Neurotoxicology最新文献

{"title":"The “route cause” of methotrexate-induced brain structure changes in a juvenile mouse model: Comparison of systemic and CNS-targeted chemotherapy","authors":"Sun Eui Choi ,&nbsp;Tiffany Ayoub ,&nbsp;Gail Lee ,&nbsp;Anne L. Wheeler ,&nbsp;Sharon L. Guger ,&nbsp;Rosanna Weksberg ,&nbsp;Shinya Ito ,&nbsp;Russell J. Schachar ,&nbsp;Johann Hitzler ,&nbsp;Brian J. Nieman","doi":"10.1016/j.neuro.2025.103363","DOIUrl":"10.1016/j.neuro.2025.103363","url":null,"abstract":"<div><div>Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and while five-year survival rates exceed 90 %, survivors display neurocognitive deficits. Magnetic resonance imaging (MRI) measurements indicate smaller volume across the brain in survivors compared to typically developing peers. Methotrexate (MTX) is the backbone of ALL chemotherapy and is delivered via various administration routes including systemic and central nervous system (CNS) targeted routes. The relative toxicities between routes have not been systematically compared. Our study aims to compare brain volume changes after systemic and CNS-targeted MTX treatment using MRI in a juvenile mouse model. MTX treatment was delivered at postnatal day 17 (P17) and P19 either via an intrathecal (IT) or intravenous (IV) injection, resulting in four total groups for the study: IV MTX (n = 14), IV saline (n = 16), IT MTX (n = 54), and IT saline (n = 51). MRI was performed pre-treatment at P14 and longitudinally after treatment at P24, P42, and P63. IT MTX was probed at a range of doses (0.5–5.0 mg/kg). Volumes of 183 segmented brain structures were compared between groups. Whole brain volume decreased after IT MTX (5.0 mg/kg) and IV MTX at P24. The number of structures significantly affected after IT MTX was highly dependent on dose. Comparison of systemic and intrathecal delivery routes revealed that systemic MTX had a wider impact on brain morphology than did IT MTX treatment, particularly at clinically relevant doses of IT MTX. This finding provides important insight into the mechanisms that likely underlie MTX-induced neurotoxicity and focuses potential interventions on systemic toxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103363"},"PeriodicalIF":3.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743596","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":"2025-12-11","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}

{"title":"Air pollution and Parkinson’s disease: A prospective cohort study with sex-stratified analysis in the UK biobank","authors":"Jianghong Liu ,&nbsp;Michael Pan ,&nbsp;Haoer Shi ,&nbsp;McKenna Sun ,&nbsp;Aimin Chen ,&nbsp;Rui Feng","doi":"10.1016/j.neuro.2025.103353","DOIUrl":"10.1016/j.neuro.2025.103353","url":null,"abstract":"<div><div>Air pollution has been suggested as a potential environmental risk factor for Parkinson’s disease (PD), but findings remain inconsistent, and sex-specific effects are understudied. This study examined associations between exposure to nitrogen dioxide (NO₂) and particulate matter ≤ 10 µm (PM₁₀) and incident PD, using data from the UK Biobank. Annual levels of NO₂ (2005–2007) and PM₁₀ (2007) were estimated based on residential addresses. Logistic regression models assessed the associations between air pollution exposure and PD onset, adjusting for age, sex, smoking status, and family history of PD. Competing risk models and inverse probability weighting were applied to address survivorship bias and missing data. Sex-stratified analyses explored potential differences by sex. Among 210,417 participants (mean follow-up = 9.17 years), 2592 developed PD. Higher exposure to both NO₂ and PM₁₀ was associated with increased PD risk. In sex-specific models, the associations remained significant in males but not in females. Competing risk models confirmed elevated PD risk with NO₂ (HR = 1.05; 95 % CI: 1.01–1.09) and PM₁₀ (HR = 1.08; 95 % CI: 1.03–1.13) in the overall cohort, with similar or stronger associations in males (NO₂: HR = 1.07; 95 % CI: 1.02–1.13; PM₁₀: HR = 1.07; 95 % CI: 1.02–1.14). In conclusion, long-term exposure to NO₂ and PM₁₀ was linked to increased PD risk, particularly in males. These findings highlight the importance of incorporating sex-specific analyses in environmental research on PD.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103353"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564727","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":"Neurotoxic potential of imatinib in aquatic vertebrates: Behavioral and biochemical disruptions in zebrafish","authors":"Gustavo Axel Elizalde-Velázquez ,&nbsp;Selene Elizabeth Herrera-Vázquez ,&nbsp;Leobardo Manuel Gómez-Oliván ,&nbsp;Nely SanJuan-Reyes ,&nbsp;José Manuel Orozco-Hernández ,&nbsp;Ana María Téllez-López ,&nbsp;Sandra García-Medina ,&nbsp;Marcela Galar-Martínez","doi":"10.1016/j.neuro.2025.103352","DOIUrl":"10.1016/j.neuro.2025.103352","url":null,"abstract":"<div><div>Imatinib mesylate (IM), a first-generation tyrosine kinase inhibitor (TKI), remains a global standard in leukemia treatment. However, its environmental persistence and structural homology with conserved kinase domains in aquatic vertebrates raise concerns about potential off-target effects in non-target organisms. This study investigates, for the first time, the neurotoxic impact of IM on adult zebrafish (<em>Danio rerio</em>), employing a multidisciplinary approach that integrates behavioral assays, enzymatic analysis, oxidative stress biomarkers, and gene expression profiling. Exposure to IM induced a distinct anxiety-like behavioral phenotype in zebrafish, characterized by increased bottom-dwelling, heightened locomotor activity, and delayed exploration of upper tank zones in the Novel Tank Test. Concurrently, IM elicited a concentration-dependent inhibition of brain acetylcholinesterase (AChE) activity without classical active-site interaction, suggesting an indirect mechanism potentially linked to oxidative stress. Biochemical analyses confirmed increased lipid and protein oxidation, decreased antioxidant enzyme activities (SOD, CAT), and transcriptional upregulation of pro-apoptotic markers (bax, p53, casp3), alongside suppression of oxidative defense and energy-regulatory genes (nrf1, nrf2, prkaa1). The downregulation of prkaa1, encoding the catalytic subunit of AMP-activated protein kinase (AMPK), implicates disrupted metabolic adaptation and redox homeostasis as central features of IM-induced toxicity. Together, these findings suggest that IM provokes neurobehavioral disturbances in zebrafish through mitochondrial dysfunction, impaired AMPK signaling, oxidative stress, and secondary inhibition of AChE, ultimately leading to cholinergic dysregulation and anxiety-like responses.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103352"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588165","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 effects of doxorubicin on blood-brain barrier integrity in hCMEC/D3","authors":"Chadni Patel ,&nbsp;Christina Glytsou ,&nbsp;Mi-Hyeon Jang ,&nbsp;Peter D. Cole","doi":"10.1016/j.neuro.2025.103355","DOIUrl":"10.1016/j.neuro.2025.103355","url":null,"abstract":"<div><div>Current chemotherapy regimens have significantly improved overall survival for children with cancer. However, these treatments are associated with detrimental side effects like chemotherapy-induced cognitive impairment (CICI), or “chemobrain.” Measurable deficits in cognitive function persist years after treatment. Specifically, doxorubicin (DOXO), a commonly used chemotherapeutic agent in curative regimens for children with cancer, plays a pivotal role in the development of CICI, even though it doesn’t cross the blood-brain barrier (BBB). Using a juvenile rat model, we found that DOXO compromises the BBB integrity. To further address the poorly understood mechanism of DOXO-related CICI, we utilized human cerebral microvascular endothelial cells (hCMEC/D3) to study the changes induced by DOXO in BBB integrity. RNA sequencing after DOXO exposure demonstrated changes in inflammatory pathways that may play a critical role in BBB integrity. Upon DOXO treatment, there was an increase in the secretion of proinflammatory cytokines including interleukin-6 (IL-6), regulated on activation, normal T cell expressed and secreted (RANTES) and granulocyte-macrophage colony stimulating factor (GM-CSF). DOXO induced the activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK1/2), and cAMP response element binding protein (CREB). Using xCELLigence Real Time Cell Analysis, we found that DOXO doesn’t immediately compromise the barrier in hCMEC/D3. Additionally, we found that DOXO treatment significantly decreases maximal respiration and the spare respiratory capacity in hCMEC/D3 cells, indicating mitochondrial bioenergetic defects. Our findings provide critical insights on how DOXO impacts the BBB and builds a foundation for developing preventative measures that may improve the quality of life for patients.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103355"},"PeriodicalIF":3.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564743","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 moderated mediation of tau phosphorylated sites in the association between occupational aluminum exposure and cognitive function","authors":"Yujun Ma ,&nbsp;Guangsen Feng ,&nbsp;Shihui Guo ,&nbsp;Jing Song ,&nbsp;Linping Wang ,&nbsp;Huifang Zhang ,&nbsp;Jinzhu Yin ,&nbsp;Xiaoting Lu","doi":"10.1016/j.neuro.2025.103354","DOIUrl":"10.1016/j.neuro.2025.103354","url":null,"abstract":"<div><div>This study aimed to elucidate the associations among occupational aluminum exposure, plasma phosphorylated tau (P-tau), and cognitive function, with particular attention to the modulatory effects of key factors involved in tau protein synthesis and degradation. A total of 208 aluminum plant workers were enrolled, with assessments conducted for plasma aluminum concentrations, cognitive performance, levels of phosphorylated tau (P-tau181 and P-tau231), and biomarkers related to tau synthesis and degradation pathways. Elevated plasma aluminum levels were inversely associated with scores on cognitive assessments, including the MMSE, DSP, DSR, DS, FOM, and CDT, while showing positive associations with STRA and STRF scores. Higher plasma aluminum concentrations were also significantly associated with increased levels of P-tau181 and P-tau231. P-tau181 and P-tau 231 concentrations are negatively correlated with MMSE, DSP, DSR, DS, and FOM scores, and positively correlated with STRA, STRF, and CDT scores. Mediation analysis revealed that P-tau181 and P-tau231 were statistically consistent with mediating 16.6 % and 35.9 % of the association between aluminum exposure and MMSE scores, respectively, with P-tau231 demonstrating a stronger mediating effect. Moderated mediation analysis further indicated that factors regulating tau synthesis had a more pronounced influence on this mediating role than those involved in degradation[Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A, CDK5)= 0.016 &gt; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CHIP, Ub)= 0; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A, CDK5)= 0.027 &gt; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CHIP, Ub)= 0], with PP2A-mediated regulation exerting a greater effect than CDK5[Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A)= 0.021 &gt; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CDK5)= 0.006; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A)= 0.016 &gt; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CDK5)= 0.008]. These results are statistically consistent with the hypothesis that P-tau231 and PP2A are critical targets for early intervention and biomonitoring in the context of aluminum-related cognitive impairment, offering novel directions for occupational health risk management and protection.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103354"},"PeriodicalIF":3.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564750","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":"Corrigendum to “Micro- and nanoplastics as neurotoxicants: Mechanistic insights from particle morphology, circadian disruption, and potential neurodegeneration – A state-of-the-art narrative review” [Neurotoxicology 111 (2025) 103338]","authors":"Angelo M. Jamerlan,&nbsp;Seong Soo A. An,&nbsp;John P. Hulme","doi":"10.1016/j.neuro.2025.103351","DOIUrl":"10.1016/j.neuro.2025.103351","url":null,"abstract":"","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103351"},"PeriodicalIF":3.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516642","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":"Blockade of NMDA-receptors mitigates autistic and cognitive behaviors via modulation of TLR-4/NLRP3 inflammasomes and microglia/astrocyte crosstalk in rat model of autism","authors":"Sawsan Aboul-Fotouh ,&nbsp;Sohir M. Zohny ,&nbsp;Ghada AM. Hassan ,&nbsp;Abeer M. Eissa ,&nbsp;Heba Hamed Elshahawi ,&nbsp;Sahar M. Abdelraouf ,&nbsp;Manar Yehia Ahmed ,&nbsp;Mohammed R. Rabei ,&nbsp;Fatma E. Hassan ,&nbsp;Ahmed Nageh Mahmoud ,&nbsp;Eman H. Eltantawy ,&nbsp;Shaimaa khedr ,&nbsp;Yasmin Ramadan ,&nbsp;Maha Khaled El-Ashry ,&nbsp;Esraa M. Elnahas","doi":"10.1016/j.neuro.2025.103350","DOIUrl":"10.1016/j.neuro.2025.103350","url":null,"abstract":"<div><div>Converging evidence proposed NMDA-receptor dysfunction as a real challenge underlying excitotoxicity implicated in neurological changes of autism spectrum disorder (ASD). Nevertheless, the role of NMDA receptors in relation to toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3), and microglia/astrocyte activity in autism-related neuroinflammation has not been investigated hitherto.</div></div><div><h3>Methods</h3><div>The present study was designed to explore the potential role of NMDA-receptor blockade in autism by chronic memantine (MEM) treatment (20 mg/kg/d, i.p.) in male Wistar rats, prenatally exposed to valproic acid (VPA).</div></div><div><h3>Results</h3><div>Prenatal VPA exposure exhibited autistic-like core symptoms and cognitive deficits that were accompanied by gene and protein overexpression of NMDAR-GluN1 &amp; GluN2B subunits, TLR-4, and NF-κB in the prefrontal cortex (PFC). Additionally, VPA increased oxidative/nitrosative stress and inflammasome markers (NLRP3, procaspase-1, and caspase-1). Similarly, histopathological and immunohistochemical studies confirmed neurodegenerative changes, together with microglia/astrocyte reactivity, increased inflammatory and apoptotic markers, along with elevated Ki-67, β-amyloid expression, and the number of neurofibrillary tangles in prefrontal and cerebellar cortices. Chronic treatment with MEM ameliorated the above-mentioned behavioral, neurochemical, and histopathological abnormalities, and interestingly, these effects significantly correlated with NMDAR expression.</div></div><div><h3>Conclusion</h3><div>To the author's knowledge, this study is the first to confirm the potential modulatory effect of NMDA-receptor blockade, via memantine, on TLR-4/NLRP3 inflammasome pathway and microglia/astrocyte crosstalk, in relation to its role in mitigating the autistic behaviors and cognitive deficits in autism. These findings therefore lend further support to the hypothesis that NMDA-receptor blockade may represent a novel and promising pharmacotherapeutic strategy for ASD.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103350"},"PeriodicalIF":3.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513489","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":"Mechanisms by which neuroinflammation modulates GABAergic neurotransmission in the hippocampus of hyperammonemic rats","authors":"María Sancho-Alonso ,&nbsp;Paula Izquierdo-Altarejos ,&nbsp;Gergana Mincheva ,&nbsp;Marta Llansola ,&nbsp;Vicente Felipo","doi":"10.1016/j.neuro.2025.103345","DOIUrl":"10.1016/j.neuro.2025.103345","url":null,"abstract":"<div><div>Hyperammonemia is a main contributor to cognitive impairment in patients with hepatic encephalopathy. Hyperammonemia-induced cognitive impairment is mediated by neuroinflammation and alteration of glutamatergic and GABAergic neurotransmission in hippocampus. Hyperammonemia enhances GABAergic neurotransmission in hippocampus but the role of neuroinflammation remains unknown. In cerebellum of hyperammonemic rats enhanced S1PR2-BDNF-TrkB pathway activation mediates enhancement of GABAergic neurotransmission. In hippocampus of hyperammonemic rats, the increase of IL-1β and Src kinase activation alters glutamatergic neurotransmission. The aims of this work were to assess if neuroinflammation is responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats and to identify the underlying mechanisms. We used ex vivo hippocampal slices from control and hyperammonemic male rats and assessed the effects of blocking the S1PR2, the IL-1 receptor, TrkB or of inhibiting the protein kinases Src or PI3K on glutamate decarboxylases and GABA content and on membrane expression of GABA_A receptor, GABA transporters and chloride co-transporters. Blocking the S1PR2-IL-1β-Src-BDNF-TrkB-PI3K pathway at any of its steps reversed the reduced membrane expression of GABA transporters, which would increase extracellular GABA, and the increased membrane expression of most of the GABA_A receptor subunits analyzed, which also enhances GABAergic neurotransmission. This would be mediated by increasing the content of gephyrin and phosphorylation of the β3 subunit of GABA_A receptors. The identification of this pathway as the origin of the enhanced GABAergic neurotransmission provides several therapeutic targets to reverse cognitive impairment in hyperammonemia and hepatic encephalopathy and, likely, in other pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103345"},"PeriodicalIF":3.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465586","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":"Metal and metalloid exposure and cognitive function among copper mine workers: A three-year longitudinal study","authors":"Narjes Soltani ,&nbsp;Tabandeh Sadeghi ,&nbsp;Majid Saadloo ,&nbsp;Mohammad Reza Baneshi ,&nbsp;Soghra Akbari Chermahini ,&nbsp;Ali Shamsizade","doi":"10.1016/j.neuro.2025.103349","DOIUrl":"10.1016/j.neuro.2025.103349","url":null,"abstract":"<div><div>Occupational exposure to heavy metals is increasingly recognized as a threat to neurological health. This three-year longitudinal study investigated the relationship between heavy metal exposure and cognitive performance among 69 copper miners and 74 non-miner controls. Blood concentrations of heavy metals were determined using atomic absorption spectrophotometry, while cognitive performance was assessed with standardized neuropsychological tests, including the Mini-Mental State Examination (MMSE), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), Psychomotor Vigilance Task (PVT), creativity measures, and the Beck Depression Inventory. The results demonstrated significantly higher blood levels of arsenic and lead in miners compared with controls, whereas copper levels showed no meaningful group difference. Elevated arsenic concentrations were strongly associated with reduced performance on the oral SDMT, reflecting impairments in information processing speed and working memory. Longitudinal analyses confirmed persistent group differences in neurocognitive outcomes, with age and education exerting notable modifying effects. Interestingly, miners consistently exhibited lower depression scores across the study period, despite greater exposure to toxic metals. These findings indicate that chronic occupational exposure to arsenic and lead contributes to subtle but measurable cognitive deficits in copper miners, particularly in domains of working memory and processing speed.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103349"},"PeriodicalIF":3.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465587","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}