Neurotoxicology最新文献

{"title":"Proposed key characteristics of neurotoxic chemicals","authors":"Pamela J. Lein ,&nbsp;Aaron B. Bowman ,&nbsp;Zhengyu Cao ,&nbsp;Monica Carson ,&nbsp;Brenda Eskenazi ,&nbsp;Ellen Fritsche ,&nbsp;G. Jean Harry ,&nbsp;Thomas Hartung ,&nbsp;Isaac N. Pessah ,&nbsp;William Slikker Jr. ,&nbsp;Lauren Zeise ,&nbsp;Martyn T. Smith","doi":"10.1016/j.neuro.2025.103370","DOIUrl":"10.1016/j.neuro.2025.103370","url":null,"abstract":"<div><div>A critical component of evaluating whether a chemical can cause human neurotoxicity is hazard identification, which typically involves a comprehensive literature search to identify and synthesize epidemiological, animal, and mechanistic data for the chemical of interest. The key characteristics (KCs) concept has proven to be a useful tool for searching, organizing, and evaluating mechanistic data for hazard identification. KCs are the established chemical and biological properties of known human neurotoxic agents based on understanding of their mechanisms of neurotoxicity. KCs were originally developed for carcinogens but have now also been published for endocrine- and metabolism-disruptors and various organ-selective toxic chemicals. To identify KCs associated with neurotoxic chemicals, an expert committee was convened to consider current mechanistic understanding of chemicals known to be neurotoxic in humans with the goal of identifying established molecular and cellular actions of neurotoxic chemicals. After extensive discussion, the committee reached consensus on 10 KCs. Here, we describe the 10 proposed KCs and provide chemical-related examples to support their inclusion. Several important considerations emerged from the committee’s deliberations including: (1) a mechanistic action need not be unique to neurotoxicity to be considered a KC of neurotoxic chemicals; (2) many, if not most, neurotoxic chemicals exhibit multiple KCs, and the relative importance of any specific KC and/or its causal relationship to other KCs may vary depending on life stage at the time of exposure and/or the exposure paradigm; and (3) data indicating a chemical exhibits one or more KCs of neurotoxic chemicals suggests that the chemical poses a neurotoxic hazard but does not necessarily identify the risk that the chemical presents to humans. These considerations, as well as potential applications of KCs in neurotoxicology, are discussed. The committee also strongly recommended that the list of proposed KCs of neurotoxic chemicals be viewed as a “living document” that is reviewed and revised in response to emerging insights on mechanisms of neurotoxicity, as well as lessons learned from the application of these proposed KCs, including but not limited to their use as a tool for the systemic identification and review of mechanistic data for assessment of neurotoxic hazards.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103370"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827615","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":"Soman-induced neurotoxicity in human iPSC-derived cerebral organoids: A whole-transcriptome analysis of ceRNA regulatory networks","authors":"Yue Wei ,&nbsp;Jingjing Shi ,&nbsp;Xuejun Chen ,&nbsp;Zhanbiao Liu ,&nbsp;Qian Jin ,&nbsp;Ruihua Zhang ,&nbsp;Tong Shi ,&nbsp;Chen Wang ,&nbsp;Liqin Li","doi":"10.1016/j.neuro.2025.103373","DOIUrl":"10.1016/j.neuro.2025.103373","url":null,"abstract":"<div><div>Traditional animal models present challenges in fully elucidating chemical-induced neurotoxicity and its underlying mechanisms in humans due to physiological and genetic differences between species. To transcend inherent species limitations, cerebral organoids were differentiated from human induced pluripotent stem cells as a human-relevant model to delineate the neurotoxic profile of soman, classified among the most potent organophosphorus nerve agents. Organoid cell diversity and architecture were assessed via immunofluorescence and single-cell RNA sequencing. A 24-hour soman exposure elicited significant nerve damage in cerebral organoids, characterized by TUNEL assay-confirmed apoptosis and Fluoro-Jade C-stained neuronal degeneration. Whole transcriptome sequencing revealed 1012 differentially expressed mRNAs, 78 differentially expressed miRNAs and 203 differentially expressed long non-coding RNAs between the soman-exposed and control groups. Bioinformatics research suggested that the differentially expressed mRNAs were linked to axon guidance, long-term potentiation, and calcium signaling pathways. Furthermore, we constructed a competive endogenous RNA network including lncRNAs, miRNAs, and mRNAs, identifying two hub lncRNAs, two hub miRNAs, and 16 key mRNAs. This regulatory network implicates soman neurotoxicity in neuroinflammation and synaptic plasticity alterations, while validating glutamate receptor dysregulation and calcium homeostasis disruption as critical pathological mediators. Concurrently, it identifies the associated lncRNAs and miRNAs as potential biomarkers and therapeutic targets for soman-induced neuronal injury. Our findings elucidate the neurotoxic effects of soman in cerebral organoids at tissue, cellular, gene expression, and regulatory network levels. This work advances our knowledge of the underlying biological processes of soman exposure by offering new insights into prospective biomarkers and treatment targets.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103373"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145842154","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":"FTH1-mediated iron dysregulation and ferroptosis in manganese-induced neurotoxicity","authors":"Xiaoli Ma ,&nbsp;Shengtao Wei ,&nbsp;Fangfei Li ,&nbsp;Guiqiang Liang ,&nbsp;Jian Wang ,&nbsp;Yunfeng Zou","doi":"10.1016/j.neuro.2025.103367","DOIUrl":"10.1016/j.neuro.2025.103367","url":null,"abstract":"<div><div>Excessive environmental manganese (Mn) exposure has been implicated in neurological disorders, with iron homeostasis imbalance emerging as a crucial aspect in neurodegeneration diagnosis and therapy. However, the intricate mechanisms underlying Mn-induced neurotoxicity, particularly the interplay between ferroptosis and iron dysregulation, remain elusive. This study investigated the role of ferritin heavy chain 1 (FTH1)-mediated iron homeostasis disruption in manganese (Mn)-induced neurotoxicity and ferroptosis. Mn exposure was found to disrupt iron homeostasis and induce ferroptosis in neuronal cells by downregulating FTH1 expression. Elevated intracellular and mitochondrial Fe²⁺ and reactive oxygen species (ROS) levels, along with increased lipid peroxidation, were observed in Mn-treated Neuro-2a (N2a) cells. Notably, both deferoxamine (DFO) treatment and FTH1 overexpression alleviated iron imbalance and reduced ferroptotic markers. Our findings suggest that Mn triggers neuronal ferroptosis via FTH1-mediated oxidative stress and iron dysregulation, highlighting the potential of iron ion inhibitors or FTH1 modulation as therapeutic strategies. This study contributes to the understanding of Mn-induced neurotoxicity and provides insights into the mechanisms underlying ferroptosis in neuronal cells.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103367"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781622","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":"Understanding similarities and differences of FASD in three zebrafish populations","authors":"João Paulo Medeiros Mamede ,&nbsp;Maria Clara Galvão-Pereira ,&nbsp;Augusto Monteiro de Souza ,&nbsp;Silvia Regina Batistuzzo de Medeiros ,&nbsp;Ana Carolina Luchiari","doi":"10.1016/j.neuro.2025.103369","DOIUrl":"10.1016/j.neuro.2025.103369","url":null,"abstract":"<div><div>Alcohol consumption during pregnancy is a major public health concern, as prenatal exposure to ethanol can disrupt embryonic development and lead to Fetal Alcohol Spectrum Disorders (FASD). These disorders are characterized by a wide range of morphological, behavioral, and cognitive impairments, which variability across individuals is strongly influenced by genetic background and environmental conditions. Animal models, particularly zebrafish, offer a powerful tool to investigate how such factors modulate susceptibility to alcohol. In this study, we examined the effects of embryonic alcohol exposure in three zebrafish populations (AB, TU, and OB), assessing developmental parameters, behavior, and gene expression. Results showed that the OB population exhibited higher mortality and pronounced alterations in genes related to metabolism and neurotransmission; AB displayed reduced body and eye growth, along with increased social cohesion under alcohol exposure; while TU was more vulnerable to behavioral effects despite showing morphological resilience. Furthermore, the expression of key genes such as <em>sox2, th1, drd1b, gabra1</em><strong>,</strong> and <em>bdnf</em> varied according to both population and alcohol concentration. These findings emphasize the relevance of genetic differences in modulating alcohol’s impact and reinforce zebrafish as a valuable translational model for FASD research, paving the way for more refined diagnostic and therapeutic approaches.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103369"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799360","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":"Power calculations for larval zebrafish in light-dark transition test for developmental neurotoxicity","authors":"Kathryn S. Konrad ,&nbsp;Katherine Allen-Moyer ,&nbsp;Lee Ellis ,&nbsp;Ellen Hessel ,&nbsp;Oihane Jaka ,&nbsp;Arantza Muriana ,&nbsp;Beatriz Molina Martínez ,&nbsp;Ana del Pozo ,&nbsp;Valentina Schiavone ,&nbsp;Vincenzo Di Donato ,&nbsp;Claudia Miguel Sanz ,&nbsp;Lisa Truong ,&nbsp;Robyn Tanguay ,&nbsp;Keith R. Shockley ,&nbsp;Kristen Ryan ,&nbsp;Jui-Hua Hsieh","doi":"10.1016/j.neuro.2025.103371","DOIUrl":"10.1016/j.neuro.2025.103371","url":null,"abstract":"<div><div>The link between environmental chemical exposures and neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder underscores the need to develop efficient developmental neurotoxicity (DNT) assays for chemical evaluation. The zebrafish Light-Dark Transition Test (LDTT) assesses changes in zebrafish larval behavioral responses to chemical exposure by recording their distance moved under alternating light and dark conditions. To gain confidence in classifying a chemical as having a DNT effect for the LDTT assay, it is important to determine the minimum sample size to obtain a robust behavioral response. We calculated statistical power under common models based on LDTT data collected from four laboratories using standard protocol parameters, where each 96-well plate contained 5–7 test concentrations and 12–16 vehicle control wells (1 larva/well). Power calculations were conducted to identify concentration effects using t-tests, analysis of variance (ANOVA), and repeated measures ANOVA (RMANOVA), with data from four endpoints: Total Distance, Movement Similarity, Distance Change, and Distance Shift. The tests showed the highest power for the Movement Similarity and Distance Change endpoints, which had the lowest intra- and inter-laboratory variability, resulting in a smaller necessary sample size to estimate dose effects. The use of these endpoints more than doubled the power of the statistical tests for the Total Distance endpoints using the same sample size and typically required between 8 and 32 samples to achieve 80 % power at a 20 % effect size. This work demonstrates that the LDTT can be improved for detecting DNT effects by careful consideration of endpoint selection, data transformation, and type of statistical test.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103371"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834322","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":"Formononetin protects against oxaliplatin-induced peripheral neurotoxicity via Nrf2/HO-1 antioxidant pathway without impairing anticancer efficacy","authors":"Yang-Chen Chang ,&nbsp;Wan-Hsuan Lin ,&nbsp;Horng-Huey Ko ,&nbsp;Yi-Ching Lo ,&nbsp;Hsun-Shuo Chang ,&nbsp;Hui-Ching Lin ,&nbsp;Yih-Fung Chen","doi":"10.1016/j.neuro.2025.103368","DOIUrl":"10.1016/j.neuro.2025.103368","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger <em>N</em>-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103368"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781620","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":"Cadmium exposure at low environmental levels induces cognitive decline in aged male mice","authors":"Gahyun Lim ,&nbsp;Ho Young Lee ,&nbsp;Zachery R. Jarrell ,&nbsp;Seong Su Kang ,&nbsp;Dean P. Jones ,&nbsp;Young-Mi Go","doi":"10.1016/j.neuro.2025.103376","DOIUrl":"10.1016/j.neuro.2025.103376","url":null,"abstract":"<div><div>Cadmium (Cd) is a neurotoxic metal that accumulates via dietary, environmental, and occupational sources and is closely linked to oxidative stress and neuroinflammation. Little is known about the mechanistic effects of low-dose environmental Cd as found in the human diet on cognition in aged mice. Male aged mice (C57BL/6 J, 20 months old) received water with or without 3.3 mg/L Cd for 12 weeks. Cognitive function was assessed using the Y-maze, thiol/disulfide redox states were analyzed by high-performance liquid chromatography, brain Cd levels were determined by inductively coupled plasma mass spectrometry, hippocampal morphology was examined by histological analysis, and metabolomics was analyzed by high-resolution mass spectrometry. Low-dose environmental Cd exposure led to brain Cd accumulation and impaired cognitive function in aged male mice, accompanied by reduced hippocampal neuronal density in the cornu ammonis 1 region. Cd shifted the plasma redox toward a more oxidizing state, along with elevated hydroxytetradecanoic acid and decreased N-oleoylethanolamine in the brain. Cd decreased bioactive signaling lipids (lysophosphatidic acid, oleamide, sphingomyelin, sphingosine) and selectively acylcarnitine levels in the brain. Increased pyridoxal phosphate and lipoamide and decreased glutamine brain levels suggest potential compensatory responses. Exposure to low environmental levels of Cd in aged male mice disrupts redox homeostasis and systemic lipid metabolism, leading to cognitive decline, accompanied by compensatory responses. The results suggest that environmental Cd at levels found in the human diet could contribute to cognitive decline.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103376"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145857364","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":"Inhibitory effects of (synthetic) cannabinoids and (designer) benzodiazepines on spontaneously active neuronal networks of primary rat cortical cultures in vitro","authors":"J. Pepijn Wopken ,&nbsp;Jack R. Thornton ,&nbsp;Regina G.D.M. van Kleef ,&nbsp;Remco H.S. Westerink","doi":"10.1016/j.neuro.2025.103379","DOIUrl":"10.1016/j.neuro.2025.103379","url":null,"abstract":"<div><div>The use of novel psychoactive substances (NPS) has been increasing over the last 20 years. Given the coinciding increasing number of health incidents, it is of paramount importance to comprehend the neurotoxic hazards associated with these often potent but poorly characterized designer drugs. The objective of this study was therefore to investigate the neuromodulatory effects of various (designer) drugs, including cannabidiol (CBD), a synthetic cannabinoid receptor agonist (RCS-4), three canonical benzodiazepines (diazepam, oxazepam, and lorazepam) and two designer benzodiazepines (flunitrazolam and fluetizolam). To that aim, we measured changes in spontaneous neuronal activity following acute drug exposure in primary rat cortical cultures grown on microelectrode arrays (MEAs). Acute exposure to ≥ 3 µM CBD resulted in a concentration-dependent decrease of all major activity parameters, such as the number of spikes, the number of bursts, the number of spikes in a burst, burst duration, the number of network bursts, the number of spikes in a network burst, and network burst duration. These effects were comparable to those observed following acute exposure to the synthetic cannabinoid receptor agonist RCS-4, which inhibited neuronal activity at ≥ 1 µM. At the highest concentration, the decrease in neuronal activity was paralleled by an increase in burst duration. The three canonical benzodiazepines (diazepam, oxazepam, and lorazepam) concentration-dependently decreased neuronal activity (number of spikes, number of bursts and number of network bursts) with lowest observed effect concentrations (LOECs) of 0.1 µM, 1 µM and 0.1 µM, respectively. The decrease in neuronal activity was paralleled by an increase in burst duration, which was particularly profound for diazepam. The two designer benzodiazepines (flunitrazolam, and fluetizolam) potently decreased neuronal activity with LOECs of 0.01 µM and 0.03 µM, respectively. Comparable to the canonical benzodiazepines, the decrease in neuronal activity was paralleled by a marked increase in burst duration. Our findings demonstrate the applicability of MEA recordings for neurotoxicity assessment and potency ranking of diverse (designer) drugs. The strong potency of some of these drugs is particularly concerning and underscores the urgent need for better regulation and control of these substances to safeguard public health.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103379"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885306","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":"Methylene blue protects oligodendroglial cell models of multiple systems atrophy against hydrogen peroxide-mediated oxidative stress","authors":"Kayla M. Elias,&nbsp;William F. Muliawan,&nbsp;Muriel J. Moon,&nbsp;Gunnar F. Kwakye","doi":"10.1016/j.neuro.2025.103366","DOIUrl":"10.1016/j.neuro.2025.103366","url":null,"abstract":"<div><div>Multiple Systems Atrophy (MSA) is a rare, neurodegenerative disorder associated with impaired alpha (α)-synuclein (α-syn) protein function. α-syn can aggregate within oligodendrocytes, activating oxidative stress pathways and ultimately leading to cell death. Point mutations in the α-syn gene (<em>SNCA</em>) are associated with MSA–A53E and G51D, but cases are mainly idiopathic. Methylene Blue (MB) is an organic dye that has been demonstrated to attenuate oxidative stress in cell models of Parkinson’s and Huntington’s disease. We hypothesized that MB would protect α-syn stably transfected oligodendroglial cell models of MSA against hydrogen peroxide (H₂O₂)-induced cellular stress. We used four α-syn stably transfected OLN-93 rat oligodendroglial cell lines expressing either an empty plasmid (EP), overexpressed humanized wild-type α-syn (WT-α-syn), or humanized α-syn with either point mutation (A53E-α-syn, G51D-α-syn). Upon 3 h (h) pre-treatment of OLN-93 cells with MB, followed by 1 h or 3 h exposure to H₂O₂, we report that MB does not enact toxic effects but rather substantially improves cell viability and metabolic capability and lowers H₂O₂-induced cell death in the OLN-93 MSA cell models. MB also significantly reduced H₂O₂-induced early (1 h) ROS production in the cytosol and mitochondria and the expression of oxidative stress and modified antioxidant-related proteins, including Nuclear factor erythroid 2-related factor 2 (NRF2), affiliated Kelch-like ECH-associated protein 1 (KEAP1), Heme Oxygenase 1 (HO1), and Adenosine Monophosphate-Activated Protein Kinase (AMPK) after 3 h exposure. Our current data suggest a novel glioprotective role for MB in MSA pathology, specifically against H₂O₂-mediated oxidative injury, and invite future work to investigate MB glioprotection in other <em>in vivo</em> MSA models.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103366"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781557","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":"Long-term air pollution exposure and cognitive impairment risk in Chinese middle-aged and older adults","authors":"Shengqiang Xie ,&nbsp;Shichao Su ,&nbsp;Wenxuan Li ,&nbsp;Yanteng Li ,&nbsp;Fangbin Hao ,&nbsp;Gang Cheng ,&nbsp;Jianning Zhang","doi":"10.1016/j.neuro.2025.103364","DOIUrl":"10.1016/j.neuro.2025.103364","url":null,"abstract":"<div><div>This prospective cohort study quantified the longitudinal associations between long-term exposure to multiple air pollutants and cognitive impairment risk among China's middle-aged and older adults. Leveraging data from 10,584 participants in the China Health and Retirement Longitudinal Study (2011–2020), we assessed high-resolution (1-km) annual exposures to particulate matter (PM₁, PM_2.5, PM₁₀), nitrogen dioxide (NO₂), and ozone (O₃) using satellite-based models. Cognitive impairment was defined through education-stratified Chinese Mini-Mental State Examination thresholds. Time-varying Cox proportional hazards models revealed significant dose-response relationships: per 10-μg/m³ increase, PM₁ (HR=1.078, 95 % CI:1.022–1.136), PM_2.5 (HR=1.042, 1.015–1.070), PM₁₀ (HR=1.038, 1.022–1.054), and NO₂ (HR=1.129, 1.061–1.200) elevated cognitive impairment risk, while O₃ showed no association (HR=0.878, 0.743–1.038). Three-year exposure windows intensified effects for NO₂ (HR=1.053) and PM₁ (HR=1.034). Multi-pollutant models demonstrated PM₁₀'s exceptional robustness (e.g., PM₁₀+NO₂ HR=1.055), whereas NO₂ attenuated finer particulate associations. Critical vulnerability emerged among adults with education below junior high (PM₁ HR=1.30), rural residents (PM₁₀ HR=1.21), those aged 60–69 years (peak PM₁ HR=1.28), and uninsured individuals (PM₁ HR=1.22). Strictly linear exposure-response relationships (all Pnonlinear&gt;0.05) indicated no safe thresholds. These findings advocate prioritizing control of PM₁₀ (particles ≤10 μm) alongside mitigation of traffic-related pollutants, while implementing targeted interventions for vulnerable educationally disadvantaged and rural populations to mitigate dementia burden.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103364"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752180","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}