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.

Dynamic alterations of locomotor activity and the microbiota in zebrafish larvae with low concentrations of lead exposure.

Lead (Pb) is a ubiquitous heavy metal associated with developmental and behavioral disorders. The establishment of pioneer microbiota overlaps with the development of the brain during early life, and Pb-induced developmental neurotoxicity may be partially caused by early-life microbiota dysbiosis. This study investigated the locomotor activity and the microbiota in developing zebrafish at multiple developmental time points (five days post fertilization [5 dpf], 6 dpf, and 7 dpf) under exposure to low concentrations of lead (0.05 mg/L). Time-dependent reductions in the number of activities and the average movement distance of larvae compared to the control were observed following Pb exposure. Furthermore, Pb exposure significantly altered the composition of the gut microbiota of zebrafish larvae. At the phylum level, the abundance of Proteobacteria decreased from 5 to 7 dpf, while that of Actinobacteria increased in the control groups. At the class level, the proportion of Alphaproteobacteria decreased, while that of Actinobacteria increased in the control groups. Notably, all showed the opposite trend in Pb groups. A correlation analysis between indices of locomotor activity and microbial communities revealed genus-level features that were clearly linked to the neurobehavioral performance of zebrafish. Seven genera were significantly correlated with the two performance indicators of the locomotion analysis, namely Rhodococcus, Deinococcus, Bacillus, Bosea, Bradyrhizobium, Staphylococcus, and Rhizobium. Rhizobium was dominant in zebrafish and increased in the Pb groups in a time-dependent manner. In addition, the expression levels of bdnf, trkb1, trkb2, and p75ntr changed in zebrafish from 5 to 7 dpf under Pb exposure. Collectively, these results suggest that Pb-induced neurotoxicity could potentially be treated by targeting the gut microbiota.

Molecular mechanisms of 1,2-dichloroethane-induced neurotoxicity.

The production of industrial solvents and adhesives often utilizes 1,2-dichloroethane (1,2-DCE), a highly toxic halogenated hydrocarbon compound. Occupational 1,2-DCE poisoning occurs frequently and is a public health concern. Exposure to 1,2-DCE can damage the brain, liver, and kidneys. The main and most severe damage caused by exposure to 1,2-DCE is to the nervous system, especially the central nervous system. Current research on 1,2-DCE mainly focuses on the mechanism of brain edema. Several possible mechanisms of 1,2-DCE neurotoxicity have been proposed, including oxidative stress, calcium overload, blood-brain barrier damage, and neurotransmitter changes. This article reviews the research progress on 1,2-DCE neurotoxicity and the mechanism behind it to provide a scientific basis for the prevention and treatment of 1,2-DCE poisoning.

Hierarchical power control of a large-scale wind farm by using a data-driven optimization method.

With the participation in automatic generation control (AGC), a large-scale wind farm should distribute the real-time AGC signal to numerous wind turbines (WTs). This easily leads to an expensive computation for a high-quality dispatch scheme, especially considering the wake effect among WTs. To address this problem, a hierarchical power control (HPC) is constructed based on the geographical layout and electrical connection of all the WTs. Firstly, the real-time AGC signal of the whole wind farm is distributed to multiple decoupled groups in proportion of their regulation capacities. Secondly, the AGC signal of each group is distributed to multiple WTs via the data-driven surrogate-assisted optimization, which can dramatically reduce the computation time with a small number of time-consuming objective evaluations. Besides, a high-quality dispatch scheme can be acquired by the efficient local search based on the dynamic surrogate. The effectiveness of the proposed technique is thoroughly verified with different AGC signals under different wind speeds and directions.

Combined effects of lead and manganese on locomotor activity and microbiota in zebrafish.

Exposure to lead (Pb) and manganese (Mn) during early life influences neurodevelopment and increases the risk of neurodegenerative disorders. However, the level of developmental neurotoxicity due to combined exposure to the two metals remains unclear. Although the microbiota plays an essential part in the development of the nervous system via the gut-brain axis, there is a paucity of information regarding the interactions between exposure to Pb and Mn, the destruction of the microbiome, and neurodevelopmental impacts. To fill in this knowledge gap, we investigated the developmental neurotoxicity and effects on the microbiota of Pb (0.05 mg·L-1) alone and in combination with Mn (0.3 mg·L-1) in zebrafish larvae. Our results revealed that combined exposure precipitated higher malformation rates and lower locomotor activity levels than exposure to either Pb or Mn alone. Additionally, when we separated the combined exposure group from the other groups by applying unsupervised principal coordinates analysis (PCoA) and linear discriminant analysis (LEfSe) of microflora sequencing results, we observed extensive alterations in microbial abundances under combined-exposure conditions. Functional prediction analysis showed that combined exposure contributed to altered amino acid and lipid metabolism, and also that combined exposure to Pb and Mn reflected the greatest number of differentially activated biological pathways compared to the other three groups. ATP-binding cassette G (ABCG) genes and genes related to serotonin signaling and metabolism were altered following combined Pb and Mn exposure and exhibited disparate trends vis-à-vis Pb or Mn exposure alone. According to the results, the combined exposure to Pb and Mn led to more severe effects on both zebrafish locomotor activity and gut microbial composition. We suggest that the microbiota contributes to the combined neurotoxicity by increasing ABCG5 and ABCG8 gene expression.

Effects of Ecologically Relevant Concentrations of Cadmium on the Microbiota, Short-Chain Fatty Acids, and FFAR2 Expression in Zebrafish.

Exposure to cadmium (Cd) can affect neurodevelopment and results in increased potential of developing neurodegenerative diseases during the early developmental stage of organisms, but the mechanisms through which exposure to environmentally relevant concentrations of Cd lead to developmental neurotoxicity remain unclear. Although we know that microbial community fixations overlap with the neurodevelopmental window during early development and that Cd-induced neurodevelopmental toxicity may be related to the disruption of microorganisms during early development, information on the effects of exposure to environmentally relevant Cd concentrations on gut microbiota disruption and neurodevelopment is scarce. Therefore, we established a model of zebrafish exposed to Cd (5 µg/L) to observe the changes in the gut microbiota, SCFAs, and free fatty acid receptor 2 (FFAR2) in zebrafish larvae exposed to Cd for 7 days. Our results indicated that there were significant changes in the gut microbial composition due to the exposure to Cd in zebrafish larvae. At the genus level, there were decreases in the relative abundances of Phascolarctobacterium, Candidatus Saccharimonas, and Blautia in the Cd group. Our analysis revealed that the acetic acid concentration was decreased (p > 0.05) while the isobutyric acid concentration was increased (p < 0.05). Further correlation analysis indicated a positive correlation between the content of acetic acid and the relative abundances of Phascolarctobacterium and Candidatus Saccharimonas (R = 0.842, p < 0.01; R = 0.767, p < 0.01), and a negative correlation between that of isobutyric acid and the relative abundance of Blautia glucerasea (R = -0.673, p < 0.05). FFAR2 needs to be activated by SCFAs to exert physiological effects, and acetic acid is its main ligand. The FFAR2 expression and the acetic acid concentration were decreased in the Cd group. We speculate that FFAR2 may be implicated in the regulatory mechanism of the gut-brain axis in Cd-induced neurodevelopmental toxicity.

Occupational health risk assessment of workplace solvents and noise in the electronics industry using three comprehensive risk assessment models.

Background: Occupational hazards such as solvents and noise in the electronics industry are serious. Although various occupational health risk assessment models have been applied in the electronics industry, they have only been used to assess the risks of individual job positions. Few existing studies have focused on the total risk level of critical risk factors in enterprises. Methods: Ten electronics enterprises were selected for this study. Information, air samples and physical factor measurements were collected from the selected enterprises through on-site investigation, and then the data were collated and samples were tested according to the requirements of Chinese standards. The Occupational Health Risk Classification and Assessment Model (referred to as the Classification Model), the Occupational Health Risk Grading and Assessment Model (referred to as the Grading Model), and the Occupational Disease Hazard Evaluation Model were used to assess the risks of the enterprises. The correlations and differences between the three models were analyzed, and the results of the models were validated by the average risk level of all of the hazard factors. Results: Hazards with concentrations exceeding the Chinese occupational exposure limits (OELs) were methylene chloride, 1,2-dichloroethane, and noise. The exposure time of workers ranged from 1 to 11 h per day and the frequency of exposure ranged from 5 to 6 times per week. The risk ratios (RRs) of the Classification Model, the Grading Model and the Occupational Disease Hazard Evaluation Model were 0.70 ± 0.10, 0.34 ± 0.13, and 0.65 ± 0.21, respectively. The RRs for the three risk assessment models were statistically different (P < 0.001), and there were no correlations between them (P > 0.05). The average risk level of all of the hazard factors was 0.38 ± 0.18, which did not differ from the RRs of the Grading Model (P > 0.05). Conclusions: The hazards of organic solvents and noise in the electronics industry are not negligible. The Grading Model offers a good reflection of the actual risk level of the electronics industry and has strong practicability.

Anti-tumor activities and mechanism study of α-pinene derivative in vivo and in vitro.

In previous study, we designed novel α-pinene derivatives based on theories of bioalkylating agents using α-pinene as lead compound and patented these compounds, in which compound α-pinene derivative GY-1 (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl-4-methylbenzenesulfonat) showed strongest inhibition on hepatoma carcinoma cell BEL-7402. In this study, we investigated effect of GY-1 on hepatocellular carcinoma in vitro and in vivo, and explored its mechanism of anti-hepatoma. The results showed that GY-1 showed good anti-liver cancer activity with the IC50 of 84.7 µmol/L in vitro, inhibited tumor growth in vivo with dose-dependent, and GY-1 could arrest the growth of hepatoma cells in the S phase and induced apoptosis in hepatoma cells, down-regulated the expression of C-myc, CDK2 and CyclinE, and up-regulate p53.