Pub Date : 2026-03-01Epub Date: 2026-01-31DOI: 10.1016/j.neuro.2026.103396
Intakhar Ahmad , Jacqueline Rocha , Zachary McDonald , Douglas L. Feinstein
Previous studies showed that exposure to long-acting anticoagulant rodenticides (LAARs) can induce neuropathology in adult rats. In the current study we tested if the potent LAAR brodifacoum similarly promoted neuropathology in adult rabbits which provide a better model of human LAAR poisoning. Adult male New Zealand White rabbits were administered by gavage a single administration of brodifacoum at its LD50 dose (200 μg/kg), followed by daily injections of vitamin K1 to prevent mortality due to anti-coagulation. After 3 weeks, examination of the cerebellum revealed an increase in glial cell activation, and a decrease in myelin content. A targeted lipidomics analysis was carried out to determine if brodifacoum altered the relative abundance of lipids enriched in myelin. We observed brodifacoum-dependent decreases in several sulfatides which were associated with an increase in expression of arylsulfatase A which degrades sulfatides. Daily treatment with the bile sequestrant cholestyramine, which accelerates LAAR clearance from the body, ameliorated brodifacoum -induced damage. These findings confirm that, despite daily vitamin K1 treatment, LAARs such as brodifacoum can induce neuropathology in adult animals and support the use of agents such as bile sequestrants to ameliorate those consequences.
{"title":"The long-acting anticoagulant rodenticide brodifacoum induces neuropathology in adult New Zealand White rabbits and is reduced by the bile sequestrant cholestyramine","authors":"Intakhar Ahmad , Jacqueline Rocha , Zachary McDonald , Douglas L. Feinstein","doi":"10.1016/j.neuro.2026.103396","DOIUrl":"10.1016/j.neuro.2026.103396","url":null,"abstract":"<div><div>Previous studies showed that exposure to long-acting anticoagulant rodenticides (LAARs) can induce neuropathology in adult rats. In the current study we tested if the potent LAAR brodifacoum similarly promoted neuropathology in adult rabbits which provide a better model of human LAAR poisoning. Adult male New Zealand White rabbits were administered by gavage a single administration of brodifacoum at its LD<sub>50</sub> dose (200 μg/kg), followed by daily injections of vitamin K1 to prevent mortality due to anti-coagulation. After 3 weeks, examination of the cerebellum revealed an increase in glial cell activation, and a decrease in myelin content. A targeted lipidomics analysis was carried out to determine if brodifacoum altered the relative abundance of lipids enriched in myelin. We observed brodifacoum-dependent decreases in several sulfatides which were associated with an increase in expression of arylsulfatase A which degrades sulfatides. Daily treatment with the bile sequestrant cholestyramine, which accelerates LAAR clearance from the body, ameliorated brodifacoum -induced damage. These findings confirm that, despite daily vitamin K1 treatment, LAARs such as brodifacoum can induce neuropathology in adult animals and support the use of agents such as bile sequestrants to ameliorate those consequences.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103396"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106596","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: 2026-01-27DOI: 10.1016/j.neuro.2026.103395
Lamiaa M. Shawky , Ahmed A. Morsi , Nermine Beshara , Omar T. Abualnasr , Ghena Hamza , Lamia Asali , Faten Asali , Eman El Bana
Lead (Pb) toxicity is a great community health problem. Brain is the primary target organ of Pb intoxication. Ascorbic acid (AA) and Gallic acid (GA) have proven to show potential anti‑inflammatory and antioxidant properties during heavy metal intoxication. So, the current paper aimed to explore the possible protection of AA, GA, and their combination in the current model of Pb neurotoxicity. Fifty-six Wistar male albino rats were assigned into seven groups: control, AA alone (10 mg/kg, oral), GA alone (20 mg/kg, oral), Pb alone (40 mg/kg, intraperitoneal), AA/Pb, GA/Pb, and AA/GA/Pb combination groups. After one month of oral treatment, the animals were humanely killed, and brain cortical samples were extracted for biochemical measurement of the inflammatory and oxidative markers in the brain tissue homogenates. Moreover, the samples were subjected to structural and ultrastructural examinations using light and electron microscopic (EM) studies. Pb resulted in brain injury indicated by remarkable structural and ultrastructural changes evident by neuronal degeneration and reduction of healthy nerve cells. EM showed atrophic nerve cells with irregular outlines, swollen, rarefied mitochondria, and enlarged, fused electron-dense lysosomes indicating possible autophagic vacuoles. Also, a significant increase in the pro-inflammatory markers was noticed, as evident by the raised immunohistochemical expression of glial fibrillary acidic protein (GFAP), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α). In addition, the anti-inflammatory marker decreased, as denoted by the decline in superoxide dismutase (SOD) and catalase. All these alterations were lessened by AA and GA with great restoration in the AA/GA combination group, which showed almost normal histological, ultrastructural, and biochemical parameters. AA and GA are suggested to alleviate Pb‑induced neurotoxicity owing to the modulation of oxidative stress, inflammation, and apoptosis. However, the AA/GA combination shows the greatest effect as evidenced by biochemical, structural, and ultrastructural analyses.
{"title":"Gallic and ascorbic acids either alone or combined contribute to ameliorating lead-induced cerebral neurotoxicity in rats: A histological and immunohistochemical study","authors":"Lamiaa M. Shawky , Ahmed A. Morsi , Nermine Beshara , Omar T. Abualnasr , Ghena Hamza , Lamia Asali , Faten Asali , Eman El Bana","doi":"10.1016/j.neuro.2026.103395","DOIUrl":"10.1016/j.neuro.2026.103395","url":null,"abstract":"<div><div>Lead (Pb) toxicity is a great community health problem. Brain is the primary target organ of Pb intoxication. Ascorbic acid (AA) and Gallic acid (GA) have proven to show potential anti‑inflammatory and antioxidant properties during heavy metal intoxication. So, the current paper aimed to explore the possible protection of AA, GA, and their combination in the current model of Pb neurotoxicity. Fifty-six Wistar male albino rats were assigned into seven groups: control, AA alone (10 mg/kg, oral), GA alone (20 mg/kg, oral), Pb alone (40 mg/kg, intraperitoneal), AA/Pb, GA/Pb, and AA/GA/Pb combination groups. After one month of oral treatment, the animals were humanely killed, and brain cortical samples were extracted for biochemical measurement of the inflammatory and oxidative markers in the brain tissue homogenates. Moreover, the samples were subjected to structural and ultrastructural examinations using light and electron microscopic (EM) studies. Pb resulted in brain injury indicated by remarkable structural and ultrastructural changes evident by neuronal degeneration and reduction of healthy nerve cells. EM showed atrophic nerve cells with irregular outlines, swollen, rarefied mitochondria, and enlarged, fused electron-dense lysosomes indicating possible autophagic vacuoles. Also, a significant increase in the pro-inflammatory markers was noticed, as evident by the raised immunohistochemical expression of glial fibrillary acidic protein (GFAP), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α). In addition, the anti-inflammatory marker decreased, as denoted by the decline in superoxide dismutase (SOD) and catalase. All these alterations were lessened by AA and GA with great restoration in the AA/GA combination group, which showed almost normal histological, ultrastructural, and biochemical parameters. AA and GA are suggested to alleviate Pb‑induced neurotoxicity owing to the modulation of oxidative stress, inflammation, and apoptosis. However, the AA/GA combination shows the greatest effect as evidenced by biochemical, structural, and ultrastructural analyses.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103395"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078703","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.2026.103406
Fang Wang , Xuanying Shi , Xuetian Gao , Dongxin Li , Youquan Guo , Li Chang , Yu Wang
Ferroptosis, an iron-dependent form of regulated cell death, contributes to polycyclic aromatic hydrocarbon (PAH)-induced neurodegeneration. Benzo[a]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.
{"title":"The miR-378a-3p/SLC7A11 axis mediates benzo[a]pyrene-induced ferroptosis in hippocampal neuronal cells","authors":"Fang Wang , Xuanying Shi , Xuetian Gao , Dongxin Li , Youquan Guo , Li Chang , 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}
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.
Methods
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. 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.
Results
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 < 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 < 0.05) suggests that the initial accumulation level is a determining factor in the amount of reduction. Following CaNa₂EDTA treatment, blood Mn levels significantly
Decreased in parallel with the observed reduction in PI.
Conclusion
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.
目的评价基线期和随访期磁共振成像患者苍白质指数（PI） （ΔPI）的变化；检查ΔPI与尿锰（Mn）水平和基线PI值之间的关系；并探讨在随访期间给予can2edta螯合治疗对白斑Mn积累的可能影响。方法27例职业性锰暴露监测对象，采用标准方案从t1加权图像测量左、右PI。ΔPI计算为基线和随访测量值之间的差异。在can2 EDTA治疗期间，在每个疗程的第一天和休息日测量全血和斑点尿锰水平，在治疗的第三天评估24小时尿锰水平。在接受can2edta治疗的个体中，评估治疗前和治疗后PI的变化作为次要分析。使用Spearman rho系数分析ΔPI和Mn生物标志物之间的关联。结果随访期间左、右PI均明显降低。当场尿锰水平与ΔPI呈负相关（右：ρ = -0.59；左：ρ = -0.45; p <； 0.05），表明在高电流暴露的个体中，PI的降低更为有限。ΔPI与初始PI呈正相关（右：ρ = 0.51；左：ρ = 0.74; p <； 0.05）表明初始积累水平是减少量的决定因素。在can2edta治疗后，血锰水平显著下降，与观察到的PI降低平行。结论pi是对锰积累变化敏感的动态成像生物标志物，反映了暴露水平和对螯合治疗的反应。基于核磁共振成像的测量与生物暴露标记的整合可以为监测和评估Mn暴露人群的治疗效果提供重要贡献。
{"title":"Longitudinal changes in pallidal index and their associations with urinary manganese and CaNa₂EDTA chelation","authors":"Tuğba Akkale , Nuriye Kayalı Şendur , Süleyman Filiz , 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 < 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 < 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}
Pub Date : 2026-03-01Epub Date: 2026-01-10DOI: 10.1016/j.neuro.2026.103390
David Mateo , Marília Cristina Oliveira Souza , Nerea Carrión , Luis Heredia , Cristian Cabrera , Montse Marquès , Eva Forcadell-Ferreres , Maria Pino , Josep Zaragoza , José Luis Domingo , Fernando Barbosa , Margarita Torrente
Background
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.
Objective
This pilot study aimed to investigate whether exposure to metals modulates the relationship between GMB composition and clinical outcomes in individuals with CI.
Methods
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.
Results
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 < 0.001).
Conclusion
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.
{"title":"Elevated fecal silver, lithium, and platinum in cognitive impairment: A pilot exploration of microbiota–metal interactions","authors":"David Mateo , Marília Cristina Oliveira Souza , Nerea Carrión , Luis Heredia , Cristian Cabrera , Montse Marquès , Eva Forcadell-Ferreres , Maria Pino , Josep Zaragoza , José Luis Domingo , Fernando Barbosa , 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 < 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}
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 (Girardia tigrina), 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.
{"title":"Promethazine provokes behavioral alterations and disrupts redox homeostasis in planarians","authors":"Kalinka Kendra Mayeski , Camila Caetano Solek , Karina Mara Carus , Juliana Feix , Luiz Carlos Cichota , Helissara Silveira Diefenthaeler , Itamar Luís Gonçalves , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-20DOI: 10.1016/j.neuro.2026.103412
Danielle Ireland , Evangeline Coffinas , Christina Rabeler , Eva-Maria S. Collins
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-D-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: Dugesia japonica and Girardia dorotocephala. 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). G. dorotocephala planarians were generally more sensitive, but D. japonica 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.
在化学品/药物开发过程中及早发现药物和其他化学品对健康的不利影响，可节省大量时间和资源。淡水涡虫是一种新兴的无脊椎动物模型，用于快速，经济有效的神经毒性筛选。因为当暴露于导致哺乳动物癫痫发作的化学物质（如n -甲基- d -天冬氨酸（NMDA）和微毒素）时，真虫表现出类似癫痫发作的行为，它们可能是有用的癫痫发作筛查的一级模型，从而减少对缓慢而昂贵的哺乳动物试验的需求。然而，迄今为止，涡虫癫痫发作的研究一直是低通量的，缺乏必要的标准化和自动化分析，使该模型成为可行的筛选解决方案。在这里，我们展示了在48孔板中进行的中通量行为测试的结果，使用了两种流行的涡虫药理和毒理学研究模型：Dugesia japonica和Girardia dorotocephala。使用自动图像分析对涡虫行为进行评分，测量平移行为和体型变化。我们发现，哺乳动物中已知的致痫性尿源化合物（NMDA、尼古丁、微毒素、匹罗卡品和戊四唑）在暴露30分钟内诱导两种涡虫发生类似癫痫的行为。我们还测试了三种杀虫剂（对硫磷、威威和氯菊酯）。对硫磷和西威因，而不是氯菊酯，引起涡虫癫痫样活动。虽然涡虫物种对大多数化合物的反应相似，但一些化合物的效力差异为10-100倍（分别为匹罗卡品和尼古丁）。多头拟涡虫总体上更敏感，而日本拟涡虫表现出更强的繁殖行为。通过标准化实验方法和分析方法，并使其可用，本工作可作为未来测试化学物质在涡虫中癫痫致尿潜能的框架。
{"title":"Planarian behavioral screening is a useful invertebrate model for evaluating seizurogenic chemicals","authors":"Danielle Ireland , Evangeline Coffinas , Christina Rabeler , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-11DOI: 10.1016/j.neuro.2026.103403
Chung-Pin Hsieh , Mei-Yi Lee , Chia-Yu Lin , Ming-Huan Chan , Hwei-Hsien Chen
Toluene is one of the most commonly abused solvents. Inhibition of N-methyl-D-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 D-serine via inhibiting D-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.
甲苯是最常被滥用的溶剂之一。n -甲基- d -天冬氨酸受体（NMDAR）的抑制与甲苯的奖励和行为效应有关。提高NMDAR功能的途径之一是通过抑制d -氨基酸氧化酶（DAAO）活性来提高d -丝氨酸水平。本研究确定了苯甲酸钠（一种DAAO抑制剂）是否可以抵消急性甲苯暴露后甲苯引起的脑刺激、奖励增强、行为障碍和海马突触功能障碍。在暴露于甲苯之前，雄性小鼠接受不同剂量的苯甲酸钠，评估其颅内自我刺激（ICSS）阈值、旋转棒测试、新物体识别任务、社会互动测试和海马突触传递的长期增强（LTP）和长期抑制（LTD）。苯甲酸钠可预防甲苯所致的ICSS阈值降低、运动不协调、社交退缩、物体识别记忆缺陷和LTP和LTD损害。这些结果表明，苯甲酸钠可以改善甲苯诱导的脑奖励功能促进、行为障碍和突触可塑性损伤，提示苯甲酸钠可能是一种有希望的化合物，用于治疗无意或故意吸入甲苯引起的急性中毒。
{"title":"Protective effects of sodium benzoate against toluene-induced reward enhancement, behavioral disturbances, and impaired synaptic plasticity in mice","authors":"Chung-Pin Hsieh , Mei-Yi Lee , Chia-Yu Lin , Ming-Huan Chan , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.neuro.2026.103399
Ahmed Elagali , Joëlle Rüegg , Nicolò Caporale , Giuseppe Testa , Maria Sapounidou , Jean-Baptiste Fini , Patrik L. Andersson , Sarah Dunlop , Carl-Gustaf Bornehag , Chris Gennings
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) ‘hMIX’ which integrates human relevant reference mixtures with experimental evidence of adverse effects; 2) the Similar Mixture Approach (SMACH) 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.
{"title":"From correlation to causation: Integrating cohorts with experimental studies in mixture toxicology","authors":"Ahmed Elagali , Joëlle Rüegg , Nicolò Caporale , Giuseppe Testa , Maria Sapounidou , Jean-Baptiste Fini , Patrik L. Andersson , Sarah Dunlop , Carl-Gustaf Bornehag , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-11DOI: 10.1016/j.neuro.2026.103404
J.A. Menezes-Filho , E.C.A. Di Giuseppe , T.M.P. Moraes , B.A.T. Couto , B.S. Ferreira , N.B. Matos da Silva , C.S. Lima , W.P. Moraes , A.C. Florentino , F. Barbosa-Jr , C.J.S. Passos
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.
{"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 , E.C.A. Di Giuseppe , T.M.P. Moraes , B.A.T. Couto , B.S. Ferreira , N.B. Matos da Silva , C.S. Lima , W.P. Moraes , A.C. Florentino , F. Barbosa-Jr , 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 Log<sub>2</sub>PbB 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. Log<sub>2</sub>Hg 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}
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