Pub Date : 2026-03-01Epub Date: 2026-02-13DOI: 10.1016/j.neuro.2026.103407
Xiaoxiao Luo , Ke Zhang , Kaishun Chen , Jiangyan Pan , Yiming Ding , Xiaoyan Zhang , Qian Li , Mingkuan Sun
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 Drosophila 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.
{"title":"Nanoplastics exacerbate lead exposure-induced developmental neurotoxicity by disrupting gut integrity in Drosophila","authors":"Xiaoxiao Luo , Ke Zhang , Kaishun Chen , Jiangyan Pan , Yiming Ding , Xiaoyan Zhang , Qian Li , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-17DOI: 10.1016/j.neuro.2026.103409
Quan Yuan , Rui Zhang , Jun Hu , Siman Lin , Ying Zhu , Junhong Geng , Ge Du , Xiao Yang , Yipin Zhao , Dongmei Wang , Binbin Wang , Hua Fan
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.
{"title":"Endoplasmic reticulum stress-induced CHOP activation mediates NLRP3 inflammasome-dependent pyroptosis in BDE-47-induced cognitive dysfunction","authors":"Quan Yuan , Rui Zhang , Jun Hu , Siman Lin , Ying Zhu , Junhong Geng , Ge Du , Xiao Yang , Yipin Zhao , Dongmei Wang , Binbin Wang , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-24DOI: 10.1016/j.neuro.2026.103413
Wenjing Dong , Xiaoxue Ren , Xutong Qu , Jiaying Li , Mingqi Li , Shaofei Wang , Peng Liu , Jiandong Sun , Lihua Jiang , Huiping Li , Changsong Wang , Zhaodi Zhang
Prenatal exposure to anesthetic drugs, such as sevoflurane, may exert a long-lasting impact on neurological function in the offspring. This study aims to investigate the consequence of prenatal sevoflurane exposure on cognitive function in offspring mice. C57BL/6 J mice of 2–3 months of age were housed under standard environmental conditions. Pregnant mice were randomly assigned to receive either sevoflurane exposure or to serve as control group. Behavioral tests conducted included the novel object recognition test and the Morris water maze test. During the terminal phase of the experiment, fecal samples from the mother and offspring, as well as serum and hippocampal samples from the offspring, were collected for microbiome and metabolomic analyses. Behavioral experiments showed that cognitive function was impaired in the offspring mice of the anesthetized group. In addition, sevoflurane altered the gut microbiota composition in pregnant mice and their offspring, with reduced Prevotella abundance in the anesthetized group. Metabolomics analyses showed that anesthetized and control offspring also exhibited significant differences in metabolites in fecal, serum, and hippocampal samples, particularly in the glycerophospholipid metabolism pathway. Further correlation analyses showed a significant correlation between the gut microbiota (especially Prevotella) and differential metabolites in the hippocampus. These results indicate that prenatal sevoflurane exposure disrupts gut microbiota and metabolic pathways, potentially contributing to cognitive deficits in offspring via the gut-brain axis, highlighting risks of anesthesia during pregnancy on fetal neurodevelopment.
{"title":"Maternal intestinal dysbiosis mediated by sevoflurane exposure during pregnancy leads to altered gut microbiota and metabolites and cognitive dysfunction in the offspring","authors":"Wenjing Dong , Xiaoxue Ren , Xutong Qu , Jiaying Li , Mingqi Li , Shaofei Wang , Peng Liu , Jiandong Sun , Lihua Jiang , Huiping Li , Changsong Wang , Zhaodi Zhang","doi":"10.1016/j.neuro.2026.103413","DOIUrl":"10.1016/j.neuro.2026.103413","url":null,"abstract":"<div><div>Prenatal exposure to anesthetic drugs, such as sevoflurane, may exert a long-lasting impact on neurological function in the offspring. This study aims to investigate the consequence of prenatal sevoflurane exposure on cognitive function in offspring mice. C57BL/6 J mice of 2–3 months of age were housed under standard environmental conditions. Pregnant mice were randomly assigned to receive either sevoflurane exposure or to serve as control group. Behavioral tests conducted included the novel object recognition test and the Morris water maze test. During the terminal phase of the experiment, fecal samples from the mother and offspring, as well as serum and hippocampal samples from the offspring, were collected for microbiome and metabolomic analyses. Behavioral experiments showed that cognitive function was impaired in the offspring mice of the anesthetized group. In addition, sevoflurane altered the gut microbiota composition in pregnant mice and their offspring, with reduced <em>Prevotella</em> abundance in the anesthetized group. Metabolomics analyses showed that anesthetized and control offspring also exhibited significant differences in metabolites in fecal, serum, and hippocampal samples, particularly in the glycerophospholipid metabolism pathway. Further correlation analyses showed a significant correlation between the gut microbiota (especially <em>Prevotella</em>) and differential metabolites in the hippocampus. These results indicate that prenatal sevoflurane exposure disrupts gut microbiota and metabolic pathways, potentially contributing to cognitive deficits in offspring via the gut-brain axis, highlighting risks of anesthesia during pregnancy on fetal neurodevelopment.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103413"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308517","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}
Pub Date : 2026-03-01Epub Date: 2026-01-28DOI: 10.1016/j.neuro.2026.103394
Anthony R. White
Airborne combustion emissions from military burn pits, wildfires, and urban/industrial sources are increasingly recognized as a component of the neurotoxic exposome, with potential consequences extending beyond cardiopulmonary disease to brain health. These aerosols comprise heterogeneous mixtures of fine and ultrafine particulate matter (PM₂.₅/PM₀.₁), polycyclic aromatic hydrocarbons, volatile organic compounds, metals, and reactive gases whose composition varies with fuel type, combustion efficiency, and atmospheric aging. Evidence from experimental models, epidemiology, and exposed human cohorts supports two principal routes by which inhaled pollutants may influence the central nervous system: (i) the lung-brain axis, where pulmonary oxidative injury and systemic immune activation promote endothelial dysfunction and compromise blood-brain barrier integrity; and (ii) the olfactory (nose-to-brain) pathway, in which ultrafine and lipophilic constituents interact with the olfactory neuroepithelium and are associated with early neuroimmune changes in olfactory-connected brain regions. At the cellular level, these exposures converge on microglial and astrocytic activation, TLR–NF-κB and inflammasome signaling, mitochondrial dysfunction, and lipid peroxidation, processes that can sustain chronic neuroinflammation and plausibly interact with ‘second hits’ such as traumatic brain injury, psychological stress, heat stress, sleep disruption, and cardiometabolic comorbidity. Veterans and wildland firefighters represent sentinel occupational groups for defining exposure-biomarker-outcome relationships. This review brings together current evidence linking combustion-derived aerosols to neuroinflammatory and neurodegeneration-relevant mechanisms, highlighting source-specific considerations for military operational exposure, and outlines translational strategies for exposure monitoring, multi-omic biomarker discovery (blood and nasal/olfactory sampling), and early risk stratification to enable targeted prevention in vulnerable populations.
{"title":"The impact of military occupational combustion smoke inhalation on neuroinflammation and brain health","authors":"Anthony R. White","doi":"10.1016/j.neuro.2026.103394","DOIUrl":"10.1016/j.neuro.2026.103394","url":null,"abstract":"<div><div>Airborne combustion emissions from military burn pits, wildfires, and urban/industrial sources are increasingly recognized as a component of the neurotoxic exposome, with potential consequences extending beyond cardiopulmonary disease to brain health. These aerosols comprise heterogeneous mixtures of fine and ultrafine particulate matter (PM₂.₅/PM₀.₁), polycyclic aromatic hydrocarbons, volatile organic compounds, metals, and reactive gases whose composition varies with fuel type, combustion efficiency, and atmospheric aging. Evidence from experimental models, epidemiology, and exposed human cohorts supports two principal routes by which inhaled pollutants may influence the central nervous system: (i) the lung-brain axis, where pulmonary oxidative injury and systemic immune activation promote endothelial dysfunction and compromise blood-brain barrier integrity; and (ii) the olfactory (nose-to-brain) pathway, in which ultrafine and lipophilic constituents interact with the olfactory neuroepithelium and are associated with early neuroimmune changes in olfactory-connected brain regions. At the cellular level, these exposures converge on microglial and astrocytic activation, TLR–NF-κB and inflammasome signaling, mitochondrial dysfunction, and lipid peroxidation, processes that can sustain chronic neuroinflammation and plausibly interact with ‘second hits’ such as traumatic brain injury, psychological stress, heat stress, sleep disruption, and cardiometabolic comorbidity. Veterans and wildland firefighters represent sentinel occupational groups for defining exposure-biomarker-outcome relationships. This review brings together current evidence linking combustion-derived aerosols to neuroinflammatory and neurodegeneration-relevant mechanisms, highlighting source-specific considerations for military operational exposure, and outlines translational strategies for exposure monitoring, multi-omic biomarker discovery (blood and nasal/olfactory sampling), and early risk stratification to enable targeted prevention in vulnerable populations.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103394"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093547","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}
Pub Date : 2026-01-01Epub Date: 2025-12-12DOI: 10.1016/j.neuro.2025.103365
Raifa Abdul Aziz , Deepa Mugudthi Venugopal , Avinash Kundadka Kudva , Ramesha Hanumanthappa , Mohammed S. Mustak , KuramkoteShivanna Devaraju , Manjeshwar Shrinath Baliga , Shamprasad Varija Raghu
Chemotherapy-induced cognitive impairment (CICI), commonly known as "chemo brain," is a significant and persistent complication of cancer therapy, characterized by memory deficits and broader cognitive dysfunction. Despite its prevalence among cancer survivors, the underlying neurotoxic mechanisms remain incompletely understood. In this study, we utilized Drosophila melanogaster as a model organism to systematically investigate the neurobiological effects of cisplatin, a widely used platinum-based chemotherapeutic agent. Cisplatin exposure led to a marked reduction in lifespan and impaired locomotor function, indicating pronounced neurotoxicity. Biochemical analyses demonstrated dose-dependent disruptions in oxidative stress parameters - such as superoxide dismutase, catalase, glutathione, and total antioxidant capacity- alongside elevated reactive oxygen species and pro-apoptotic gene expression within neural tissues. Furthermore, cisplatin altered the synthesis and regulation of key neurotransmitters, including acetylcholine, GABA, dopamine, and serotonin. Collectively, these findings establish Drosophila as a robust, translationally relevant model for elucidating the molecular pathways of CICI and for high-throughput screening of neuroprotective interventions.
{"title":"Chemotherapy-induced cognitive impairment (CICI): Cisplatin’s effects on neurotransmitter regulation and oxidative stress in Drosophila melanogaster","authors":"Raifa Abdul Aziz , Deepa Mugudthi Venugopal , Avinash Kundadka Kudva , Ramesha Hanumanthappa , Mohammed S. Mustak , KuramkoteShivanna Devaraju , Manjeshwar Shrinath Baliga , Shamprasad Varija Raghu","doi":"10.1016/j.neuro.2025.103365","DOIUrl":"10.1016/j.neuro.2025.103365","url":null,"abstract":"<div><div>Chemotherapy-induced cognitive impairment (CICI), commonly known as \"chemo brain,\" is a significant and persistent complication of cancer therapy, characterized by memory deficits and broader cognitive dysfunction. Despite its prevalence among cancer survivors, the underlying neurotoxic mechanisms remain incompletely understood. In this study, we utilized <em>Drosophila melanogaster</em> as a model organism to systematically investigate the neurobiological effects of cisplatin, a widely used platinum-based chemotherapeutic agent. Cisplatin exposure led to a marked reduction in lifespan and impaired locomotor function, indicating pronounced neurotoxicity. Biochemical analyses demonstrated dose-dependent disruptions in oxidative stress parameters - such as superoxide dismutase, catalase, glutathione, and total antioxidant capacity- alongside elevated reactive oxygen species and pro-apoptotic gene expression within neural tissues. Furthermore, cisplatin altered the synthesis and regulation of key neurotransmitters, including acetylcholine, GABA, dopamine, and serotonin. Collectively, these findings establish <em>Drosophila</em> as a robust, translationally relevant model for elucidating the molecular pathways of CICI and for high-throughput screening of neuroprotective interventions.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103365"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753743","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}
Pub Date : 2026-01-01Epub Date: 2025-12-24DOI: 10.1016/j.neuro.2025.103374
Hong Yang , Weihao Fan , Xinyu Yang , Ying Wei , Li Xiao , Hongkun Yang , Linzhi Jiang , Jian Li , Kaiting Shi , Shuang Zhao , Lin Yang , Yi Ye , Linchuan Liao
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits both therapeutic potential and abuse liability. However, the spatial distribution of ketamine across brain regions remains poorly characterized. Meanwhile, elucidating the mechanism underlying ketamine-induced psychiatric disorders through the investigation of metabolite alterations in the specific brain regions targeted by ketamine is of crucial significance. This study investigated the neurochemical effects of chronic ketamine administration in C57BL/6 mice using in situ mass spectrometry imaging (MSI) and metabolomics. Mice treated with ketamine (30 mg/kg daily for 15 days) exhibited increased anxiety-like behaviors without cognitive deficits. MSI revealed ketamine accumulation in the cerebral cortex, midbrain, and cerebellum, while the key neurotransmitter γ-aminobutyric acid (GABA) distribution shifted toward thalamic and striatum regions. The prefrontal cortex and cerebellum were selected as targeted brain regions for metabolomics analysis based on the MSI results. In metabolomics results, 73 and 134 differential metabolites in the prefrontal cortex and cerebellum were identified, respectively, predominantly linked to Alanine, aspartate, and glutamate metabolism, Estrogen signaling pathway, and GABAergic synapse pathways. This study integrated behavioral assessments, in situ MSI, and metabolomics to visually resolve and multidimensionally correlate ketamine's spatial distribution in the brain with region-specific metabolic changes in a ketamine-induced anxiety model. The findings reveal distinct neurochemical disruptions across brain regions and offer a groundwork for further elucidating the mechanisms of ketamine-related anxiety.
氯胺酮是一种n -甲基- d -天冬氨酸（NMDA）受体拮抗剂，具有治疗潜力和滥用危险。然而，氯胺酮在大脑区域的空间分布特征仍然很差。同时，通过研究氯胺酮靶向的特定脑区代谢物改变来阐明氯胺酮致精神障碍的机制具有重要意义。本研究采用原位质谱成像（MSI）和代谢组学方法研究慢性氯胺酮给药对C57BL/6小鼠神经化学的影响。氯胺酮（每天30mg/kg，连续15天）治疗的小鼠表现出焦虑样行为增加，但没有认知缺陷。MSI显示氯胺酮在大脑皮层、中脑和小脑积聚，而关键的神经递质γ-氨基丁酸（GABA）分布向丘脑和纹状体区域转移。根据MSI结果，选择前额叶皮层和小脑作为代谢组学分析的目标脑区。在代谢组学结果中，分别在前额叶皮层和小脑中鉴定出73种和134种差异代谢物，主要与丙氨酸、天冬氨酸和谷氨酸代谢、雌激素信号通路和gaba能突触通路有关。本研究综合了行为评估、原位MSI和代谢组学，在氯胺酮诱导的焦虑模型中，视觉分析氯胺酮在大脑中的空间分布与区域特异性代谢变化之间的多维关联。研究结果揭示了不同大脑区域的神经化学破坏，并为进一步阐明氯胺酮相关焦虑的机制提供了基础。
{"title":"Ketamine's brain spatial distribution and metabolic effects in a mouse model of anxiety: Insight into in situ mass spectrometry imaging and metabolomics methods","authors":"Hong Yang , Weihao Fan , Xinyu Yang , Ying Wei , Li Xiao , Hongkun Yang , Linzhi Jiang , Jian Li , Kaiting Shi , Shuang Zhao , Lin Yang , Yi Ye , Linchuan Liao","doi":"10.1016/j.neuro.2025.103374","DOIUrl":"10.1016/j.neuro.2025.103374","url":null,"abstract":"<div><div>Ketamine, an N-methyl-<span>D</span>-aspartate (NMDA) receptor antagonist, exhibits both therapeutic potential and abuse liability. However, the spatial distribution of ketamine across brain regions remains poorly characterized. Meanwhile, elucidating the mechanism underlying ketamine-induced psychiatric disorders through the investigation of metabolite alterations in the specific brain regions targeted by ketamine is of crucial significance. This study investigated the neurochemical effects of chronic ketamine administration in C57BL/6 mice using in situ mass spectrometry imaging (MSI) and metabolomics. Mice treated with ketamine (30 mg/kg daily for 15 days) exhibited increased anxiety-like behaviors without cognitive deficits. MSI revealed ketamine accumulation in the cerebral cortex, midbrain, and cerebellum, while the key neurotransmitter γ-aminobutyric acid (GABA) distribution shifted toward thalamic and striatum regions. The prefrontal cortex and cerebellum were selected as targeted brain regions for metabolomics analysis based on the MSI results. In metabolomics results, 73 and 134 differential metabolites in the prefrontal cortex and cerebellum were identified, respectively, predominantly linked to Alanine, aspartate, and glutamate metabolism, Estrogen signaling pathway, and GABAergic synapse pathways. This study integrated behavioral assessments, in situ MSI, and metabolomics to visually resolve and multidimensionally correlate ketamine's spatial distribution in the brain with region-specific metabolic changes in a ketamine-induced anxiety model. The findings reveal distinct neurochemical disruptions across brain regions and offer a groundwork for further elucidating the mechanisms of ketamine-related anxiety.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103374"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844049","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}
Pub Date : 2026-01-01Epub Date: 2025-12-11DOI: 10.1016/j.neuro.2025.103363
Sun Eui Choi , Tiffany Ayoub , Gail Lee , Anne L. Wheeler , Sharon L. Guger , Rosanna Weksberg , Shinya Ito , Russell J. Schachar , Johann Hitzler , Brian J. Nieman
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.
急性淋巴细胞白血病（ALL）是最常见的儿童癌症，虽然5年生存率超过90%，但幸存者表现出神经认知缺陷。磁共振成像（MRI）测量表明，与正常发育的同龄人相比，幸存者的大脑体积更小。甲氨蝶呤（MTX）是ALL化疗的主要药物，可通过多种给药途径，包括全身和中枢神经系统（CNS）靶向途径。不同途径的相对毒性尚未进行系统比较。我们的研究旨在通过MRI比较幼年小鼠模型全身和中枢靶向MTX治疗后脑容量的变化。MTX治疗在出生后第17天（P17）和P19天通过鞘内注射（IT）或静脉注射（IV）进行，总共分为四组：IV MTX (n=14)， IV生理盐水（n=16）， IT MTX （n=54）和IT生理盐水（n=51）。MRI分别在治疗前的P14和治疗后的P24、P42和P63进行纵向扫描。在剂量范围（0.5-5.0mg/kg）下对IT MTX进行探针。比较两组间183个脑节段结构的体积。注射甲氨蝶呤（5.0mg/kg）和静脉注射甲氨蝶呤后全脑体积减小。经甲氨蝶呤治疗后显著影响的结构数高度依赖于剂量。全身和鞘内给药途径的比较显示，全身MTX对脑形态的影响比IT MTX治疗更广泛，特别是在临床相关剂量的IT MTX治疗下。这一发现为mtx诱导神经毒性的机制提供了重要的见解，并将潜在的干预措施集中在全身毒性上。
{"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 , Tiffany Ayoub , Gail Lee , Anne L. Wheeler , Sharon L. Guger , Rosanna Weksberg , Shinya Ito , Russell J. Schachar , Johann Hitzler , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-12-22DOI: 10.1016/j.neuro.2025.103370
Pamela J. Lein , Aaron B. Bowman , Zhengyu Cao , Monica Carson , Brenda Eskenazi , Ellen Fritsche , G. Jean Harry , Thomas Hartung , Isaac N. Pessah , William Slikker Jr. , Lauren Zeise , Martyn T. Smith
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.
{"title":"Proposed key characteristics of neurotoxic chemicals","authors":"Pamela J. Lein , Aaron B. Bowman , Zhengyu Cao , Monica Carson , Brenda Eskenazi , Ellen Fritsche , G. Jean Harry , Thomas Hartung , Isaac N. Pessah , William Slikker Jr. , Lauren Zeise , 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}
Pub Date : 2026-01-01Epub Date: 2025-12-24DOI: 10.1016/j.neuro.2025.103373
Yue Wei , Jingjing Shi , Xuejun Chen , Zhanbiao Liu , Qian Jin , Ruihua Zhang , Tong Shi , Chen Wang , Liqin Li
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.
{"title":"Soman-induced neurotoxicity in human iPSC-derived cerebral organoids: A whole-transcriptome analysis of ceRNA regulatory networks","authors":"Yue Wei , Jingjing Shi , Xuejun Chen , Zhanbiao Liu , Qian Jin , Ruihua Zhang , Tong Shi , Chen Wang , 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}
Pub Date : 2026-01-01Epub Date: 2025-12-16DOI: 10.1016/j.neuro.2025.103367
Xiaoli Ma , Shengtao Wei , Fangfei Li , Guiqiang Liang , Jian Wang , Yunfeng Zou
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.
{"title":"FTH1-mediated iron dysregulation and ferroptosis in manganese-induced neurotoxicity","authors":"Xiaoli Ma , Shengtao Wei , Fangfei Li , Guiqiang Liang , Jian Wang , 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}
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