Neurotoxicology最新文献

{"title":"Combined exposure to 6PPD and 6PPD-Q induced neurotoxic responses in zebrafish and SH-SY5Y cells: Evidence from neurotransmitter disruption, oxidative damage, and apoptosis","authors":"Ziwei Wang,&nbsp;Shutao Wang,&nbsp;Wanlun Li,&nbsp;Xingyu Wang,&nbsp;Yingying Liu,&nbsp;Hong Qi","doi":"10.1016/j.neuro.2026.103491","DOIUrl":"10.1016/j.neuro.2026.103491","url":null,"abstract":"<div><div>The rubber antioxidant N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD) and its quinone derivative (6PPD-Q) are coexisting environmental contaminants with documented neurobehavioral effects. However, the neurotoxic consequences arising from their combined exposure remain unclear. In this study, adult zebrafish and SH-SY5Y cells were used to investigate the neurotoxic effects associated with co-exposure to 6PPD and 6PPD-Q. In zebrafish, 100 μg/L 6PPD+100 μg/L 6PPD-Q increased time spent and distance traveled in the non-reward area of the T-maze after 28 d exposure, accompanied by pathological damage in brain tissue, including reduced neuronal density, decreased Nissl bodies, and apoptosis. 6PPD-Q exacerbated oxidative damage and the decreased levels of neurotransmitters induced by 6PPD. Metabolomics implicated disruptions in neuroactive ligand-receptor interaction and citrate cycle. Transcriptomic analysis further identified dysregulation in oxidative stress, cell death, and nervous system processes related pathways, such as Peroxisome, Axon guidance, and PI3K-Akt pathway. In SH-SY5Y cells, co-exposure reduced cell viability and produced predominantly synergistic effects across concentration combinations tested. 6PPD-Q aggravated mitochondrial damage and enhanced the protein expression levels related to apoptosis induced by 6PPD, including caspase-3 and bax/bcl-2. Moreover, co-exposure inhibited the PI3K-AKT pathway, which might exacerbate neurotransmitter disturbance and apoptosis. The findings enrich the understanding of neurological health risks linked to 6PPD and 6PPD-Q, highlighting the importance of preventive strategies to mitigate the exposure risks.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103491"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanism of dopaminergic neuron injury induced by PAHs: Regulation of AhR-RORα/Nrf2 axis and α-syn O-GlcNAc modification","authors":"Yitian Gao,&nbsp;Chenyang Duan,&nbsp;Xiaohan Zheng,&nbsp;Liming Qu","doi":"10.1016/j.neuro.2026.103494","DOIUrl":"10.1016/j.neuro.2026.103494","url":null,"abstract":"<div><div>Parkinson’s disease (PD) ranks second among prevalent global neurodegenerative disorders. It is pathologically characterized by gradual degeneration of midbrain substantia nigra compacta dopaminergic neurons and excessive α-synuclein (α-syn) accumulation forming Lewy bodies. Clinically, patients suffer from motor dysfunctions including resting tremor and muscle stiffness, accompanied by cognitive decline and other non-motor complications, which greatly impair daily life, and there is still no definitive cure. Both genetic predisposition and environmental stimuli jointly drive PD onset. Fine particulate matter PM2.5, a major environmental hazard, carries lipophilic quinone substances capable of crossing the blood-brain barrier and inducing central nervous system injuries. Certain polycyclic aromatic hydrocarbon (PAH) congeners in PM2.5 are highly toxic and produce abundant reactive oxygen species (ROS) to disrupt intracellular signal transduction. This review centers on PD pathogenesis induced by well-studied PAHs and experimental PAH mixtures. In vitro cell assays and in vivo animal studies demonstrate that these tested PAHs aggravate neuronal damage via established suppression of the aryl hydrocarbon receptor (AhR)-retinoid-related orphan receptor α (RORα)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis and emerging evidence of reduced α-syn O-linked β-N-acetylglucosaminylation (O-GlcNAc) modification. Two mutually crosstalk pathways (partially speculative regulatory models) further trigger oxidative stress, mitochondrial damage, abnormal protein deposition and cell apoptosis. Notably, PAHs represent a large and structurally diverse family; the summarized mechanisms are validated based on limited PAH species with distinct toxicity, bioavailability and environmental abundance, and cannot be generalized to all PAH congeners. further triggering oxidative stress, mitochondrial damage, abnormal protein deposition and cell apoptosis. The paper also clarifies the crosstalk and positive feedback between the two pathways, summarizes targeted therapeutic strategies and research prospects, aiming to lay theoretical and experimental foundations for exploring environmental pollutant-related PD etiology, prevention and clinical treatment.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103494"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of gastrodin on methamphetamine-induced apoptosis in rat hippocampus via the NF-κB/NLRP3/Caspase-8 signaling pathway","authors":"Zhang Yuan,&nbsp;Liu Pengliang,&nbsp;Dong Wenjuan,&nbsp;Zhu Tingna,&nbsp;Cao Yuanyuan,&nbsp;Y.U. Hao,&nbsp;L.I. Lihua,&nbsp;Zhao Yongna,&nbsp;Hong Shijun","doi":"10.1016/j.neuro.2026.103503","DOIUrl":"10.1016/j.neuro.2026.103503","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to elucidate the correlation between changes in key factors of the NF-κB/NLRP3/Caspase-8 signaling pathway and neuronal apoptosis in the hippocampus resulting form methamphetamine (METH) addiction and to investigate how gastrodin (Gas) modulation of this signal transduction pathway influences both apoptosis and neurotoxicity.</div></div><div><h3>Methods</h3><div>We used a Conditioned place preference (CPP) model to evaluate the effect of methamphetamine on the behavior of rats. Hematoxylin and eosin staining was used to detect histological changes in the hippocampus of rats, while western blotting and immunohistochemical analysis were used to detect changes in the expression of NF-κB/NLRP3/Caspase-8 signaling pathway related proteins in the hippocampus of METH exposed rats.</div></div><div><h3>Results</h3><div>The research results indicated that NF-κB inhibitors ammonium pyrrolidine dithiocarbamate (PDTC) could elevate the reduced expression levels of Bcl-2 induced by METH (<em>P</em> &lt; 0.05). Following Gas intervention, the expression levels of Bcl-2 demonstrated a significant dose-dependent increase (<em>P</em> &lt; 0.05). Additionally, PDTC could reverse the METH-induced increases in Caspase-8, NLRP3, and the p-NF-κB/NF-κB ratio (<em>P</em> &lt; 0.05). Gas intervention led to a dose-dependent decrease in the expression levels of Caspase-8 and NLRP3.</div></div><div><h3>Conclusions</h3><div>METH induces neuronal apoptosis through the NF-κB/NLRP3/Caspase-8 signaling pathway, and NF-κB inhibitors can alleviate METH-induced ne-uronal apoptosis through this pathway. Gas weakens the CPP effect in rats caused by METH exposure and reverses METH-induced neuronal apoptosis.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103503"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148331494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic dose–time proteomic profiling of cadmium exposure in rat prefrontal cortex","authors":"Zhijian Hu ,&nbsp;Feng Han ,&nbsp;Hao Gao ,&nbsp;Sheng Wan ,&nbsp;Hui Liu ,&nbsp;Li Jie ,&nbsp;Yinghui Yin ,&nbsp;Maoqin Tian ,&nbsp;Yong Yang ,&nbsp;Wenjie Chen ,&nbsp;Xiao Tan ,&nbsp;Xinxin Shi ,&nbsp;Qiwen Chen ,&nbsp;Shaoxin Huang","doi":"10.1016/j.neuro.2026.103463","DOIUrl":"10.1016/j.neuro.2026.103463","url":null,"abstract":"<div><h3>Background</h3><div>Cadmium (Cd) is a well-recognized neurotoxic metal whose effects on the central nervous system accumulate with both exposure intensity and duration. However, how dose and time jointly sculpt brain proteome trajectories—and which early molecular events emerge under low-dose, short-duration exposure—remain insufficiently resolved. Time-resolved proteomics can map these trajectories, but requires explicit dose–time deconvolution to separate main effects from interaction-driven changes while accounting for biological heterogeneity.</div></div><div><h3>Methods</h3><div>We conducted a 3 × 3 oral-exposure design in Sprague–Dawley rats (vehicle control, CdCl2 30 μg/kg/day and 1 mg/kg/day; 2/4/8 weeks) and profiled the prefrontal cortex using deep DIA (diaPASEF) proteomics. An integrative pipeline combined Mfuzz (soft trend clustering), STEM (short time-series pattern discovery), and linear mixed-effects modeling (LMM) with an explicit Dose×Time interaction to deconvolve main and interaction effects while adjusting for sex, baseline body weight, and batch. Functional context was derived from GO/KEGG enrichment and protein–protein interaction (PPI) analyses with FDR control.</div></div><div><h3>Results</h3><div>After QC, 8209 proteins were quantified. LMM identified 173 proteins significant for the Dose main effect, 476 proteins significant for the Time main effect, and 356 proteins significant for the Dose×Time interaction term (BH-FDR q &lt; 0.05). Across the coefficient matrix, Dose×Time coefficients frequently exceeded the corresponding main-effect coefficients in magnitude, indicating substantial interaction-associated structure in cadmium-responsive proteome variation. Cross-method trend analyses converged on Itpr1 and Pde5a as early-response candidates, each down-regulated at 2 weeks/30 μg/kg and accompanied by coherent shifts in Ca²⁺ handling (e.g., Camk2a/b, Atp2b3, Slc8a1) and glutamatergic receptors (e.g., Grin2d, Gria3/4). Enrichment highlighted network-level perturbations spanning calcium signaling, cGMP–PKG, and glutamatergic synapse (e.g., synaptic membrane, q = 2.1 × 10⁻⁵).</div></div><div><h3>Conclusions</h3><div>By explicitly deconvolving dose, time, and their interaction, we map dynamic proteome responses in the prefrontal cortex and highlight an early Itpr1/Pde5a-centered calcium–cGMP–glutamatergic signature that is detectable under low-dose, short-duration exposure. The accompanying DIA dataset and analytical workflow provide a reusable resource for mechanistic hypothesis generation and candidate readout nomination across neurotoxicants.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103463"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A critical review of potential modifiers of air pollutant associations with dementia and related outcomes","authors":"JeongWon Han ,&nbsp;Yina Li ,&nbsp;Sangji Lee ,&nbsp;Katie M. Lynch ,&nbsp;Erin E. Bennett ,&nbsp;Qi Ying ,&nbsp;Eun Sug Park ,&nbsp;Richard L. Smith ,&nbsp;James D. Stewart ,&nbsp;Eric A. Whitsel ,&nbsp;Melinda C. Power ,&nbsp;Xiaohui Xu","doi":"10.1016/j.neuro.2026.103470","DOIUrl":"10.1016/j.neuro.2026.103470","url":null,"abstract":"<div><h3>Background</h3><div>Air pollution has been linked with poor cognitive and brain health, including Alzheimer's Disease and Related Dementia (ADRD). However, whether specific individuals are more susceptible than others remains unclear.</div></div><div><h3>Purpose</h3><div>We aimed to review potential modifiers of the air pollution-cognitive/brain health association and identify subgroups potentially susceptible to adverse effects of air pollution exposure.</div></div><div><h3>Methods</h3><div>We identified published, peer-reviewed articles in the Embase and Medline databases through the Ovid and PubMed search platforms and used Covidence, an online software tool, to extract relevant data from eligible articles. We then systematically reviewed and summarized the evidence on how health behaviors, genetic/molecular factors, environmental factors, and individual factors modify the association between ambient air pollution and cognitive/brain health.</div></div><div><h3>Results</h3><div>Seventy-four publications, out of 6372 relevant publications, met the eligibility criteria and were included in this review. Available studies suggested that race/ethnicity, geographic location, <em>apolipoprotein E (APOE) e</em>4 allele, socioeconomic status (SES), body mass index (BMI), and diet may modify the air pollution-ADRD association, and that age and education do not, although the available evidence precludes firm conclusions. Limited reporting precludes conclusions about other modifiers.</div></div><div><h3>Conclusion</h3><div>Efforts to reduce the harmful effects of air pollution exposure should consider sensitive groups. The current literature suggests differential susceptibility to the adverse effects of air pollution on cognitive and brain health. Future studies should include standardized reporting of effect modification for the likely modifiers identified here, allowing for more robust conclusions.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103470"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lead (Pb) exposure results in cell type specific changes in the mouse retina and optic nerve","authors":"Labony Khandokar ,&nbsp;Luke L. Liu ,&nbsp;Wei Zheng ,&nbsp;Patrick C. Kerstein","doi":"10.1016/j.neuro.2026.103461","DOIUrl":"10.1016/j.neuro.2026.103461","url":null,"abstract":"<div><div>Chronic exposure to lead (Pb) is known to cause deficits in neuronal function across the nervous system, including the visual nervous system. Visual deficits have been observed in both humans and rodent models following Pb exposure. However, how Pb exposure causes visual deficits is poorly understood. In this study, we evaluated the effects of Pb toxicity on the retina and optic nerve of the mouse visual nervous system. We used C57BL/6 adult mice of both sexes and divided them into one of three different exposure groups. Adult mice received daily oral gavage of 108 mg/kg Na-acetate (control), 54 mg/kg Pb-acetate (low dose), or 108 mg/kg Pb-acetate (high dose) for 4 weeks. At the end of Pb exposure, whole blood, retina, and optic nerve samples were collected for Pb quantification by atomic absorption spectroscopy and tissue immunohistochemical analyses. Cell type specific markers were used to quantify changes in cell density of retinal ganglion cells (RGCs), oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), and myelin structure. Following Pb exposure, we observed a significant reduction in the cell density of RGCs in the retina. However, we found no significant changes in branch thickness or coverage of retinal vasculature following Pb exposure. In the optic nerve after Pb exposure, we found a significant reduction in the cell density of OLs and OPCs. Finally, using immunolabeling for Caspr and Nav1.6, we observed significant structural changes in nodes of Ranvier, suggesting a disruption in myelin structure. Our findings suggested that Pb toxicity may impair survival and maturation process of OLs, changes in myelin structures, and potential demyelination of the optic nerve. These results provide the foundation for future investigations into the molecular mechanisms of Pb-dependent changes in myelination and visual nervous system function.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103461"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-associated variables – A framework for neurotoxicology","authors":"Cameron P. Hamson ,&nbsp;Morgan L. Atkinson ,&nbsp;Troy A. Roepke","doi":"10.1016/j.neuro.2026.103475","DOIUrl":"10.1016/j.neuro.2026.103475","url":null,"abstract":"<div><div>As the implementation of ‘sex as a biological variable’ policies have been enacted across the world, the study of sex differences or comparisons across the sexes has steadily increased. In the field of neurotoxicology, the study of sex-dependent variability is necessary due to the plastic nature of the brain and the response to factors that influence this variability such as gonadal hormones and sex chromosomal complement. The phrase ‘sex differences’ is not inherently wrong, but it is an underdefined generalization that creates a distinct binary. While this binary is reductive at best, it creates the expectation of direct comparison and therefore a standard of the two groups when sex is a spectrum containing a mosaic of factors. The generalization of sex to one, often undefined, factor reduces the rigor of the research and overlooks potential variability both within and between sexes. This review provides a guide to help break down sex differences into a conglomeration of variables that can then be assessed for differences. By examining the mechanisms underlying sex difference, research can also be applied to groups and individuals who do not fit into the prescribed binary. People with chromosomal differences, cisgender atypical endocrine profiles, and transgender, nonbinary, and gender diverse (TNG) individuals should have research that can be tailored to their unique experiences and provide additional insight as to how a particular drug or toxicant can impact them in a way that may not be a predicted response based on the binary of male and female.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103475"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148043196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between exposure to flame retardants and cognitive function in the elderly: Unveiling potential intervention strategies","authors":"Yu Liu ,&nbsp;Shiqi Luo ,&nbsp;Jianjun Liu ,&nbsp;Benhong Xu","doi":"10.1016/j.neuro.2026.103478","DOIUrl":"10.1016/j.neuro.2026.103478","url":null,"abstract":"<div><h3>Background</h3><div>Human beings have been widely exposed to various types of flame retardants, but little is known about their effects on cognitive function in the elderly.</div></div><div><h3>Objective</h3><div>To investigate the individual and combined effects of four common flame retardants on cognitive function and the gender differences in the relationship between the four flame retardants and cognitive function.</div></div><div><h3>Results</h3><div>Results revealed that BDCPP and BCEP are both negatively correlated to cognitive function scores (β = −0.06; 95% CI: −0.23, 0.36; β = −0.01; 95% CI: −0.26, 0.28). Notably, two flame retardants, BDCPP and BCEP showed higher relative contribution weights in the WQS model, suggesting they may play a more important role in the mixture effect, pending further validation. Furthermore, Serum Klotho levels were statistically associated with exposure to flame retardants and cognitive outcomes, supporting the exploratory hypothesis that Klotho acts as a potential mediating factor. In the bioinformatics analysis, we identified 622 target genes associated with cognitive decline observed in relation to flame retardant exposure. In addition, enrichment analysis showed that flame retardant-related cognitive decline was associated with pathways such as Apoptosis, Gene expression, Cell proliferation, Metabolic pathways, Pathways of neurodegeneration, PI3K-Akt signaling pathway, MAPK signaling and Alzheimer disease. Cytoscape was used to identify key genes, including MDM2, CASP3, ACTB, TP53, SQSTM1, and PCNA.</div></div><div><h3>Conclusions</h3><div>Our results showed a negative correlation between the four flame retardants and cognitive function. Potential biological pathways of the association between mixed flame retardants exposure and cognitive function may involve Apoptosis, Metabolic pathways, PI3K-Akt signaling pathway, MAPK signaling, and Alzheimer disease. The causality and mechanisms underlying this association require further validation through longitudinal studies or interventional research.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103478"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148056108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxic metal exposure and biomarkers of neurotoxic effects: A study in metal recycling workers","authors":"Meşide Gündüzöz ,&nbsp;Murat Büyükşekerci ,&nbsp;Osman Gökhan Özakıncı ,&nbsp;Mehmet Erdem Alagüney ,&nbsp;Gülsüm Abuşoğlu ,&nbsp;Servet Birgin İritaş ,&nbsp;Vugar Ali Türksoy ,&nbsp;Mustafa Polat ,&nbsp;Berrin Telatar","doi":"10.1016/j.neuro.2026.103469","DOIUrl":"10.1016/j.neuro.2026.103469","url":null,"abstract":"<div><h3>Background</h3><div>Occupational exposure to toxic metals is a critical global health concern, particularly in the metal scrap recycling industry where simultaneous exposure to complex mixtures is common. Chronic exposure to these mixtures can disrupt redox homeostasis and trigger neuronal injury; however, human data on biomarkers reflecting early neural alterations in asymptomatic populations remain limited.</div></div><div><h3>Aims</h3><div>This study evaluates biomarkers of neurotoxic effects in male recycling workers by measuring a comprehensive panel of neuronal and glial injury markers measure biomarkers indicative of possible neural damage associated with chronic toxic metal exposure.</div></div><div><h3>Study design</h3><div>Cross-sectional study</div></div><div><h3>Methods</h3><div>The study included 123 male subjects: 62 recycling workers employed in a metal scrap recovery facility (exposed group) and 61 healthy controls. Blood and urine concentrations of lead (Pb), cadmium (Cd), chromium (Cr), nickel (Ni), copper (Cu), manganese (Mn), cobalt (Co), iron (Fe), arsenic (As), and selenium (Se) were quantified using inductively coupled plasma mass spectrometry (ICP-MS). Serum levels of S100B, Neuron-specific enolase (NSE), Microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP), Myelin basic protein (MBP), and Calprotectin (CALPRO) were measured by ELISA. Statistical associations were examined using correlation and multivariate regression analyses.</div></div><div><h3>Results</h3><div>Recycling workers exhibited markedly higher concentrations of Pb, Mn, Cd, Ni, Cu, Cr, Co, and Fe, alongside significantly decreased Se levels (p &lt; 0.001), indicating substantial toxic metal overload and antioxidant depletion. Correspondingly, serum levels of S100B, NSE, MAP2, and GFAP were significantly elevated in the exposed group (p &lt; 0.001), indicating subclinical neuronal and astroglial stress rather than established disease<strong>.</strong> Multivariate regression identified Pb, Fe, Cr, and Co as the most consistent independent predictors of biomarker alterations, with the NSE model demonstrating the highest explanatory power.</div></div><div><h3>Conclusion</h3><div>Chronic occupational exposure to toxic metal mixtures is associated with significant alterations in neuronal biomarkers indicative of possible neurotoxic damage in an asymptomatic population, reflecting preclinical neural stress rather than established disease. The inverse relationship between selenium and neuronal injury markers suggests a potential protective role, although this requires further confirmation. These findings support the use of an integrated multi-biomarker approach as a sensitive early warning tool for monitoring neurotoxic risks in industrial populations.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103469"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosomal dysfunction contributes to lead (Pb) and high-fat diet (HFD)-induced neuronal apoptosis: A link with cathepsin B","authors":"Yongke Yuan ,&nbsp;Mengchen Liu ,&nbsp;Mengdi Zhai ,&nbsp;Meijia Wu ,&nbsp;Wenhui Zhang ,&nbsp;Yongjuan Xin ,&nbsp;Yue Ba ,&nbsp;Yu Zhang ,&nbsp;Lin Han ,&nbsp;Lihua Gao ,&nbsp;Hui Huang","doi":"10.1016/j.neuro.2026.103462","DOIUrl":"10.1016/j.neuro.2026.103462","url":null,"abstract":"<div><div>Environmental lead (Pb) exposure and high-fat diet (HFD) intake are known to trigger massive neuronal apoptosis that contributes to neurologic dysfunction. Previous studies mainly focused on isolated mitochondrial dysfunction, autophagy-lysosomal pathway damage, and neuronal apoptosis from Pb or HFD. Nevertheless, the precise role of the lysosomal and proteasomal clearance processes in promoting neuronal cell death induced by Pb and HFD remains unclear. In this study, male Sprague-Dawley (SD) rats were employed to elucidate the mechanisms underlying Pb-induced neurotoxic mitochondrial apoptosis and to investigate the effects of co-exposure to HFD. <em>In vitro</em>, PC12 cells were treated with Pb and palmitic acid (PA) to mimic the <em>in vivo</em> conditions. Specifically, such exposures prompted the translocation of cathepsin B (CTSB) from lysosomes to the cytosol and downregulation of lysosomal-associated membrane protein 1 (LAMP1), ATPase H⁺ Transporting V1 Subunit A (ATP6V1A), and Bcl-2 within rat cortex. In contrast, the levels of pro-apoptotic factors including BID, Bax, mitochondrial cytochrome C (Cyt C), and caspase 3 were significantly elevated. We also observed a significant decrease in the fluorescence intensity of lysosomes while lysosomal pH was ascertained to have ascended appreciably. Concurrently, CTSB inhibition by CA-074 me prevented neural apoptosis processing triggered by Pb and/or PA via mitigating lysosomal damage and mitochondrial Cyt C translocation, indicating that CTSB is a key mediator in the apoptotic process induced by Pb and HFD.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103462"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}