Associations between phenols, parabens, and phthalates and depressive symptoms: The role of inflammatory markers and bioinformatic insights.

Phenols, parabens, and phthalates are commonly found in consumer products, yet there is limited research on their individual and combined effects on depressive symptoms, particularly regarding the role of inflammation in these associations. This study aimed to evaluate these effects and explore potential molecular mechanisms, with a focus on inflammation as a mediator. We conducted a cross-sectional analysis involving 2766 adult participants from the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Urine samples were analyzed for 15 chemicals, including 3 phenols, 2 parabens, and 10 phthalates. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Statistical analyses included linear regression, restricted cubic splines, Bayesian Kernel Machine Regression and quantile g-computation models to investigate the relationships between chemical exposures and depressive symptoms. Additionally, mediation analysis was employed to explore the potential role of inflammation (immune cells, CRP, NLR) in these associations. The underlying molecular mechanisms were analyzed using bioinformatic approaches. Notably, BPA, MECPP, MEHHP, MiBP and MBP were found to be positively associated with depressive symptoms among females. Besides, BPA was the most significant positive contributor to the effect in the context of the chemical mixture, while the overall mixture effect was relatively weak. Furthermore, WBC were found to mediate a marginal portion (4 %) of the potential effects of MBP on depressive symptoms. The 15 genes identified are primarily involved in neurotransmission, mood regulation, and stress response. Further research is needed to elucidate the mechanisms underlying the observed associations.

Metabolic signatures of population exposure to metal mixtures: A metabolome-wide association study.

Numerous studies have explored the health impacts of individual metal exposures, yet the effects of metal mixtures on human endogenous metabolism remain largely unexplored. We aimed to assess the serum metabolic signatures of people exposed to metal mixtures. Serum and urine samples were collected from 186 workers at a steel factory in Anhui, China, in September 2019. Inductively coupled plasma mass spectrometry was used to analyze the concentrations of 23 metal elements. The serum metabolome was determined by liquid chromatography-mass spectrometry (LC-MS). A metabolome-wide association study (MWAS) was performed across the metal exposures and metabolism using quantile g-computation modeling. Pathway enrichment analysis was performed using MetaboAnalyst. We identified 226 metabolites associated with metal mixtures, primarily involving lipid metabolism (glycerophospholipids, sphingolipids), amino acid metabolism (arginine and proline, alanine, aspartate and glutamate metabolism) and caffeine metabolic pathways. Exposure to metal mixtures is mainly associated with alterations in lipid metabolism and amino acid metabolism, particularly in the glycerophospholipid and arginine and proline metabolism pathways.

[Effects of PM2.5 and O3 sub-chronic combined exposure on ATP amount and ATPase activities in rat nasal mucosa].

OBJECTIVE: To evaluate the effects of fine particle matter (PM2.5) and ozone (O3) combined exposure on adenosine triphosphate (ATP) amount and ATPase activities in nasal mucosa of Sprague Dawley (SD) rats. METHODS: Twenty male SD rats were divided into control group (n=10) and exposure group (n=10) by random number table method. The rats were fed in the conventional clean environment and the air pollutant exposure system established by our team, respectively, and exposed for 208 d. During the exposure period, the concentrations of PM2.5 and O3 in the exposure system were monitored, and a comprehensive assessment of PM2.5 and O3 in the exposure system was conducted by combining self-measurement and site data. On the 208 d of exposure, the core, liver, spleen, kidney, testis and other major organs and nasal mucosal tissues of the rats were harvested. Each organ was weighed and the organ coefficient calculated. The total amount of ATP was measured by bioluminescence, and the activities of Na+-K+ -ATPase and Ca2+ -ATPase were detected by spectrophotometry. The t test of two independent samples was used to compare the differences among the indicator groups. RESULTS: From the 3rd week to the end of exposure duration, the body weight of the rats in the exposure group was higher than that in the control group (P < 0.05), and there was no significant difference in organ coefficients between the two groups. The average daily PM2.5 concentration in the exposure group was (30.68±19.23) µg/m3, and the maximum 8 h ozone concentration (O3-8 h) was (82.45±35.81) µg/m3. The chemiluminescence value (792.4±274.1) IU/L of ATP in nasal mucosa of the rats in the exposure group was lower than that in the control group (1 126.8±218.1) IU/L. The Na+-K+-ATPase activity (1.53±0.85) U/mg in nasal mucosa of the rats in the exposure group was lower than that in the control group (4.31±1.60) U/mg (P < 0.05). The protein content of nasal mucosa in the control group and the exposure group were (302.14±52.51) mg/L and (234.58±53.49) mg/L, respectively, and the activity of Ca2+-ATPase was (0.81±0.27) U/mg and (0.99±0.73) U/mg, respectively. There was no significant difference between the groups. CONCLUSION: The ability of power capacity decreased in the rat nasal mucossa under the sub-chronic low-concentration exposure of PM2.5 and O3.

Expose to volatile organic compounds is associated with increased risk of depression: A cross-sectional study.

With increasing prevalence rate of depression by years, more attention has been paid to the influence of environmental pollutants on depression, but relationship between exposure to volatile organic compounds (VOCs) and depression is rarely studied. Therefore, this cross-sectional study use the National Center for Health Statistics (NHANES) database (2013-2016 years) to explore association between exposure to multiple VOCs and depression in general population. Multiple linear and logistic regression models were used to analyze the association between urinary VOC metabolism (mVOCs) and depression. To further analyze effect of multiple mVOCs mixed exposure, Bayesian kernel machine regression (BKMR) models were performed. A total of 3240 participants and 16 mVOCs were included in the analysis. Results showed that 10 mVOCs exposure were positively correlated with depression by multiple linear and logistic regression models, especially CYMA and MHBMA3, which also showed significant positive association with depression in BKMR model. Mixed exposure of multiple mVOCs was significantly positively correlated with depression. Gender differences were existed in effects of some VOCs concentrations on depression. AAMA, CYMA and MA had significant positive correlations with depression by women, and DHBMA had significant positive correlations with depression by men. Hence, this study showed that exposing to VOCs might have negative impacts on depression, and impact of CYMA and MHBMA3 on depression may be more evident, which provide new ideas for prevention and control of depression. But further research and exploration are needed to clarify the mechanism and influence factors of this relationship, to demonstrate the reliability of these relationship.

Association between volatile organic compounds exposure and periodontitis: A representative cross-sectional study.

AIM: Periodontitis is one of the most common oral diseases and a major cause of tooth loss in adults. Environmental pollution is closely associated with the prevalence of periodontitis. However, few studies have focused on the association between volatile organic compounds (VOCs) and periodontitis. This cross-sectional study aims to examine whether exposure to VOCs is associated with periodontitis, based on data from the National Health and Nutrition Examination Survey (NHANES, 2011-2014). MATERIALS AND METHODS: We analysed data on blood VOC levels, periodontitis and related covariates from 2772 participants of the NHANES. The association between the blood VOCs and periodontitis was analysed using weighted logistic regression analysis, the restricted cubic spline (RCS) model and the weighted quantile sum (WQS) regression model. Interaction tests and mediation analysis were also conducted. RESULTS: After adjusting for covariates, for each natural constant-fold increase in 1,4-dichlorobenzene, the odds of having periodontitis increased by 16% (odds ratio = 1.16; 95% confidence interval: 1.08-1.24, p < .001). WQS regression model indicated that 1,4-dichlorobenzene contributed the most to the association between VOC co-exposure and periodontitis. Mediation analysis further revealed that total bilirubin levels mediated the association between 1,4-dichlorobenzene and the prevalence of periodontitis, accounting for 4.32%. In addition, the positive association between o-xylene and periodontitis was more pronounced in the <65-year-old group. CONCLUSIONS: This study has provided relatively little evidence to demonstrate a specific link between VOCs and periodontitis. Nonetheless, exposure to VOCs remains a non-negligible public health concern, and further research is required to investigate the association and potential mechanisms of action between VOCs and periodontitis.

Small extracellular vesicles-derived from 3d cultured human nasal mucosal mesenchymal stem cells during differentiation to dopaminergic progenitors promote neural damage repair via miR-494-3p after manganese exposed mice.

Manganese (Mn) exposure is a common environmental risk factor for Parkinson's disease (PD), with pathogenic mechanisms associated with dopaminergic neuron damage and neuroinflammation. Mesenchymal stem cells (MSCs)-derived small extracellular vesicles (sEVs) have emerged as a novel therapeutic approach for neural damage repair. The functional sEVs released from MSCs when they are induced into dopaminergic progenitors may have a better repair effect on neural injury. Therefore, we collected sEVs obtained from primary human nasal mucosal mesenchymal stem cells (hnmMSC-sEVs) or cells in the process of dopaminergic progenitor cell differentiation (da-hnmMSC-sEVs), which were cultured in a 3D dynamic system, and observed their repair effects and mechanisms of Mn-induced neural damage by intranasal administration of sEVs. In Mn-exposed mice, sEVs could reach the site of brain injury after intranasal administration, da-hnmMSC enhanced the repair effects of sEVs in neural damage and behavioral competence, as evidenced by restoration of motor dysfunction, enhanced neurogenesis, decreased microglia activation, up-regulation of anti-inflammatory factors, and down-regulation of pro-inflammatory factors. The transcriptomics of hnmMSC-sEVs and da-hnmMSC-sEVs revealed that miRNAs, especially miR-494-3p in sEVs were involved in neuroprotective and anti-inflammatory effects. Overexpression of miR-494-3p in sEVs inhibited Mn-induced inflammation and neural injury, and its repair mechanism might be related to the down-regulation of CMPK2 and NLRP3 in vitro experiments. Thus, intranasal delivery of da-hnmMSC-sEVs is an effective strategy for the treatment of neural injury repair.

Melatonin mitigates manganese-induced neural damage via modulation of gut microbiota-metabolism in mice.

Manganese (Mn), a common environmental and occupational risk factor for Parkinson's disease (PD), can cause central nervous system damage and gastrointestinal dysfunction. The melatonin has been shown to effectively improve neural damage and intestinal microbiota disturbances in animal models. This research investigated the mechanism by which exogenous melatonin prevented Mn-induced neurogenesis impairment and neural damage. Here, we established subchronic Mn-exposed mice model and melatonin supplement tests to evaluate the role of melatonin in alleviating Mn-induced neurogenesis impairment. Mn induced neurogenesis impairment and microglia overactivation, behavioral dysfunction, gut microbiota dysbiosis and serum metabolic disorder in mice. All these events were reversed with the melatonin supplement. The behavioral tests revealed that melatonin group showed approximately 30 % restoration of motor activity. According to quantitative real time polymerase chain reaction (qPCR) results, melatonin group showed remarkable restoration of the expression of dopamine neurons and neurogenesis markers, approximately 46.4 % (TH), 68.4 % (DCX in hippocampus) and 48 % (DCX in striatum), respectively. Interestingly, melatonin increased neurogenesis probably via the gut microbiota and metabolism modulation. The correlation analysis of differentially expressed genes associated with hippocampal neurogenesis indicated that Firmicutes-lipid metabolism might mediate the critical repair role of melatonin in neurogenesis in Mn-exposed mice. In conclusion, exogenous melatonin supplementation can promote neurogenesis, and restore neuron loss and neural function in Mn-exposed mice, and the multi-omics results provide new research ideas for future mechanistic studies.

The Associations between Exposure to Multiple Heavy Metals and Total Immunoglobulin E in U.S. Adults.

Immunoglobulin E (IgE) is a type of immunoglobulin, and elevated serum total IgE is often present in allergic diseases. Exposure to environmental heavy metals has been markedly linked to allergic diseases, leading to elevated total IgE levels. However, studies concerning the effects of multiple metal exposures on total IgE levels are limited. Therefore, the current study seeks to explore the correlation between heavy-metal co-exposure and total IgE levels based on the National Health and Nutrition Examination Survey (NHANES, 2005-2006). Participants possessed complete data on total IgE levels, 11 urinary metal concentrations and other covariates. The correlations between 11 metals and total IgE levels were analyzed using multiple linear regression, and total IgE levels were a continuous variable. Total IgE levels exceeding 150 kU/L were considered sensitized. Binary logistic regression analyses were employed to assess the correlation between metal exposure and the occurrence of an allergic state. Then, the association between co-exposure to the 11 metals and total IgE levels or the occurrence of sensitization status was further analyzed by Bayesian kernel machine regression (BKMR), a multi-contaminant model. There were 1429 adults with complete data included. Based on the median concentration, molybdenum (Mo) had the highest concentration (46.60 µg/L), followed by cesium (Cs), barium (Ba), lead (Pb), and mercury (Hg). And the median (interquartile range) for total IgE levels was 43.7 (17.3, 126.0) kU/L. Multiple linear regression results showed that Pb was significantly and positively associated with total IgE levels (ß = 0.165; 95% CI: 0.046, 0.284). Binary logistic regression showed a significant positive correlation between urinary Pb (OR: 1.258; 95% CI: 1.052, 1.510) and tungsten (W) (OR: 1.251; 95% CI: 1.082, 1.447). Importantly, the BKMR model found a positive correlation between combined-metal exposure and total IgE levels and the occurrence of sensitization status. The mixed heavy-metal exposure was associated with increased total IgE levels, and this association may be driven primarily by the exposure of Pb and W. This study provides new insights into the relationship between heavy-metal exposure and allergic diseases. More research is needed to confirm these findings.

Mediation effect of serum zinc on insulin secretion inhibited by methyl tert-butyl ether in gas station workers.

Methyl tert-butyl ether (MTBE), a type of gasoline additive, has been found to affect insulin function and glucose homeostasis in animal experiments, but there is still no epidemiological evidence. Zinc (Zn) is a key regulatory element of insulin secretion and function, and Zn homeostasis can be disrupted by MTBE exposure through inducing oxidative stress. Therefore, we suspected that Zn might be involved and play an important role in the process of insulin secretion inhibited by MTBE exposure. In this study, we recruited 201 male subjects including occupational and non-occupational MTBE exposure from Anhui Province, China in 2019. Serum insulin and functional analog fibroblast growth factor 1 (FGF1) and blood MTBE were detected by Elisa and headspace solid-phase microextraction and gas chromatography-high-resolution mass spectrometry. According to MTBE internal exposure level, the workers were divided into low- and high-exposed groups and found that the serum insulin level in the high-exposed group was significantly lower than that in the low-exposed group (p = 0.003) while fasting plasma glucose (FPG) level increased obviously in the high-exposed group compared to the low-exposed group (p = 0.001). Further analysis showed that MTBE exposure level was positively correlated with FPG level, but negatively correlated with serum insulin level, which suggested that the FPG level increase might be related to the decrease of serum insulin level induced by MTBE exposure. The results of further mediation effect analysis showed that changes in serum zinc levels played a major intermediary role in the process of insulin secretion inhibition and blood glucose elevation caused by MTBE exposure. In addition, a significant negative correlation was found between MTBE exposure and serum Zn level, which might play a strong mediating effect on the inhibition of insulin secretion induced by MTBE exposure. In conclusion, our study provided evidence that MTBE could inhibit insulin secretion and interfere with Zn metabolism in gas station workers for the first time, and found that Zn might play an important mediation effect during the process of inhibiting insulin secretion and interfering with glucose metabolism induced by MTBE exposure.

MTBE exposure may increase the risk of insulin resistance in male gas station workers.

Insulin resistance is closely related to many metabolic diseases and has become a serious public health problem worldwide. So, it is crucial to find its environmental pathogenic factors. Methyl tert-butyl ether (MTBE), a widely used unleaded gasoline additive, has been proven to affect glycolipid metabolism. However, results from population studies are lacking. For this purpose, the potential relationships between MTBE exposure and the triglyceride glucose (TyG) index, a useful surrogate marker of insulin resistance, were evaluated using a small-scale occupational population. In this study, 201 participants including occupational and non-occupational MTBE exposure workers were recruited from the Occupational Disease Prevention and Control Hospital of Huaibei, and their health examination information and blood samples with informed consent were collected. The internal exposure levels were assessed by detecting blood MTBE using solid-phase-micro-extraction gas chromatography-mass spectrometry. Then the adjusted linear regression model was used to assess the relationship between MTBE exposure and fasting plasma glucose (FPG), or TyG index. Then, receiver-operating-characteristic (ROC) curves were performed to calculate the optimal cut-off points. Multivariable and hierarchical logistic regression models were used to analyze the impact of MTBE exposure on the risk of insulin resistance. Obvious correlations were observed between blood MTBE levels with TyG index (p = 0.016) and FPG (p = 0.001). Further analysis showed that using the mean of the TyG index (8.77) as a cutoff value had a good effect on reflecting the risk of insulin resistance. Multivariable logistic regression analysis also indicated that MTBE exposure was an independent risk factor for a high TyG index (OR = 1.088, p = 0.038), which indicated that MTBE exposure might be a new environmental pathogenic factor leading to insulin resistance, and MTBE exposure might increase the risk of insulin resistance by independently elevating the TyG index in male gas station workers.

Single-cell transcriptomics analysis of zebrafish brain reveals adverse effects of manganese on neurogenesis.

Manganese (Mn) is considered as an important environmental risk factor for Parkinson's disease. Excessive exposure to Mn can damage various neural cells and affect the neurogenesis, resulting in neurological dysfunction. However, the specific mechanisms of Mn exposure affecting neurogenesis have not been well understood, including compositional changes and heterogeneity of various neural cells. Zebrafish have been successfully used as a neurotoxicity model due to its homology with mammals in several key regions of the brain, as well as its advantages such as small size. We performed single-cell RNA sequencing of zebrafish brains from normal and Mn-exposed groups. Our results suggested that low levels of Mn exposure activated neurogenesis in the zebrafish brain, including promoting the proliferation of neural progenitor cells and differentiation to newborn neurons and oligodendrocytes, while high levels of Mn exposure inhibited neurogenesis and neural function. Mn could affect neurogenesis through specific molecular pathways. In addition, Mn regulated intercellular communication and affected cellular communication in neural cells through specific signaling pathways. Taken together, our study elucidates the cellular composition of the zebrafish brain and adds to the understanding of the mechanisms involved in Mn-induced neurogenesis damage.

The association of serum neurofilament light chains with early symptoms related to Parkinson's disease: A cross-sectional study.

Neurofilament light chains (NfL), released with neural axon injury, is considered as a potential biomarker for Parkinson's disease (PD). The relationship between NfL and PD has been studied mainly in diagnosed patients. Few large-scale studies analyze the association between NfL levels and multiple non-motor symptoms linked to early PD in the general population. Therefore, this study aims to determine the association of NfL with early symptoms of PD, and effectively respond to the development of early symptoms of PD. We examined the relationship between serum NfL and early non-motor symptoms of PD (smell dysfunction, sleep problems, cognitive function) and serum Klotho levels in the general population using data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES). The relationship between serum NfL and early symptoms of PD in 1125 participants was analyzed by multiple linear regression and logistic regression models. The results showed a significant association between serum NfL and early symptoms of PD. There was a significant positive correlation between NfL and smell dysfunction, short sleep and long sleep. There was a significant negative correlation between NfL and Klotho levels and cognitive function test results. Further, we observed gender and age differences in the association of NfL with early symptoms of PD. Our study demonstrate that elevated serum NfL levels are positively associated with an increased risk of early PD-related symptoms, suggesting that serum NfL can be a promising biomarker for early PD.

The association between nasal mucosa bacteria and serum metals in children with nasal diseases.

Allergic rhinitis (AR) and adenoid hypertrophy (AH) are common nasal diseases in children. Studies have shown that heavy metals are environmental risk factors for nasal diseases, and the pathogenic mechanisms may be related to dysregulation of nasal mucosal microbiota. However, it is unclear how heavy metal exposure relates to the nasal mucosal microbiota in nasal diseases. Therefore, we explored serum metal exposure levels and nasal mucosal microbiota composition in children with different nasal disease, and further studied the potential correlation between metal exposure and disease-related taxa. There were 64 children recruited for this study. The 23 metals concentrations in serum were measured by inductively coupled plasma mass spectrometry, and nasal mucosal bacteria was identified by 16S rRNA sequencing. Nasal diseases (AR and AH) in children were associated with alterations in the abundance and diversity of the nasal mucosal microbiota. The nasal microbiota of children with AR showed lower diversity, while the microbiota of children with AH showed higher diversity. Linear discriminant analysis Effect Size showed 108 differentially abundant taxa between AR and control groups, 35 differentially abundant taxa among large adenoid, moderate adenoid and small adenoid groups. The serum zinc concentration was negatively correlated with Pielou's eveness index and Simpson's Index in children classified by adenoid size. The spearman correlation analysis showed that multiple disease-related taxa were closely associated with metal concentrations in serum. Our findings may support a link between metal exposure and the diversity and composition of nasal bacteria in children with nasal disease, which present new evidence for the effects of metals on children health.

Exposure to volatile organic compounds is a risk factor for diabetes: A cross-sectional study.

Currently, more studies showed that environmental chemicals were associated with the development of diabetes. However, the effect of volatile organic compounds (VOCs) on diabetes remained uncertain and needed to be studied. This cross-sectional study examined whether exposure to low levels of VOCs was associated with diabetes, insulin resistance (TyG index) and glucose-related indicators (FPG,HbA1c, insulin) in the general population by using the NHANES dataset (2013-2014 and 2015-2016). We analyzed the association between urinary VOC metabolism (mVOCs) and these indicators in 1409 adults by multiple linear regression models or logistic regression models, further Bayesian kernel machine regression (BKMR) models were performed for mixture exposure analysis. The results showed positive associations between multiple mVOCs and diabetes, TyG index, FPG, HbA1c and insulin, respectively. Among them, HPMMA concentration in urine was significantly positively correlated with diabetes and related indicators (TyG index, FPG and HbA1c), and the concentration of CEMA was significantly positively correlated with insulin. The positive association of mVOCs with diabetes and its related indicators was more significant in the female group and in the 40-59 years group. Thus, our study suggested that exposure to VOCs affected insulin resistance and glucose homeostasis, further affecting diabetes levels, which had important public health implications.

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.

Glutaminase 1 isoform up-regulation associated with lipid metabolism disorder induced by methyl tertiary-butyl ether in male rats.

Methyl tertiary-butyl ether (MTBE) is a new unleaded gasoline additive, which is considered to be associated with abnormal lipid metabolism in many studies, but the metabolic characteristics and mechanism are still unclear. To observe the characteristics of lipid metabolism induced by MTBE and possible pathways, 21 male Wistar rats got intragastric administration for 24 weeks. The serum lipid metabolism indexes and metabolites were analyzed separately by a biochemical analyzer and untargeted metabolomics. And found that serum high-density lipoprotein cholesterol (HDL-C) levels in the exposure group were significantly reduced, and serum very low-density lipoprotein (VLDL) levels were significantly increased. In untargeted metabolomics, 190 differential metabolites were obtained. Among them, 23 metabolites were found to show the same trend in MTBE exposure groups, which might play a key role in systemic energy metabolism. Further metabolic pathways analysis showed that D-Glutamine, D-glutamate metabolism, and the other three pathways were affected by MTBE significantly. Therefore, we evaluated serum glutamine and glutamate levels and found that MTBE exposure significantly reduced glutamine levels and increased glutamate levels in rat serum and L-02 cells. Further, the key regulatory gene of glutamine metabolism, glutaminase 1 isoform (GLS1), was significantly up-regulated in rat liver and L-02 cells exposed to MTBE. While the effect of glutamine and glutamate metabolism induced by MTBE could be weakened by BPTES, an antagonist of GLS1. In conclusion, our results indicated that MTBE exposure could change the level of glutamine metabolism by promoting GLS1 expression and ultimately lead to abnormal lipid metabolism.

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.

Transcriptome Evidence Reveals Mitochondrial Unfolded Protein Response Participate in SH-SY5Y Cells Exposed to Manganese.

BACKGROUND: Overexposure to manganese (Mn) can lead to neurodegenerative damage, resulting in manganism with similar syndromes to Parkinson's disease (PD). However, little is known about changes in transcriptomics induced by the toxicological level of Mn. In this study, we conducted RNA-seq to explore the candidate genes and signaling pathways included by Mn in human SH-SY5Y neuroblastoma cells. METHODS: The differentially expressed genes (DEGs) between the Mn-treated group and the control group were screened, and weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes. Then, pathway enrichment analyses for those candidate genes were performed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We further validated the concentration- and time-response effects of Mn exposure (0-500 µM, 3-12 h) on mitochondrial unfolded protein response (UPRMT) by real-time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results showed 179 up-regulated differentially expressed genes (DEGs) and 681 down-regulated DEGs after Mn exposure. Based on the intersection of DEGs genes and hub genes, 73 DEGs were related to neurotoxicity. The comprehensive pathway analysis showed Mn had widespread effects on the mitogen-activated protein kinase (MAPK) signaling pathway, unfolded protein response, longevity regulating pathway, inflammatory bowel disease, and mitophagy signaling pathway. After Mn exposure, the expressions of activating transcription factor 3 (ATF3) and C-C motif chemokine ligand 2 (CCL2) increased, while the expressions of C/EBP homologous protein (CHOP), caseinolytic protease P (CLPP), and Lon protease 1 (LONP1) decreased in a concentration- and time-dependent manner. CONCLUSIONS: Overall, our study suggests that UPRMT is a new sight in understanding the mechanism of Mn-induced neurotoxicity.