Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.

Excessive exposure to manganese (Mn) can cause neurological abnormalities, but the mechanism of Mn neurotoxicity remains unclear. Previous studies have shown that abnormal mitochondrial metabolism is a crucial mechanism underlying Mn neurotoxicity. Therefore, improving neurometabolic in neuronal mitochondria may be a potential therapy for Mn neurotoxicity. Here, single-cell sequencing revealed that Mn affected mitochondrial neurometabolic pathways and unfolded protein response in zebrafish dopaminergic neurons. Metabolomic analysis indicated that Mn inhibited the glutathione metabolic pathway in human neuroblastoma (SH-SY5Y) cells. Mechanistically, Mn exposure inhibited glutathione (GSH) and mitochondrial unfolded protein response (UPRmt). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPRmt which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPRmt is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPRmt to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.

Multi-omics analysis reveals Mn exposure affects ferroptosis pathway in zebrafish brain.

Manganese (Mn) accumulates in the central nervous system and can cause neurotoxicity, but the mechanisms of Mn-induced neurotoxicity remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of zebrafish brain after Mn exposure and identified 10 cell types by marker genes: cholinergic neurons, dopaminergic (DA) neurons, glutaminergic neurons, GABAergic neurons, neuronal precursors, other neurons, microglia, oligodendrocyte, radial glia, and undefined cells. Each cell type has its distinct transcriptome profile. Pseudotime analysis revealed that DA neurons had a critical role in Mn-induced neurological damage. Combined with metabolomic data, chronic Mn exposure significantly impaired amino acid and lipid metabolic processes in the brain. Furthermore, we found that Mn exposure disrupted the ferroptosis signaling pathway in the DA neurons in zebrafish. Overall, our study employed joint analysis of multi-omics and revealed ferroptosis signaling pathway is a novel potential mechanism of Mn neurotoxicity.

Associations between multiple heavy metals exposure and neural damage biomarkers in welders: A cross-sectional study.

BACKGROUND: Both occupational and environmental exposure to heavy metals are associated with various neurodegenerative diseases. However, limited evidence is available on the potential effects of exposure to metallic mixtures and neural damage. OBJECTIVES: This study aimed to evaluate the association between metal mixtures in urine and neural damage biomarkers in welders. METHODS: In this cross-sectional study, a total of 186 workers were recruited from steel mills. Twenty-three metals in urine were measured by inductively coupled plasma mass spectrometry. Serum neural damage biomarkers, including neurofilament light chain (NfL), sphingosine-1-phosphate (S1P), prolactin (PRL), and dopamine (DA) were detected using enzyme-linked immunosorbent assay kits. Multivariable linear regression, Bayesian kernel machine regression (BKMR), and Quantile g-computation (QG-C) were employed to estimate the association between metals exposure and neural damage biomarkers. RESULTS: Inverted u-shaped associations of nickel with NfL, S1P, and DA were observed in the BKMR model. A non-linear relationship was also found between Fe and PRL. Urinary cobalt was positively associated with serum PRL and had the strongest positive weights in the QG-C model. Urinary lead was associated with higher serum S1P levels. We also found the interaction among nickel, zinc, arsenic, strontium, iron, and lead with the neural damage biomarkers. CONCLUSION: This study provides new evidence of a direct association between metal mixture exposure and the serum biomarkers of neural damage. Several metals Ni, Co, Pb, Sr, As and Fe, may have adverse effects on the nervous system, while Zn may have neuroprotective effects.

Associations of multiple metals with lung function in welders by four statistical models.

BACKGROUND: Exposure to heavy metals has been related to decreased lung function in workers. However, due to limitations in statistical methods for mixtures, previous studies mainly focused on single or several toxic metals, with few studies involving metal exposome and lung function. OBJECTIVES: The study aimed to evaluate the effects of co-exposure to the metal mixtures on multiple parameters of pulmonary function tests and to identify the elements that play an essential role in elastic-net regression (ENET), multivariate linear regression, bayesian kernel machine regression (BKMR), and quantile g-computation (QG-C) models. METHODS: We have recruited 186 welders from Anhui (China) in 2019. And their end-of-shift urine and lung function measure data were collected with informed consent. The urinary concentrations of 23 metals were measured by inductively coupled urinary mass spectrometry. The lung function measures including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) were also detected as outcome indicators. Four statistical methods, ENET, multivariate linear regression, BKMR, and QG-C models were used to evaluate the associations of element mixtures on lung function comprehensively. RESULTS: Lead and cadmium were negatively associated with FVC and FEV1, nickel and chromium were inversely associated with PEF, and strontium showed significant positive effects in linear regression models, which were consistent with the results in BKMR and QG-C models. Both BKMR and QG-C models showed a significantly negative overall effect of metal mixtures on lung function parameters (FVC, FEV1, and PEF). Meanwhile, BKMR showed the non-linear relationships of cadmium with FVC. CONCLUSION: Multi-pollutant mixtures of metals were negatively associated with lung function. Lead, cadmium, nickel, and strontium might be crucial elements. Our findings highlight a need to prioritize workers' environmental health, and guide future research into the toxic mechanisms of metal-mediated lung function injury.