Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure.

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity.

Association of blood metals with anxiety among adults: A nationally representative cross-sectional study.

BACKGROUND: Previous evidence demonstrated the inconsistent associations between metals and anxiety. The purpose of this study was to evaluate the individual and joint effects of blood lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se) and manganese (Mn) on anxiety in the general population. METHODS: Data of 4000 participants (aged≥20 years) in the study were retrieved from the National Health and Nutrition Examination Survey (NHANES) 2011-2012. Multiple logistic regression, restricted cubic splines (RCS) logistic analysis, and weighted quantile sum (WQS) regression were fitted to explore the possible effects of single and mixed metal exposures on anxiety. Moreover, this association was assessed by smoking group. RESULTS: In the study, 24.60 % of participants were in an anxiety state. In logistic regression, blood Pb, Cd, Hg, Se and Mn were not significantly associated with anxiety in all participants. After stratified by smoking group, blood Cd was positively associated with anxiety in the current smoking group [P = 0.029, OR (95 %): 1.708(1.063, 3.040)], whereas not in other groups. In RCS regression, we observed a linear dose-response effect of blood Cd on anxiety stratified by smoking group. In WQS analysis, mixed metal exposures were positively associated with anxiety [P = 0.033, OR (95 %): 1.437(1.031, 2.003)], with Cd (33.69 %) contributing the largest weight to the index. CONCLUSIONS: Our study showed that excessive exposure to Cd is a significant risk factor for anxiety, and the co-exposures to Pb, Cd, Hg, Se and Mn were positively related with the risk of anxiety in current smokers.

Sodium butyrate alleviates lead-induced neuroinflammation and improves cognitive and memory impairment through the ACSS2/H3K9ac/BDNF pathway.

Lead is an environmentally widespread neurotoxic pollutant. Although the neurotoxicity of lead has been found to be closely associated with metabolic disorders, the effects of short-chain fatty acids on the neurotoxicity of lead and its mechanisms have not yet been explored. In this study, the results of open field tests and Morris water maze tests demonstrated that chronic lead exposure caused learning and memory deficits and anxiety-like symptoms in mice. The serum butyric acid content of lead-treated mice decreased in a dose-dependent manner, and oral administration of butyrate significantly improved cognitive memory impairment and anxiety symptoms in lead-exposed mice. Moreover, butyrate alleviated neuroinflammation caused by lead exposure by inhibiting the STAT3 signaling in microglia. Butyrate also promoted the expression of acetyl-CoA synthetase ACSS2 in hippocampal neurons, thereby increasing the content of acetyl-CoA and restoring the expression of both histone H3K9ac and the downstream BDNF. We also found that the median butyric acid concentration in high-lead exposure humans was remarkably lower than that in the low-lead exposure humans (45.16 µg/L vs. 60.92 µg/L, P < 0.01), and that butyric acid significantly mediated the relationship of lead exposure with the Montreal cognitive assessment scores, with a contribution rate of 27.57 %. In conclusion, our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced neurotoxicity.

Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by COX17.

Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aß1-42-treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aß1-42, and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aß1-42-treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.

Association of Serum Concentrations of Copper, Selenium, and Zinc with Grip Strength Based on NHANES 2013-2014.

Increasing evidence has found metals to be strongly associated with muscle strength, but the correlations between serum copper (Cu), selenium (Se), and zinc (Zn) with grip strength in adult populations have not yet been established. We examined the linear and non-linear associations between these three metals and grip strength via multiple linear regression and restricted cubic spline (RCS) regression using data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014. A higher concentration of serum Cu was monotonically linked with lower grip strength [ß = - 0.004 m2 (95% CI: - 0.005, - 0.002)], and serum Zn was positively associated with grip strength [ß = 0.004 m2 (95% CI: 0.002, 0.006)]. We observed a positive association between serum Se and grip strength in the unadjusted model but not in covariate-adjusted models. Interestingly, the results of RCS regression showed that serum Cu had an L-shaped non-linear association with grip strength in all participants and subgroups. We further found a linear-increased trend between serum Zn and the grip strength in all participants. There were also non-linear associations that varied across different subgroups. Taken together, serum Cu and Zn were significantly associated with grip strength, while Se was not. This study offers new evidence to help formulate a reference concentration range for serum Cu and Zn.

The Circ_CARM1 controls cell migration by regulating CTNNBIP1 in anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide-transformed 16HBE cells.

BACKGROUND: Circular RNAs (circRNAs) have an important role in the development and progression of human tumors, including lung cancer. Yet, their role in lung cancer induced by benzo(a)pyrene (B[a]P) remains unclear. In this study, circRNA chips and qRT-PCR were used to examine downregulated circRNAs in malignantly transformed 16HBE cells (16HBE-T) induced by B[a]P. Five down-regulated circRNAs were found, among which hsa_circ_0004552 (circ_CARM1) had the most significant downregulation. Consequently, the role of circ_CARM1 on 16HBE-T cells biological behavior was further examined using several in vitro experiments. MATERIALS AND METHODS: Detecting RNA expression via qRT-PCR. Fluorescence in situ hybridization (FISH) was used to identify the localization of circ_CARM1 in 16HBE-T. The effect of circ_CARM1 on cell behavior (cell migration, proliferation, and apoptosis) was explored by transfecting cells with a vector carrying an overexpression and then using wound healing, transwell migration assay, and flow cytometry. Also, the regulation mechanism for circ_CARM1, miR-1288-3p, and CTNNBIP1 was studied by Dual-Luciferase® Reporter (DLR™) Assay System and western blotting. RESULTS: Reduced expression of circ_CARM1 is observed in 16HBE-T. The overexpression of circ_CARM1 further inhibited the migration of 16HBE-T cells but did not affect cell proliferation and apoptosis. Furthermore, bioinformatic analysis and Dual-Luciferase® Reporter (DLR™) Assay System showed that the competitive binding of circ_CARM1 and miR-1288-3p enhanced the expression of CTNNBIP1, thereby inhibiting the migration of 16HBE-T cells. CONCLUSION: Downregulation of circ_CARM1 can stimulate the expression of miR-1288-3p, thereby reducing the expression of CTNNBIP1, spurring cell migration.