarbon metabolite concentration in urine and occupational stress in underground coal miners in China: propensity score and bayesian kernel machine regression.

This study intends to examine the association of urinary monohydroxyl PAHs (OH-PAHs) concentration and occupational stress in coal miners. We sampled 671 underground coal miners from Datong, China, assessed their occupational stress using the Occupational Stress Inventory-Revised edition (OSI-R), and categorized them into the high stress miners and controls based on that. We determined urinary OH-PAHs concentration using ultrahigh performance liquid chromatography-tandem mass spectrometry, and analyzed its association with occupational stress using multiple linear regression, covariate balancing generalized propensity score (CBGPS), and Bayesian kernel machine regression (BKMR). The low molecular weight (LMW) OH-PAHs in quartile or homologue was significantly positively associated with Occupational Role Questionnaire (ORQ) and Personal Strain Questionnaire (PSQ) score, but was not associated with Personal Resources Questionnaire (PRQ) score. The OH-PAHs concentration was positively associated with ORQ and PSQ scores in coal miners, particularly the LMW OH-PAHs. Non-association was found in the OH-PAHs with PRQ score.

Focusing on testosterone levels in male: A half-longitudinal study of polycyclic aromatic hydrocarbon exposure and diastolic blood pressure in coke oven workers.

Polycyclic aromatic hydrocarbons (PAHs) can interfere with testosterone levels, and low levels of testosterone are associated with increased cardiovascular events. To explore the role of testosterone in PAHs exposure and cardiovascular health, we used data from the 2011-2016 National Health and Nutrition Examination Survey (NHANES) and a longitudinal database of 332 male coke oven workers from China. The urine PAHs, tobacco metabolites and plasma testosterone levels of coke oven workers were measured. There were inverse associations between serum (plasma) testosterone concentrations and the risk of dysarteriotony and dyslipidemia among the NHANES participants and coke oven workers. The results of the cross-lagged panel analysis among workers showed that the decrease in testosterone preceded the increase in diastolic blood pressure (DBP), and the absolute value of the path coefficient from baseline testosterone to follow-up DBP (ß2 = -8.162, P = 0.077) was significantly larger than the absolute value of the path coefficient from baseline DBP to follow-up testosterone (ß1 = -0.001, P = 0.781). Results from the half-longitudinal mediation analysis showed that baseline hydroxyfluorene predicted significant decreases in plasma testosterone from baseline to follow-up (path a: 0.71, 95% CI: 1.26, -0.16), whereas plasma testosterone at baseline also predicted significant increments in DBP from baseline to follow-up (path b: 9.22, 95% CI: 17.24, -1.19). The indirect effect of PAHs on DBP via plasma testosterone level was marginally significant (test for indirect effects a*b (P = 0.08)). In conclusion, testosterone level is a longitudinal precursor to increased DBP and plays an essential role in the association between PAHs exposure and damage to the cardiovascular system. Coke oven workers with low plasma testosterone levels are more likely to experience adverse changes in blood pressure and lipid levels after exposure to PAHs.

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.

Effect of Club cell secretory proteins on the association of tobacco smoke and PAH co-exposure with lung function decline: A longitudinal observation of Chinese coke oven workers.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAH) and tobacco smoke is associated with epithelial damage and reduced lung function. Club cell secretory protein (CC16) is a known biomarker for lung epithelial cells. However, the potential relationships between PAH and tobacco smoke exposure, CC16 levels, and reduced lung function remain unclear. OBJECTIVES: This longitudinal study aimed to explore the potential role of CC16 in the association of tobacco smoke and PAH co-exposure with lung function. METHODS: We enrolled 313 workers from a coking plant in China in 2014 and followed them up in 2019. The concentrations of PAH and nicotine metabolites in urine were determined using high-performance liquid chromatography (HPLC) with a fluorescence detector and HPLC-tandem mass spectrometry, respectively. The plasma CC16 concentration was determined using an enzyme-linked immunosorbent assay. RESULTS: An analysis of the generalized estimating equation showed that each 1-unit increase in log-transformation of the last tertile of trans-3'-hydroxycotinine (3HC) was associated with a 3.30 ng/ml decrease in CC16. Restricted cubic spline analysis revealed a significant nonlinear dose-effect association between cotinine (COT) and CC16 (Pnonlinear = 0.018). In the low- CC16 subgroup, we found a significant association between total nicotine metabolites and forced vital capacity (FVC%) (ß: 1.45, 95% CI: 2.87, -0.03), and the associations of nicotine (NIC), COT, and 3HC with FVC% were all of marginal significance. High levels of total hydroxyl polycyclic aromatic hydrocarbons (ΣOH-PAH) and NIC in the urine had an interactive effect on the decline of CC16 (P < 0.05). Cross-lagged panel analysis indicated that the decrease in CC16 preceded the decrease in FVC%. CC16 mediated the association between elevated nicotine metabolites and decreased FVC% in the low- CC16 subgroup. CONCLUSIONS: CC16 plays an essential role in the association of PAH and tobacco smoke exposure with reduced lung function. Coke oven workers with low plasma CC16 levels are more likely to experience decreased lung function after tobacco smoke exposure.

Prenatal benzo[a]pyrene exposure impairs hippocampal synaptic plasticity and cognitive function in SD rat offspring during adolescence and adulthood via HDAC2-mediated histone deacetylation.

Benzo[a]pyrene (B[a]P) is a widespread carcinogenic pollutant in the environment. Although previous studies have demonstrated the neurodevelopmental toxicity of B[a]P, the precise mechanisms underlying the neurotoxic effects induced by prenatal B[a]P exposure remain largely unknown. In the present study, pregnant Sprague-Dawley (SD) rats were injected intraperitoneally with 0, 10, 20, or 40 mg/kg-bw of B[a]P for three consecutive days on embryonic days 17-19. The learning and memory abilities of offspring were determined by Morris Water Maze (MWM) test, while the number of dendritic branches and the density of dendritic spines in hippocampal CA1 and DG regions were evaluated by Golgi-Cox staining at PND 45 and PND 75. The mRNA expression of BDNF, PSD-95, and SYP in offspring hippocampus were detected by qRT-PCR, and the protein expression of BDNF, PSD-95, SYP, HDAC2, acH3K9, and acH3K14 were measured by Western blotting or immunohistochemistry. CHIP-PCR was performed to further detect the levels of acH3K9 and acH3K14 in the promoter regions of BDNF and PSD-95 genes. Our results showed that rats prenatally exposed to B[a]P exhibited impaired spatial learning and memory abilities and the number of dendritic branches and the density of dendritic spines in the hippocampal CA1 and DG regions were significantly reduced during adolescence and adulthood. The expression of HDAC2 protein was significantly upregulated, while acH3K9, acH3K14, BDNF, PSD-95, and SYP protein levels were significantly downregulated in the hippocampus of B[a]P- exposed rats. In addition, CHIP results showed that prenatal B[a]P exposure markedly decreased the level of acH3K9 and acH3K14 in the promoter region of BDNF and PSD-95 gene in the hippocampus of PND 45 and PND 75 offspring. All of the results suggest that prenatal B[a]P exposure impairs cognitive function and hippocampal synaptic plasticity of offspring in adolescence and adulthood, and HDAC2-mediated histone deacetylation plays a crucial role in these deficits.

Urinary polycyclic aromatic hydrocarbon metabolites, plasma p-tau231 and mild cognitive impairment in coke oven workers.

BACKGROUND: As a group of environmental pollutants, polycyclic aromatic hydrocarbons (PAHs) may be neurotoxic，especially in high-exposure occupational populations. However, the effect of PAHs on mild cognitive impairment (MCI) is still unclear. OBJECTIVE: We aimed to investigate the relationship between PAH metabolites and MCI and to explore whether plasma p-tau231 can be used as a potential biomarker to reflect MCI in coke oven workers. METHOD: A total of 330 workers were recruited from a coke oven plant as the exposure group, and 234 workers were recruited from a water treatment plant as the control group. The concentrations of eleven PAH metabolites and plasma p-tau231 were determined by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) and ELISA. Cognitive function was measured by the Montreal Cognitive Assessment (MoCA) questionnaire. A multivariate logistic regression model and multiple linear regression model were used to analyze the associations of urinary PAH metabolites with the detection rate of MCI, MoCA scores and plasma p-tau231. The dose-response relationships were evaluated using restricted cubic spline models. RESULTS: We found 146 MCI-positive workers in coke oven plant (44.24%), and 69 MCI-positive workers in water treatment plant (29.49%). In addition, the urinary sum of PAH metabolites (Æ©-OH PAHs) was significantly associated with MCI (OR, 1.371; 95% CI:1.102-1.705). Each one-unit increase in ln-transformed Æ©-OH PAHs was associated with a 0.429 decrease in the sum of MoCA, a 0.281 reduction in the visuospatial/executive function and a 9.416 increase in the level of plasma P-Tau231. We found a negative association between plasma P-Tau231 and visuospatial/executive function (ß = -0.007, 95% CI: -0.011, -0.003). CONCLUSION: Our data indicated that urinary Æ©-OH PAHs levels of workers were positively associated with MCI and the level of plasma P-Tau231.

Tobacco smoke exposure and mitochondrial DNA copy number on neurobehavioural performance: A community study.

The influence of tobacco smoke has been a controversial and very questionable subject within the field of neurological behaviours. To examine the dose-response relationships between tobacco smoke and neurological performance, we investigated whether mitochondrial DNA copy number (mtDNAcn) mediates these relationships. We used restricted cubic spline models to estimate the dose-response relationships. A mediation model was also used to detect the mediating effect. Increased cotinine was negatively associated with auditory memory scores and a 0.51 decrease in mtDNAcn. MtDNAcn acts as a mediator between cotinine and auditory memory. Tobacco smoke levels were inversely associated with mtDNAcn and neurobehavioural changes, and there was a mediation effect between cotinine levels and auditory memory by mtDNAcn.

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.

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.

Phosphorylation of p53 by Cdk5 contributes to benzo[a]pyrene-induced neuronal apoptosis.

Benzo[a]pyrene (B[a]P) is a ubiquitous carcinogenic pollutant in the environment, however, the potential neurotoxic effects of B[a]P has not been elucidated clearly. In the present study, we explored the potential involvement of p53 phosphorylation by Cdk5 in B[a]P-induced neuronal apoptosis at both in vitro and in vivo settings. For in vitro studies, primary cortical neurons isolated from the brains of Sprague Dawley (SD) rat pup were exposed to 0, 10, 20, and 40 µM of B[a]P for 12, 24, or 48 h. For in vivo studies, SD rats were injected intraperitoneally with 0, 1.0, 2.5, and 6.25 mg/kg of B[a]P every other day for 1, 2, or 3 months. Our results demonstrated that exposure to B[a]P caused a dose- and a time-dependent increase in neuronal apoptotic ratio in both in vitro and in vivo studies. There was also a dose- and a time-dependent upregulation of p35, p25, Cdk5, and phosphorylated p53 at Ser15 after B[a]P exposure. In order to explore whether B[a]P-induced increased neuronal apoptosis was through Cdk5/p53 pathway, roscovitine, a specific Cdk5 inhibitor, was applied to pretreat neurons prior to B[a]P exposure. The results showed that pretreatment of neurons with roscovitine partially rescued cells from B[a]P-induced apoptosis, and alleviated B[a]P-induced upregulation of phosphorylated p53 at Ser15. Our results suggest that Cdk5/p53 signaling pathway may be involved in B[a]P-induced neuronal apoptosis, which will provide information to further elucidate the molecular mechanisms of B[a]P-induced neurotoxicity.

Aluminum inhibits non-amyloid pathways via retinoic acid receptor.

BACKGROUND: Aluminium neurotoxicity has been widely confirmed and mainly manifests as cognitive impairment. Al3+ can inhibit the expression of ADAM10, a key enzyme of the nonamyloid pathway, but its mechanism of toxicity has not been fully elucidated. Studies have shown that RARs can regulate ADAM10 expression. METHODS: We explored whether Al3+ affects the expression of ADAM10 through RARs, thereby affecting the nonamyloid pathway. RESULTS: Al3+ reduced the expressions of RARα, RARß and ADAM10. The expression levels of the RARα, RARß and ADAM10 proteins were upregulated in the RA group compared with the control group. In the RA + 200 µmol Al(mal)3 group, the downregulation of RARα, RARß and ADAM10 was weaker than that of the 200 µmol Al(mal)3 group, which indicated that RA participated in and upregulated the expression of ADAM10 through RARα and RARß. CONCLUSION: Al3+ inhibits ADAM10 expression through RARα and RARß and results in a decrease in the nonamyloid pathway.

Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al.

Aluminum is a known neurotoxin that can induce Aß deposition and abnormal phosphorylation of tau protein, leading to Alzheimer disease (AD)-like damages such as neuronal damage and decreased learning and memory functions. In this study, we constructed a rat model of subchronic aluminum maltol exposure, and the whole-transcriptome sequencing was performed on the hippocampus of the control group and the middle-dose group. A total of 167 miRNAs, 37 lncRNAs, 256 mRNAs, and 64 circRNAs expression changed. The Kyoto Encyclopedia of Genes and Genomes showed that PI3K/AKT pathway was the most enriched pathway of DEGs, and IRS1 was the core molecule in the PPI network. circRNA/lncRNA-miRNA-mRNA networks of all DEGs, DEGs in the PI3K/AKT pathway, and IRS1 were constructed by Cytoscape. Molecular experiment results showed that aluminum inhibited the IRS1/PI3K/AKT pathway and increased the content of Aß and tau. In addition, we also constructed an AAV intervention rat model, proving that inhibition of miR-96-5p expression might resist aluminum-induced injury by upregulating expression of IRS1. In general, these results suggest that the ceRNA networks are involved in the neurotoxic process of aluminum, providing a new strategy for studying the toxicity mechanism of aluminum and finding biological targets for the prevention and treatment of AD.

Dose-response relationship between urinary PAH metabolites and blood viscosity among coke oven workers: a cross-sectional study.

OBJECTIVES: Polycyclic aromatic hydrocarbons (PAHs) have been proven to be a risk factor for cardiovascular disease in coke oven workers, and increased plasma viscosity is a signal for higher risk of catching up cardiovascular disease. We want to explore whether the plasma viscosity is affected by the concentration of PAHs. DESIGN: Our study is a cross-sectional dose-response study. SETTING: Participants in this study came from a coke plant in Taiyuan, Shanxi. PARTICIPANTS: We used data of 693 coke oven workers in Taiyuan. PRIMARY AND SECONDARY OUTCOME MEASURES: We assumed that plasma viscosity would increase as the concentration of PAHs metabolites in urine increases. We found that 2-hydroxyfluorene (OHFLU2) and plasma viscosity have a stable linear relationship in different statistical methods. RESULTS: We found that plasma viscosity increased by 1.14 (mPa.s,30/s) for each ng/mL of 2-OHFLU urinary (correlation coefficient range: 0.54-1.74, p<0.05). CONCLUSIONS: The results of this study could provide evidence for coke oven workers to prevent cardiovascular disease by checking whether plasma viscosity is elevated.

The Role of PKC in Regulating NMDARs in Aluminum-Induced Learning and Memory Impairment in Rats.

Aluminum is a widespread environmental neurotoxicant that can induce Alzheimer's disease (AD)-like damage, such as neuronal injury and impairment of learning and memory. Several studies have shown that aluminum could reduce the synaptic plasticity, but its molecular mechanism remains unclear. In this study, rats were treated with aluminum maltol (Al(mal)3) to establish a toxic animal model and PMA was used to interfere with the expression of PKC. The Morris water maze and open field test were used to investigate the behavioral changes of the rats. Western blotting and RT-PCR were used to detect the expression levels of NMDAR subunits, PKC and CaMKII. The results showed that Al(mal)3 damaged learning and memory function and reduced anxiety in rats. During this process, the expression of PKC was downregulated and it inhibited the expression of NMDARs through the phosphorylation of CaMKII.

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.

Effect of aluminum combined with ApoEε4 on Tau phosphorylation and Aß deposition.

BACKGROUND: Aluminum is an environmental neurotoxin widely exposed to animals and humans. Studies have shown that Alzheimer's disease (AD) is characterized by abnormally phosphorylated tau and Aß deposition, aluminum exposure can lead to abnormal phosphorylated tau and Aß deposition. Numerous epidemiological data and studies have confirmed that ApoEε4 is a risk factor for AD. However, whether there is an interaction effect between aluminum and ApoEε4 has yet to be verified. METHODS: SH-SY5Y cells were exposed with AlCl3 and transfected with ApoEε4 respectively. The experimental groups included the blank control group, the low dose group (200 µM AlCl3), the medium dose group (400 µM AlCl3), the high dose group (800 µM AlCl3), empty plasmid group, ApoEε4 group and 400 µM AlCl3+ApoEε4 group. The cell viability was determined by CCK-8 kit after transfection for 48 h.The contents of total tau proteins, tau-181, tau-231, tau-262, tau-396 and Aß42, were determined by ELISA kit. The interaction between AlCl3 and ApoEε4 was analyzed by factorial design. RESULTS: With the increase of aluminum exposure, SH-SY5Y cell viability decreased, and the expression of the total tau, tau-181, tau-231, tau-262, tau-396 and Aß content increased. The viability of cells transfected with ApoEε4 is significantly lower than control group, and the expressions of total tau, tau-181, tau-231, tau-262, tau-396 and Aß in ApoEε4 transfected cells were significantly higher than control group. The viability of cells treated with AlCl3 plus ApoEε4 was lower than those treated with, either AlCl3, or ApoEε4. The expression of total tau, tau-181, tau-231, tau-262, tau-396 and Aß in the cells treated with AlCl3 plus ApoEε4 were significantly higher than those in other groups (p < 0.05). Moreover, analyzing data based on the factorial design, there was existed an interaction between AlCl3 and ApoEε4 (p < 0.05). CONCLUSION: Al and ApoEε4 gene can cause morphological changes of SH-SY5Y cells, reduce cell activity, and have obvious cytotoxic effects, and increase the phosphorylation levels of tau and the deposition of Aß increases. In the presence of both Al and ApoEε4 genes, the two factors interact with each other and show a synergistic effect.