Neurotoxicology最新文献

{"title":"The miR-378a-3p/SLC7A11 axis mediates benzo[a]pyrene-induced ferroptosis in hippocampal neuronal cells","authors":"Fang Wang ,&nbsp;Xuanying Shi ,&nbsp;Xuetian Gao ,&nbsp;Dongxin Li ,&nbsp;Youquan Guo ,&nbsp;Li Chang ,&nbsp;Yu Wang","doi":"10.1016/j.neuro.2026.103406","DOIUrl":"10.1016/j.neuro.2026.103406","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent form of regulated cell death, contributes to polycyclic aromatic hydrocarbon (PAH)-induced neurodegeneration. Benzo[<em>a</em>]pyrene (BaP), a neurotoxic polycyclic aromatic hydrocarbon, induces ferroptosis in neuronal cells, but the molecular mechanisms remain unclear. We examined the association between PAH exposure and SLC7A11 promoter methylation in human peripheral blood. Additionally, we employed molecular and genetic methods (RT-PCR, SLC7A11 knockdown/overexpression, and miR-378a-3p inhibition) to validate BaP-induced ferroptosis in HT22 neurons through the miR-378a-3p/SLC7A11 axis. The results indicated that high PAH exposure significantly reduced the average methylation level of the SLC7A11 promoter region, and BaP exposure induced ferroptosis in HT22 cells. Notably, SLC7A11 knockdown exacerbated ferroptosis, while SLC7A11 overexpression or miR-378a-3p inhibition attenuated ferroptosis. Our study therefore establishes the miR-378a-3p/SLC7A11 axis as a crucial mechanism in BaP-induced neuronal ferroptosis, providing a novel mechanistic insight into BaP-induced neurotoxicity. Targeting the miR-378a-3p/SLC7A11 pathway may mitigate environmental pollutant-induced neuronal damage in neurodegenerative diseases.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103406"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227618","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":"Longitudinal changes in pallidal index and their associations with urinary manganese and CaNa₂EDTA chelation","authors":"Tuğba Akkale ,&nbsp;Nuriye Kayalı Şendur ,&nbsp;Süleyman Filiz ,&nbsp;Nilüfer Merve Çelik","doi":"10.1016/j.neuro.2026.103397","DOIUrl":"10.1016/j.neuro.2026.103397","url":null,"abstract":"<div><h3>Objectives</h3><div>In this study, the evaluation of the change in pallidal index (PI) (ΔPI) between baseline and follow-up magnetic resonance imaging; the examination of the relationship between ΔPI and spot urine manganese (Mn) levels and baseline PI values; and the investigation of the possible effect of CaNa₂EDTA chelation therapy administered during the follow-up period on pallidal Mn accumulation were aimed.</div></div><div><h3>Methods</h3><div>In 27 participants monitored due to occupational Mn exposure, right and left PI were measured from T1-weighted images using standard protocols. ΔPI was calculated as the difference between the baseline and follow-up measurements. During CaNa₂EDTA treatment, whole blood and spot urine Mn levels were measured on the first day of each treatment course and on rest days, while 24-hour urinary Mn levels were assessed on the third day of treatment<strong>.</strong> In individuals treated with CaNa₂EDTA, the pre- and post-treatment change in PI was evaluated as a secondary analysis. Associations between ΔPI and Mn biomarkers were analyzed using the Spearman rho coefficient.</div></div><div><h3>Results</h3><div>It was determined that both right and left PI significantly decreased during the follow-up period. A negative correlation was found between spot urine Mn levels and ΔPI (right: ρ = –0.59; left: ρ = –0.45; p &lt; 0.05), indicating that the reduction in PI is more limited in individuals with higher current exposure. The positive correlation of ΔPI with the initial PI (right: ρ = 0.51; left: ρ = 0.74; p &lt; 0.05) suggests that the initial accumulation level is a determining factor in the amount of reduction. Following CaNa₂EDTA treatment, blood Mn levels significantly</div><div>Decreased in parallel with the observed reduction in PI.</div></div><div><h3>Conclusion</h3><div>PI is a dynamic imaging biomarker sensitive to changes in Mn accumulation, reflecting both the exposure level and the response to chelation therapy. The integration of MRI-based measurements with biological exposure markers can provide significant contributions to the monitoring and evaluation of treatment efficacy in populations exposed to Mn.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103397"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146170366","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":"Elevated fecal silver, lithium, and platinum in cognitive impairment: A pilot exploration of microbiota–metal interactions","authors":"David Mateo ,&nbsp;Marília Cristina Oliveira Souza ,&nbsp;Nerea Carrión ,&nbsp;Luis Heredia ,&nbsp;Cristian Cabrera ,&nbsp;Montse Marquès ,&nbsp;Eva Forcadell-Ferreres ,&nbsp;Maria Pino ,&nbsp;Josep Zaragoza ,&nbsp;José Luis Domingo ,&nbsp;Fernando Barbosa ,&nbsp;Margarita Torrente","doi":"10.1016/j.neuro.2026.103390","DOIUrl":"10.1016/j.neuro.2026.103390","url":null,"abstract":"<div><h3>Background</h3><div>Gut microbiota (GMB) and metal exposure have both been implicated in cognitive impairment (CI), including amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). However, studies integrating these areas remain scarce.</div></div><div><h3>Objective</h3><div>This pilot study aimed to investigate whether exposure to metals modulates the relationship between GMB composition and clinical outcomes in individuals with CI.</div></div><div><h3>Methods</h3><div>Stool samples were collected from aMCI (n = 12), AD (n = 18), and cognitively healthy controls (HC, n = 30). Participants were categorized into CI (n = 30) and HC (n = 30). Gut microbial diversity was assessed using shotgun sequencing, and 25 metals were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Cognitive, neuropsychological, neuropsychiatric, and functional assessments were also conducted.</div></div><div><h3>Results</h3><div>No significant differences were observed between groups in microbial richness, alpha-diversity (Shannon index), or beta-diversity (Bray–Curtis). Likewise, microbial diversity measures were not associated with cognitive outcomes. In contrast, aMCI and AD participants exhibited significantly higher fecal concentrations of silver (Ag), lithium (Li), and platinum (Pt) compared to HC (all p &lt; 0.001).</div></div><div><h3>Conclusion</h3><div>This multidimensional pilot study integrating microbiota profiling, metal exposure assessment, and cognitive evaluation, revealed elevated fecal excretion of Ag, Li, and Pt in participants with cognitive impairment, suggesting potential interactions between trace metals and neurodegenerative processes. While no significant differences in overall microbial diversity were observed between groups, these findings emphasize the need for larger, longitudinal investigations to elucidate the complex relationships among gut microbiota, metal homeostasis, and cognitive decline.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103390"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958737","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":"Protective effects of sodium benzoate against toluene-induced reward enhancement, behavioral disturbances, and impaired synaptic plasticity in mice","authors":"Chung-Pin Hsieh ,&nbsp;Mei-Yi Lee ,&nbsp;Chia-Yu Lin ,&nbsp;Ming-Huan Chan ,&nbsp;Hwei-Hsien Chen","doi":"10.1016/j.neuro.2026.103403","DOIUrl":"10.1016/j.neuro.2026.103403","url":null,"abstract":"<div><div>Toluene is one of the most commonly abused solvents. Inhibition of N-methyl-<span>D</span>-aspartate receptor (NMDAR) has been linked to the rewarding and behavioral effects of toluene. One of the avenues to enhance NMDAR function is to increase the levels of <span>D</span>-serine via inhibiting <span>D</span>-amino acids oxidase (DAAO) activity. The present study determined whether sodium benzoate, a DAAO inhibitor, could counteract the toluene-induced brain stimulation reward enhancement, behavioral disturbances, and hippocampal synaptic dysfunction after acute toluene exposure. Male mice received various doses of sodium benzoate before toluene exposure for assessment of intracranial self-stimulation (ICSS) thresholds, rotarod test, novel object recognition task, social interaction test, and long-term potentiation (LTP) and long-term depression (LTD) of hippocampal synaptic transmission. Sodium benzoate prevented the lowering of ICSS thresholds, motor incoordination, social withdrawal, object recognition memory deficit, and impaired LTP and LTD induced by toluene. These results indicate that sodium benzoate could ameliorate toluene-induced facilitation of brain reward function, behavioral disturbances, and synaptic plasticity impairment, suggesting that sodium benzoate may be a promising compound against acute toluene intoxication caused by unintentional or deliberate inhalation.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103403"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146170365","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":"Promethazine provokes behavioral alterations and disrupts redox homeostasis in planarians","authors":"Kalinka Kendra Mayeski ,&nbsp;Camila Caetano Solek ,&nbsp;Karina Mara Carus ,&nbsp;Juliana Feix ,&nbsp;Luiz Carlos Cichota ,&nbsp;Helissara Silveira Diefenthaeler ,&nbsp;Itamar Luís Gonçalves ,&nbsp;Alexandre Umpierrez Amaral","doi":"10.1016/j.neuro.2026.103408","DOIUrl":"10.1016/j.neuro.2026.103408","url":null,"abstract":"<div><div>Promethazine is a first-generation H1 antihistamine that affects a variety of targets in the vertebrate nervous system, which explains its sedative effects and other neurological actions that are not fully clarified. To better understand the neurobiological activity of promethazine, the aim of this study was to evaluate the effects of promethazine on behavioral and redox homeostasis parameters in planarians (<em>Girardia tigrina</em>), in order to better understand its potential neurobiological effects. Planarians were pre-incubated for 1 h, 6 h or directly exposed to different concentrations of promethazine (5, 10, 25, and 50 µM) and, subsequently, the behavioral and redox homeostasis parameters were assessed. Locomotor activity was recorded for 5 min and analyzed using ToxTrac software, measuring parameters such as average speed, average acceleration, exploration rate, mobility rate, distance and trajectory. Redox homeostasis markers were also assessed, including malondialdehyde (MDA) levels, sulfhydryl content, reduced glutathione (GSH) concentrations, and superoxide dismutase (SOD) activity. Low concentrations of promethazine (5 and 10 µM) increased locomotor activity, while higher concentrations (25 and 50 µM) led to a significant reduction in average speed and exploration rate. Additionally, 1 h pre-incubation in the presence of promethazine increased MDA levels, GSH concentrations, and SOD activity, without affecting sulfhydryl content, suggesting lipid peroxidation and changes in antioxidant response in planarians. Overall, the study demonstrates that promethazine significantly alters planarian behavior and disrupts redox homeostasis, indicating a strong neuroactive response in planarians.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103408"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146207407","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":"Planarian behavioral screening is a useful invertebrate model for evaluating seizurogenic chemicals","authors":"Danielle Ireland ,&nbsp;Evangeline Coffinas ,&nbsp;Christina Rabeler ,&nbsp;Eva-Maria S. Collins","doi":"10.1016/j.neuro.2026.103412","DOIUrl":"10.1016/j.neuro.2026.103412","url":null,"abstract":"<div><div>Detecting adverse health effects of drugs and other chemicals early during chemical/drug development saves significant time and resources. Freshwater planarians are an emerging invertebrate model for rapid, cost-effective neurotoxicity screening. Because planarians exhibit seizure-like behavior when exposed to chemicals that cause seizures in mammals, such as N-methyl-<span>D</span>-aspartate (NMDA) and picrotoxin, they could be a useful first-tier model for seizure screening and thus reduce the need for slow and expensive mammalian tests. However, planarian seizure studies to date have been low-throughput and lacking the necessary standardization and automated analysis to make this model a viable screening solution. Here, we present results from medium-throughput behavioral testing conducted in 48-well plates using two popular models for planarian pharmacological and toxicological studies: <em>Dugesia japonica</em> and <em>Girardia dorotocephala</em>. Planarian behavior was scored using automated image analysis, measuring both translational behavior and body shape changes. We found that known seizurogenic compounds in mammals (NMDA, nicotine, picrotoxin, pilocarpine, and pentylenetetrazole (PTZ)) induced seizure-like behavior in both planarian species within 30 min of exposure. We also tested three pesticides (parathion, carbaryl, and permethrin). Parathion and carbaryl, but not permethrin, caused planarian seizure-like activity. While the planarian species responded similarly to most compounds, some compounds showed potency differences of 10–100-fold (pilocarpine and nicotine, respectively). <em>G. dorotocephala</em> planarians were generally more sensitive, but <em>D. japonica</em> planarians displayed more reproducible behaviors. By standardizing both experimental approach and analysis methods and making them available, this work can serve as a framework for future testing of chemicals for seizurogenic potential in planarians.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103412"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271540","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":"From correlation to causation: Integrating cohorts with experimental studies in mixture toxicology","authors":"Ahmed Elagali ,&nbsp;Joëlle Rüegg ,&nbsp;Nicolò Caporale ,&nbsp;Giuseppe Testa ,&nbsp;Maria Sapounidou ,&nbsp;Jean-Baptiste Fini ,&nbsp;Patrik L. Andersson ,&nbsp;Sarah Dunlop ,&nbsp;Carl-Gustaf Bornehag ,&nbsp;Chris Gennings","doi":"10.1016/j.neuro.2026.103399","DOIUrl":"10.1016/j.neuro.2026.103399","url":null,"abstract":"<div><div>Harmful chemical mixtures are pervasive in the environment, yet traditional epidemiological designs face major challenges in establishing causal links between individual chemicals or mixture exposures and health outcomes. These challenges arise from the high dimensionality and inter-correlation of exposures, their mediation through complex molecular pathways, and the practical absence of truly unexposed control groups, due to the ubiquity of synthetic chemicals. However, environmental health research is entering a new era defined by integration of epidemiological and experimental studies as well as recent advances in molecular technologies and computational modelling. Here, we introduce four approaches designed to advance our understanding of chemical mixtures and move beyond correlation to causation and intervention: 1) ‘<em>hMIX’</em> which integrates human relevant reference mixtures with experimental evidence of adverse effects; 2) the Similar Mixture Approach <em>(SMACH</em>) that translates hazards of chemical mixtures to risks across populations; 3) hybrid epidemiology that bridges experimental and population-based mechanistic insights; and 4) counterfactual theoretical interventions tailored to examine the health benefits of reducing exposure to specific harmful chemicals or mixtures. We propose an integrative framework combining these four approaches to move the chemical mixture field towards causality — a critical step toward predicting and preventing chemical mixture related health effects.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103399"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137802","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":"Schoolchildren’s exposure to potentially toxic metals/metalloids and cognitive impairments in communities of the Brazilian Amazon new agricultural frontiers","authors":"J.A. Menezes-Filho ,&nbsp;E.C.A. Di Giuseppe ,&nbsp;T.M.P. Moraes ,&nbsp;B.A.T. Couto ,&nbsp;B.S. Ferreira ,&nbsp;N.B. Matos da Silva ,&nbsp;C.S. Lima ,&nbsp;W.P. Moraes ,&nbsp;A.C. Florentino ,&nbsp;F. Barbosa-Jr ,&nbsp;C.J.S. Passos","doi":"10.1016/j.neuro.2026.103404","DOIUrl":"10.1016/j.neuro.2026.103404","url":null,"abstract":"<div><div>Brazilian Amazon communities near new agricultural frontiers are affected by the extensive use of pesticides and dust exposure due to soil erosion. This study investigated the exposure to potentially toxic metals/metalloids and associations with cognitive impairments in Amazonian children living near new agricultural frontiers (soybean crops). This cross-sectional study was conducted in six communities in the Santarém plateau, State of Pará, Brazil. During the 2024 rainy season soy plantation, we collected cubital blood samples of 69 children aged 6–12 years. Metals/metalloids were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Cognitive evaluation was performed in 53 children using Raven Colorful Matrix, NEPSY II, and FDT tests. Blood lead (PbB) median (range) was 1.9 μg/dL (0.6–40.1), 14.3 % above 3.5 μg/dL. Total blood mercury (THgB) concentrations were 2.11 μg/L (0.45–17.07), of which 17.4 % were above the reference level of 5 μg/L. Non-linear and linear associations were evaluated between metal levels and cognitive outcomes, adjusting for children’s age, sex, and maternal education. OLS regressions detected a significant inverse association between Log₂PbB levels and the verbal domain scores (β= −2.71, 95 %-CI: −4.46 to −0.95), which was also non-linearly negatively associated with Raven raw scores. Log₂Hg levels were negatively associated with Raven percentile scores (β= −5.05, 95 %-CI= −10.20–0.11), with Se levels significantly affecting the association. Amazonian children are vulnerable to cognitive impairments associated with lead exposure, likely originating from foods cultivated in naturally Pb-rich soils, and to mercury exposure resulting from a diet rich in contaminated fish.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103404"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195335","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":"Nanoplastics exacerbate lead exposure-induced developmental neurotoxicity by disrupting gut integrity in Drosophila","authors":"Xiaoxiao Luo ,&nbsp;Ke Zhang ,&nbsp;Kaishun Chen ,&nbsp;Jiangyan Pan ,&nbsp;Yiming Ding ,&nbsp;Xiaoyan Zhang ,&nbsp;Qian Li ,&nbsp;Mingkuan Sun","doi":"10.1016/j.neuro.2026.103407","DOIUrl":"10.1016/j.neuro.2026.103407","url":null,"abstract":"<div><div>Lead (Pb), a neurotoxic heavy metal, can accumulate in the central nervous system (CNS) by crossing the blood-brain barrier and cause damage, while micro-nanoplastics (MNPs) are known to absorb Pb and enhance its toxicity. However, the synergistic effects of co-exposure on neurodevelopment remain unclear. This study established a <em>Drosophila</em> model to systematically evaluate the neurodevelopmental toxicity of combined nanoplastics (NPs) and Pb exposure. Behavioral tests revealed that co-exposure significantly exacerbated learning and memory deficits compared to Pb exposure alone, accompanied by reduced pupation and eclosion rates, as well as delayed development. Female flies showed decreased survival rates and more severe impairments in climbing and motor activity. Mechanistic investigations indicated that co-exposure promoted Pb accumulation in neural tissues, aggravated oxidative stress (elevated SOD activity, decreased CAT activity, and increased MDA levels), disrupted neuromuscular junction (NMJ) development and Mushroom body (MB) axon guidance, and induced intestinal damage (increased epithelial cell mortality and microvilli structural abnormalities). This study demonstrates that NPs synergistically enhance Pb-induced neurodevelopmental toxicity through multiple pathways, providing critical toxicological evidence for the health risks of environmental composite pollutants.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103407"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202237","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":"Endoplasmic reticulum stress-induced CHOP activation mediates NLRP3 inflammasome-dependent pyroptosis in BDE-47-induced cognitive dysfunction","authors":"Quan Yuan ,&nbsp;Rui Zhang ,&nbsp;Jun Hu ,&nbsp;Siman Lin ,&nbsp;Ying Zhu ,&nbsp;Junhong Geng ,&nbsp;Ge Du ,&nbsp;Xiao Yang ,&nbsp;Yipin Zhao ,&nbsp;Dongmei Wang ,&nbsp;Binbin Wang ,&nbsp;Hua Fan","doi":"10.1016/j.neuro.2026.103409","DOIUrl":"10.1016/j.neuro.2026.103409","url":null,"abstract":"<div><div>Recent studies have unraveled a striking association between endoplasmic reticulum (ER) stress and the NLRP3 inflammasome. Prior research has documented that activation of the NLRP3 inflammasome contributes to BDE-47-induced cytotoxicity, while ER stress has also been implicated in mediating the toxic effects of brominated diphenyl ethers (BDEs). However, the intricate interplay between ER stress and the NLRP3 inflammasome, as well as their combined impact on neuronal pyroptosis and cognitive deficits following BDE-47 exposure, remains underexplored. Our results revealed pronounced ER stress in BDE-47-treated mouse hippocampi and SH-SY5Y cells, as evidenced by significantly elevated expression of key ER stress markers, including p-PERK, p-IRE1α, ATF6, and CHOP, and accompanied by observable ER dilation. Further mechanistic investigations demonstrated that BDE-47-induced upregulation of CHOP activates the NLRP3 inflammasome, thereby triggering subsequent neuronal pyroptosis in SH-SY5Y cells. Notably, intervention with either the ER stress inhibitor 4-PBA or CHOP siRNA effectively abrogated BDE-47-induced, NLRP3 inflammasome-dependent neuronal pyroptosis. Furthermore, administration of the ER stress inhibitor 4-PBA or the NLRP3 inflammasome inhibitor MCC950 substantially mitigated hippocampal neuronal injury and synaptic dysfunction, while concomitantly alleviating cognitive deficits in BDE-47-exposed mice. Collectively, integrative analysis of our experimental data illuminates previously unrecognized mechanisms underlying BDE-47-induced neurotoxicity, suggesting that targeting ER stress-mediated activation of the NLRP3 inflammasome and the ensuing neuronal pyroptosis could represent a potential therapeutic strategy for ameliorating BDE-47-associated neurobehavioral impairments.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103409"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227644","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}