Pub Date : 2025-10-24DOI: 10.1016/j.neuro.2025.103338
Angelo M. Jamerlan, Seong Soo A. An, John P. Hulme
Micro- and nanoplastics (MNPs) are becoming increasingly ubiquitous in the environment, with emerging reports of their accumulation in animal and human tissues. Particle size, morphology, concentration, and surface functionalization modulate MNP cellular internalization, yet the roles of size and shape in toxicity remain underexplored. To address these gaps, we applied an AI-assisted search across fifty studies to uncover the most common outcomes of MNP exposure: inflammation and oxidative stress. A PRISMA-guided search was performed to investigate how these cascades influence microtubule disruption and revealed that neonatal tissues and tauopathy models in older populations (characterized by dynamic changes in the cytoskeleton) are more vulnerable to this disruption. A branch objective involved transcriptomic analyses of human major depressive disorder and murine circadian datasets to explore common inflammatory and clock gene networks that possibly amplify MNP toxicity. Finally, we reviewed the current state of research on how particle size and morphology influence toxicity, noting a paucity of mechanistic studies that used various particle sizes and shapes. This multifaceted framework underscores the need for additional studies on size-, shape-dependent toxicity mechanisms, and their association with cytoskeletal destabilization and neurodegenerative risk.
{"title":"Micro- and nanoplastics as neurotoxicants: Mechanistic insights from particle morphology, circadian disruption, and potential neurodegeneration – A state-of-the-art narrative review","authors":"Angelo M. Jamerlan, Seong Soo A. An, John P. Hulme","doi":"10.1016/j.neuro.2025.103338","DOIUrl":"10.1016/j.neuro.2025.103338","url":null,"abstract":"<div><div>Micro- and nanoplastics (MNPs) are becoming increasingly ubiquitous in the environment, with emerging reports of their accumulation in animal and human tissues. Particle size, morphology, concentration, and surface functionalization modulate MNP cellular internalization, yet the roles of size and shape in toxicity remain underexplored. To address these gaps, we applied an AI-assisted search across fifty studies to uncover the most common outcomes of MNP exposure: inflammation and oxidative stress. A PRISMA-guided search was performed to investigate how these cascades influence microtubule disruption and revealed that neonatal tissues and tauopathy models in older populations (characterized by dynamic changes in the cytoskeleton) are more vulnerable to this disruption. A branch objective involved transcriptomic analyses of human major depressive disorder and murine circadian datasets to explore common inflammatory and clock gene networks that possibly amplify MNP toxicity. Finally, we reviewed the current state of research on how particle size and morphology influence toxicity, noting a paucity of mechanistic studies that used various particle sizes and shapes. This multifaceted framework underscores the need for additional studies on size-, shape-dependent toxicity mechanisms, and their association with cytoskeletal destabilization and neurodegenerative risk.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103338"},"PeriodicalIF":3.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145415714","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 : 2025-10-21DOI: 10.1016/j.neuro.2025.103339
Manuela Sozo Cecchini, Madson Silveira de Melo , Evelise Maria Nazari
Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine levels, is linked to developmental abnormalities, yet its impact on early eye development remains poorly understood. Given the well-documented neurotoxic effects of HHcy on central nervous system (CNS) development, this study aimed to investigate the age-specific effects of HHcy on eye development, focusing on retinal morphology, ultrastructure, vascular integrity, DNA integrity, apoptosis, and neural survival and differentiation. Fertilized Gallus domesticus embryos received 20 μmol homocysteine at embryonic day 2 (E2) and were analyzed at E6 and E10, key stages of eye organization and retinal layering. Although HHcy exposure did not alter retinal thickness, ultrastructural abnormalities indicating subcellular stress, such as dilated perinuclear space and rough endoplasmic reticulum cisternae, were observed. Disruptions on vascular integrity, induced by HHcy exposure were evident at both ages. DNA damage and upregulation of cell cycle regulators were noted at E6 but normalized by E10. Despite this, a reduction in cell proliferation was observed at both ages. Apoptosis increased at E10, suggesting heightened cell death during later retinal development. Neural differentiation and expression of neurotrophic factors were also impaired. Although overall retinal morphology appeared intact, HHcy induced significant molecular and structural disruptions, indicating a multifactorial, temporally dynamic mechanism of toxicity. These findings highlight the sensitivity of developing eye tissues to metabolic imbalance and suggest that even transient elevations in HHcy can interfere with critical developmental processes. This study underscores the potential role of HHcy in eye congenital anomalies and emphasizes the importance of maintaining homocysteine homeostasis during early embryogenesis.
{"title":"Age-dependent effects of hyperhomocysteinemia on neural differentiation and retinal development","authors":"Manuela Sozo Cecchini, Madson Silveira de Melo , Evelise Maria Nazari","doi":"10.1016/j.neuro.2025.103339","DOIUrl":"10.1016/j.neuro.2025.103339","url":null,"abstract":"<div><div>Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine levels, is linked to developmental abnormalities, yet its impact on early eye development remains poorly understood. Given the well-documented neurotoxic effects of HHcy on central nervous system (CNS) development, this study aimed to investigate the age-specific effects of HHcy on eye development, focusing on retinal morphology, ultrastructure, vascular integrity, DNA integrity, apoptosis, and neural survival and differentiation. Fertilized <em>Gallus domesticus</em> embryos received 20 μmol homocysteine at embryonic day 2 (E2) and were analyzed at E6 and E10, key stages of eye organization and retinal layering. Although HHcy exposure did not alter retinal thickness, ultrastructural abnormalities indicating subcellular stress, such as dilated perinuclear space and rough endoplasmic reticulum cisternae, were observed. Disruptions on vascular integrity, induced by HHcy exposure were evident at both ages. DNA damage and upregulation of cell cycle regulators were noted at E6 but normalized by E10. Despite this, a reduction in cell proliferation was observed at both ages. Apoptosis increased at E10, suggesting heightened cell death during later retinal development. Neural differentiation and expression of neurotrophic factors were also impaired. Although overall retinal morphology appeared intact, HHcy induced significant molecular and structural disruptions, indicating a multifactorial, temporally dynamic mechanism of toxicity. These findings highlight the sensitivity of developing eye tissues to metabolic imbalance and suggest that even transient elevations in HHcy can interfere with critical developmental processes. This study underscores the potential role of HHcy in eye congenital anomalies and emphasizes the importance of maintaining homocysteine homeostasis during early embryogenesis.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103339"},"PeriodicalIF":3.9,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355447","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 : 2025-10-18DOI: 10.1016/j.neuro.2025.103336
Lili Liang , Perry E. Sheffield , Rose Saint Fleur-Calixte , Tianxu Xia , Spencer Xinyi Zhang , Jenny J. Lin
Background
Occupational exposure to exhaust fumes, containing neurotoxic particulate matter and polycyclic aromatic hydrocarbons (PAHs), is associated with cardiopulmonary diseases, but its cognitive effects in aging workers remain insufficiently studied. Given increasing occupational longevity, understanding these risks is critical for dementia prevention.
Methods
We analyzed data from 1110 adults aged 60 years and older in the 2011–2012 National Health and Nutrition Examination Survey (NHANES), comparing cognitive performance between exposed (24 %) and unexposed groups. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer’s Disease Word List Learning Test (CERAD-WL), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Distributed lag nonlinear models (DLNMs) evaluated non-linear and time-lagged effects of exposure duration.
Results
Exposed workers were predominantly male (81.6 % vs. 41.8 %), had lower educational attainment (31.2 % vs. 24.4 % with less than high school education), and exhibited higher rates of smoking (65.0 % vs. 48.6 %) and excessive alcohol use (15.7 % vs. 7.0 %). Occupational exposure was associated with significant cognitive impairments in delayed memory (odds ratio [OR] = 2.55, 95 % confidence interval [CI]: 1.61–4.05), verbal fluency (OR 2.41, 1.48–3.94), and processing speed (OR 1.95, 1.19–3.18). The DLNM analyses revealed a biphasic response: minimal effects at < 20 years of exposure, but major declines after 30 years, with a 15–25-year latency period.
Conclusion
Prolonged occupational exhaust fume exposure is associated with domain-specific cognitive decline, particularly affecting memory and executive function. The dose-response relationship underscores cumulative neurotoxicity, emphasizing the need for targeted protections for high-exposure workers.
{"title":"Long-term occupational exhaust fumes exposure and delayed cognitive impairment in older adults: A cross-sectional study in U.S","authors":"Lili Liang , Perry E. Sheffield , Rose Saint Fleur-Calixte , Tianxu Xia , Spencer Xinyi Zhang , Jenny J. Lin","doi":"10.1016/j.neuro.2025.103336","DOIUrl":"10.1016/j.neuro.2025.103336","url":null,"abstract":"<div><h3>Background</h3><div>Occupational exposure to exhaust fumes, containing neurotoxic particulate matter and polycyclic aromatic hydrocarbons (PAHs), is associated with cardiopulmonary diseases, but its cognitive effects in aging workers remain insufficiently studied. Given increasing occupational longevity, understanding these risks is critical for dementia prevention.</div></div><div><h3>Methods</h3><div>We analyzed data from 1110 adults aged 60 years and older in the 2011–2012 National Health and Nutrition Examination Survey (NHANES), comparing cognitive performance between exposed (24 %) and unexposed groups. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer’s Disease Word List Learning Test (CERAD-WL), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Distributed lag nonlinear models (DLNMs) evaluated non-linear and time-lagged effects of exposure duration.</div></div><div><h3>Results</h3><div>Exposed workers were predominantly male (81.6 % vs. 41.8 %), had lower educational attainment (31.2 % vs. 24.4 % with less than high school education), and exhibited higher rates of smoking (65.0 % vs. 48.6 %) and excessive alcohol use (15.7 % vs. 7.0 %). Occupational exposure was associated with significant cognitive impairments in delayed memory (odds ratio [OR] = 2.55, 95 % confidence interval [CI]: 1.61–4.05), verbal fluency (OR 2.41, 1.48–3.94), and processing speed (OR 1.95, 1.19–3.18). The DLNM analyses revealed a biphasic response: minimal effects at < 20 years of exposure, but major declines after 30 years, with a 15–25-year latency period.</div></div><div><h3>Conclusion</h3><div>Prolonged occupational exhaust fume exposure is associated with domain-specific cognitive decline, particularly affecting memory and executive function. The dose-response relationship underscores cumulative neurotoxicity, emphasizing the need for targeted protections for high-exposure workers.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103336"},"PeriodicalIF":3.9,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337259","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 : 2025-10-17DOI: 10.1016/j.neuro.2025.103337
Weiwei Feng , Yue Chu , Xiang Ji , Guanghua Mao , Ting Zhao , Yao Chen , Emmanuel Sunday Okeke , Lei Ai , Liuqing Yang , Xiangyang Wu
Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used and is present in the environment and can be readily absorbed from inhalation or oral exposure. Previous studies have demonstrated that individuals with type 2 diabetes mellitus (T2DM) exhibit heightened sensitivity to environmental pollutants. Given the escalating prevalence of T2DM among adolescents, there is a growing concern regarding the impact of pollutants on this specific population. Consequently, researchers are increasingly focusing their attention on investigating the relationship between pollutants and individuals with diabetes. This paper investigates the toxicity and mechanism of action of DEHP exposure on the nervous system of female pubertal T2DM mice. The study found that DEHP had a significant impact on behavioral indicators including total distance, CW rotation count, residence time in the target quadrant, and latency in locating the platform, in T2DM mice. Transcriptomics analysis revealed that DEHP exposure significantly affected the expression of genes related to synapses and behavior, specifically those involved in the 5-hydroxytryptamine synapse and the signaling pathways associated with neuroactive ligand receptors and neuroreceptors in T2DM mice. Western blotting analyses indicated that DEHP treatment led to inhibition of the cAMP-PKA-ERK1/2-CREB pathway and increased levels of Ca2+ , CaM, and p-CaMKII, which negatively affected the nervous system. Furthermore, factorial analysis demonstrated that DEHP had a greater neurotoxicity in T2DM mice. In conclusion, DEHP impaired exploration and learning memory in female pubertal T2DM mice through the calcium signaling pathway and the cAMP-PKA-ERK1/2-CREB signaling pathway. Additionally, female pubertal T2DM mice were found to be more susceptible to DEHP toxicity compared to healthy mice.
{"title":"Behavioral and transcriptomic analyses reveal neurotoxicity and mechanism of action of DEHP in female pubertal mice with or without type 2 diabetes mellitus","authors":"Weiwei Feng , Yue Chu , Xiang Ji , Guanghua Mao , Ting Zhao , Yao Chen , Emmanuel Sunday Okeke , Lei Ai , Liuqing Yang , Xiangyang Wu","doi":"10.1016/j.neuro.2025.103337","DOIUrl":"10.1016/j.neuro.2025.103337","url":null,"abstract":"<div><div>Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used and is present in the environment and can be readily absorbed from inhalation or oral exposure. Previous studies have demonstrated that individuals with type 2 diabetes mellitus (T2DM) exhibit heightened sensitivity to environmental pollutants. Given the escalating prevalence of T2DM among adolescents, there is a growing concern regarding the impact of pollutants on this specific population. Consequently, researchers are increasingly focusing their attention on investigating the relationship between pollutants and individuals with diabetes. This paper investigates the toxicity and mechanism of action of DEHP exposure on the nervous system of female pubertal T2DM mice. The study found that DEHP had a significant impact on behavioral indicators including total distance, CW rotation count, residence time in the target quadrant, and latency in locating the platform, in T2DM mice. Transcriptomics analysis revealed that DEHP exposure significantly affected the expression of genes related to synapses and behavior, specifically those involved in the 5-hydroxytryptamine synapse and the signaling pathways associated with neuroactive ligand receptors and neuroreceptors in T2DM mice. Western blotting analyses indicated that DEHP treatment led to inhibition of the cAMP-PKA-ERK1/2-CREB pathway and increased levels of Ca<sup>2</sup>+ , CaM, and p-CaMKII, which negatively affected the nervous system. Furthermore, factorial analysis demonstrated that DEHP had a greater neurotoxicity in T2DM mice. In conclusion, DEHP impaired exploration and learning memory in female pubertal T2DM mice through the calcium signaling pathway and the cAMP-PKA-ERK1/2-CREB signaling pathway. Additionally, female pubertal T2DM mice were found to be more susceptible to DEHP toxicity compared to healthy mice.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103337"},"PeriodicalIF":3.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329720","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 : 2025-10-15DOI: 10.1016/j.neuro.2025.103328
SL Boyd , M. Mayil Vahanan , J. Monroe , JA Conley , KE Carstens , TJ Shafer
Exposure of the developing brain to environmental neurotoxicants can result in permanent alterations in structure and/or function. To investigate the effects of chemical exposures on neurodevelopment, the human induced-pluripotent stem cell (iPSC)-derived neural BrainSphere model has been utilized due to its ability to form mature neuronal populations and exhibit spontaneous electrical activity. To model network formation for developmental neurotoxicity screening, developing BrainSpheres were plated on high-density microelectrode arrays (hdMEA) three weeks after beginning differentiation. Starting two days post-plating, BrainSpheres were treated three times per week with compounds known to disrupt in vitro network formation (i.e. assay positive controls; loperamide, dieldrin and deltamethrin), or with an assay negative control, glyphosate, expected to have no effect. For 29 days, BrainSphere activity was recorded to measure neural network activity, general activity, and features of action potential propagation. Concentration-dependent disruption in neural network formation was observed for positive controls at concentrations below cytotoxicity. Dieldrin, deltamethrin, and loperamide exposure disrupted several features of general activity, neural network formation, and action potential propagation. BrainSpheres on hdMEAs detected chemically induced perturbations in neural network formation and may represent a valuable complex in vitro model useful for developmental neurotoxicity screening.
{"title":"Development of a network formation assay for developmental neurotoxicity hazard screening using 3D human iPSC derived BrainSpheres","authors":"SL Boyd , M. Mayil Vahanan , J. Monroe , JA Conley , KE Carstens , TJ Shafer","doi":"10.1016/j.neuro.2025.103328","DOIUrl":"10.1016/j.neuro.2025.103328","url":null,"abstract":"<div><div>Exposure of the developing brain to environmental neurotoxicants can result in permanent alterations in structure and/or function. To investigate the effects of chemical exposures on neurodevelopment, the human induced-pluripotent stem cell (iPSC)-derived neural BrainSphere model has been utilized due to its ability to form mature neuronal populations and exhibit spontaneous electrical activity. To model network formation for developmental neurotoxicity screening, developing BrainSpheres were plated on high-density microelectrode arrays (hdMEA) three weeks after beginning differentiation. Starting two days post-plating, BrainSpheres were treated three times per week with compounds known to disrupt <em>in vitro</em> network formation (i.e. assay positive controls; loperamide, dieldrin and deltamethrin), or with an assay negative control, glyphosate, expected to have no effect. For 29 days, BrainSphere activity was recorded to measure neural network activity, general activity, and features of action potential propagation. Concentration-dependent disruption in neural network formation was observed for positive controls at concentrations below cytotoxicity. Dieldrin, deltamethrin, and loperamide exposure disrupted several features of general activity, neural network formation, and action potential propagation. BrainSpheres on hdMEAs detected chemically induced perturbations in neural network formation and may represent a valuable complex <em>in vitro</em> model useful for developmental neurotoxicity screening.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103328"},"PeriodicalIF":3.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313346","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 : 2025-10-15DOI: 10.1016/j.neuro.2025.103335
Melinda C. Power , Ziwei Song , Annie Chen , Katie M. Lynch , Naa Adoley Parker-Allotey , Erin E. Bennett , Xiaohui Xu , Eric A. Whitsel , Richard L. Smith , James D. Stewart , Eun Sug Park , Qi Ying , Emma K. Stapp
Midlife ambient air pollution exposures may be etiologically relevant to late-life cognition. We considered whether midlife air pollution and traffic exposures are associated with midlife to late-life cognitive change. Our sample included Atherosclerosis Risk in Communities (ARIC) cohort study participants with cognitive testing at Visit 2 (1990–1992, ages 48–67), which was repeated at Visit 4 (1996–1998), Visit 5 (2011–2013), Visit 6 (2016–2017), and Visit 7 (2018–2019). At participant addresses, we estimated: [i] 1990–1992 average ambient air pollutant concentrations for 18 pollutants using Community Multiscale Air Quality chemical transport model output fused with observed annual concentrations, and [ii] distance to major roads and road density within a 500-meter radius. We used meta-analysis of site-specific adjusted linear mixed-effects models to quantify associations between each exposure and 29-year cognitive change. Among 12,700 eligible participants, mean age was 57 years, 56 % were female, 24 % identified as Black, and 79 % had at least a high school education. There was no statistical support linking higher exposures to criteria air pollutants, most PM components, or roadway proximity in midlife and cognitive change. However, there was some suggestion that higher midlife exposures to nitrates, copper, iron, lead, and zinc may be associated with greater 29-year decline in executive function and that higher midlife exposures to copper and lead may be associated with greater declines in a global z-score. Our cohort study does not support a link between midlife exposures to most air pollutants and mid- to late-life-cognitive change. Confirmation or repudiation of suggestive findings in an independent dataset is warranted.
{"title":"Association of midlife air pollution and road proximity exposure with 29-year cognitive decline","authors":"Melinda C. Power , Ziwei Song , Annie Chen , Katie M. Lynch , Naa Adoley Parker-Allotey , Erin E. Bennett , Xiaohui Xu , Eric A. Whitsel , Richard L. Smith , James D. Stewart , Eun Sug Park , Qi Ying , Emma K. Stapp","doi":"10.1016/j.neuro.2025.103335","DOIUrl":"10.1016/j.neuro.2025.103335","url":null,"abstract":"<div><div>Midlife ambient air pollution exposures may be etiologically relevant to late-life cognition. We considered whether midlife air pollution and traffic exposures are associated with midlife to late-life cognitive change. Our sample included Atherosclerosis Risk in Communities (ARIC) cohort study participants with cognitive testing at Visit 2 (1990–1992, ages 48–67), which was repeated at Visit 4 (1996–1998), Visit 5 (2011–2013), Visit 6 (2016–2017), and Visit 7 (2018–2019). At participant addresses, we estimated: [i] 1990–1992 average ambient air pollutant concentrations for 18 pollutants using Community Multiscale Air Quality chemical transport model output fused with observed annual concentrations, and [ii] distance to major roads and road density within a 500-meter radius. We used meta-analysis of site-specific adjusted linear mixed-effects models to quantify associations between each exposure and 29-year cognitive change. Among 12,700 eligible participants, mean age was 57 years, 56 % were female, 24 % identified as Black, and 79 % had at least a high school education. There was no statistical support linking higher exposures to criteria air pollutants, most PM components, or roadway proximity in midlife and cognitive change. However, there was some suggestion that higher midlife exposures to nitrates, copper, iron, lead, and zinc may be associated with greater 29-year decline in executive function and that higher midlife exposures to copper and lead may be associated with greater declines in a global z-score. Our cohort study does not support a link between midlife exposures to most air pollutants and mid- to late-life-cognitive change. Confirmation or repudiation of suggestive findings in an independent dataset is warranted.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103335"},"PeriodicalIF":3.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313393","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 : 2025-10-10DOI: 10.1016/j.neuro.2025.103334
Johann Vulin , Fabien Chauveau , Chloé Duret , Muris Humo , Marco Valdebenito , Claire Aufauvre , Louis Vidal , Eric Morignat , Jérémy Verchere , Aude Decesar , Damien Gaillard , Latifa Lakdhar , Thierry Baron , Gwenaëlle Lavison-bompard , Benjamin VIDAL
Background
Chlordecone (CLD) is a persistent organochlorine pesticide formerly used against banana weevil. It is detectable in blood samples from a large proportion of the population in the French Caribbean Islands. Several experimental studies have demonstrated acute neurotoxicity of CLD, but the effects of a subchronic exposure to CLD remains to be studied.
Methods
Young adult male mice were injected intraperitoneally with 3 mg/kg CLD (n = 34) or vehicle (n = 22), twice a week, for eight weeks. Behavior, regional brain accumulation, and effects on the dopaminergic system were studied. In addition, functional ultrasound imaging (fUSi) was used to probe the visual, somatosensory and dopaminergic pathways.
Results
CLD was detected in all brain regions (5–15 mg/kg) after two-month exposure, without any marked impact on behavior (anxiety, motor coordination, memory). The dopaminergic system was mostly unaffected, despite slight decreases in the number of TH-positive neurons and the expression of VMAT2, quantified in a subset of animals. fUSi highlighted a decreased response to the visual stimulation in CLD-exposed animals, in contrast to the sensorimotor response, which was found unaltered.
Conclusion
The two-month-long, systemic, exposure to an intermediate dose of CLD resulted in a mostly unaffected phenotype, with a normal behavior and a largely intact dopaminergic system. Interestingly, functional ultrasound imaging was able to detect an altered visual response. This study position functional ultrasound imaging as a promising technique to capture early signs of neurotoxicity, opening up opportunities for “toxico-fUS” in the field of neurotoxicology.
{"title":"Behavioural, biochemical and functional phenotyping of subchronic exposure to chlordecone in mice","authors":"Johann Vulin , Fabien Chauveau , Chloé Duret , Muris Humo , Marco Valdebenito , Claire Aufauvre , Louis Vidal , Eric Morignat , Jérémy Verchere , Aude Decesar , Damien Gaillard , Latifa Lakdhar , Thierry Baron , Gwenaëlle Lavison-bompard , Benjamin VIDAL","doi":"10.1016/j.neuro.2025.103334","DOIUrl":"10.1016/j.neuro.2025.103334","url":null,"abstract":"<div><h3>Background</h3><div>Chlordecone (CLD) is a persistent organochlorine pesticide formerly used against banana weevil. It is detectable in blood samples from a large proportion of the population in the French Caribbean Islands. Several experimental studies have demonstrated acute neurotoxicity of CLD, but the effects of a subchronic exposure to CLD remains to be studied.</div></div><div><h3>Methods</h3><div>Young adult male mice were injected intraperitoneally with 3 mg/kg CLD (n = 34) or vehicle (n = 22), twice a week, for eight weeks. Behavior, regional brain accumulation, and effects on the dopaminergic system were studied. In addition, functional ultrasound imaging (fUSi) was used to probe the visual, somatosensory and dopaminergic pathways.</div></div><div><h3>Results</h3><div>CLD was detected in all brain regions (5–15 mg/kg) after two-month exposure, without any marked impact on behavior (anxiety, motor coordination, memory). The dopaminergic system was mostly unaffected, despite slight decreases in the number of TH-positive neurons and the expression of VMAT2, quantified in a subset of animals. fUSi highlighted a decreased response to the visual stimulation in CLD-exposed animals, in contrast to the sensorimotor response, which was found unaltered.</div></div><div><h3>Conclusion</h3><div>The two-month-long, systemic, exposure to an intermediate dose of CLD resulted in a mostly unaffected phenotype, with a normal behavior and a largely intact dopaminergic system. Interestingly, functional ultrasound imaging was able to detect an altered visual response. This study position functional ultrasound imaging as a promising technique to capture early signs of neurotoxicity, opening up opportunities for “toxico-fUS” in the field of neurotoxicology.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103334"},"PeriodicalIF":3.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267199","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 : 2025-10-02DOI: 10.1016/j.neuro.2025.103333
Ji-Hang Yin, Katharine A. Horzmann
1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is an endogenous metabolite of the industrial waste trichloroethylene (TCE) and has been implicated as a potent neurotoxicant in TCE-induced neurotoxicity. TaClo has been associated with Parkinson’s disease (PD) due to its neurotoxic effects and structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Despite the similarities, limited studies have explored the comparative neurotoxicity of MPTP and TaClo within the same experimental models. Zebrafish (Danio rerio) are a powerful high throughput platform for neurotoxicology studies and have been used to evaluate TCE-associated developmental neurotoxicity; however, the role of TaClo in TCE-associated neurotoxicity in the zebrafish model is unknown. To address these gaps, we established an MPTP-induced PD zebrafish larval model and investigated the role of TaClo by comparing its neurotoxic effects with those of MPTP. We exposed embryonic zebrafish to TaClo (5, 50, or 500 ppb) or MPTP (0–17,325 ppb) for 5 consecutive days. We demonstrate that TaClo at 5 ppb elicits 303.2 ppb MPTP-like neurotoxicity in the developmental zebrafish. We determined the lethal concentration 50 of TaClo at the zebrafish larval model at 120 h post-fertilization was 7890 ppb. We show that embryonic zebrafish exposed to TaClo exhibit neurobehavioral impairments, diencephalic dopaminergic neuronal damage, increased cellular apoptosis, astrocytic loss, microgliosis, and altered glutathione peroxidase activity levels. These findings provide important insights into the neurotoxic mechanisms of TaClo and emphasize the utility of developmental zebrafish as a model for studying TaClo-induced neurotoxicity. Our work contributes to environmental contaminants research in neurodegenerative diseases by providing evidence of the potential link between TaClo exposure and PD.
{"title":"Developmental exposure of zebrafish to 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) elicits MPTP-like neurotoxicity","authors":"Ji-Hang Yin, Katharine A. Horzmann","doi":"10.1016/j.neuro.2025.103333","DOIUrl":"10.1016/j.neuro.2025.103333","url":null,"abstract":"<div><div>1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is an endogenous metabolite of the industrial waste trichloroethylene (TCE) and has been implicated as a potent neurotoxicant in TCE-induced neurotoxicity. TaClo has been associated with Parkinson’s disease (PD) due to its neurotoxic effects and structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Despite the similarities, limited studies have explored the comparative neurotoxicity of MPTP and TaClo within the same experimental models. Zebrafish (<em>Danio rerio</em>) are a powerful high throughput platform for neurotoxicology studies and have been used to evaluate TCE-associated developmental neurotoxicity; however, the role of TaClo in TCE-associated neurotoxicity in the zebrafish model is unknown. To address these gaps, we established an MPTP-induced PD zebrafish larval model and investigated the role of TaClo by comparing its neurotoxic effects with those of MPTP. We exposed embryonic zebrafish to TaClo (5, 50, or 500 ppb) or MPTP (0–17,325 ppb) for 5 consecutive days. We demonstrate that TaClo at 5 ppb elicits 303.2 ppb MPTP-like neurotoxicity in the developmental zebrafish. We determined the lethal concentration 50 of TaClo at the zebrafish larval model at 120 h post-fertilization was 7890 ppb. We show that embryonic zebrafish exposed to TaClo exhibit neurobehavioral impairments, diencephalic dopaminergic neuronal damage, increased cellular apoptosis, astrocytic loss, microgliosis, and altered glutathione peroxidase activity levels. These findings provide important insights into the neurotoxic mechanisms of TaClo and emphasize the utility of developmental zebrafish as a model for studying TaClo-induced neurotoxicity. Our work contributes to environmental contaminants research in neurodegenerative diseases by providing evidence of the potential link between TaClo exposure and PD.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103333"},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228288","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 : 2025-10-01DOI: 10.1016/j.neuro.2025.103332
Ayang Zhao , Hongjiang Jin , Xiaofei Ma , Guibo Fan , Yueyue Gao , Yuting Rong , Siqi Sun , Ao Zhang , Sihua Qi
Background
Exposure to general anesthetics during early postnatal development is linked to enduring cognitive deficits in rodent and non-human primate models. However, the mechanisms by which inhaled anesthetics induce neuronal death and synaptic alterations remain unclear.
Methods
C. elegans and neonatal male mice were administered sevoflurane. Subsequently, their learning and memory capabilities were assessed, and the potential mechanisms influencing learning and memory in C. elegans and mice were explored.
Results
Early developmental exposure to sevoflurane resulted in learning and memory impairment in C. elegans. The eIF3l and ced-3 genes are critical for sevoflurane-induced developmental neurotoxicity in C. elegans. Endoplasmic reticulum stress is a possible mechanism underlying developmental neurotoxicity induced by sevoflurane in C. elegans. In neonatal mice, sevoflurane induced endoplasmic reticulum stress in hippocampal neurons independently of eIF3l, which was mitigated by TUDCA ( tauroursodeoxycholic acid, an ER stress inhibitor). Additionally, mature mice exposed to sevoflurane during the neonatal period exhibited decreased synaptic function in the hippocampus, which was alleviated by TUDCA. Persistent cognitive dysfunction was observed in adult mice exposed to sevoflurane during the neonatal period, which was alleviated by TUDCA.
Conclusion
Our findings demonstrate that early developmental exposure to sevoflurane induces endoplasmic reticulum stress, which may result in a decrease in memory and learning capabilities. TUDCA may alleviate these effects.
{"title":"Sevoflurane exposure in juvenile causes persistent learning and memory impairment via inducing endoplasmic reticulum stress in caenorhabditis elegans and mice","authors":"Ayang Zhao , Hongjiang Jin , Xiaofei Ma , Guibo Fan , Yueyue Gao , Yuting Rong , Siqi Sun , Ao Zhang , Sihua Qi","doi":"10.1016/j.neuro.2025.103332","DOIUrl":"10.1016/j.neuro.2025.103332","url":null,"abstract":"<div><h3>Background</h3><div>Exposure to general anesthetics during early postnatal development is linked to enduring cognitive deficits in rodent and non-human primate models. However, the mechanisms by which inhaled anesthetics induce neuronal death and synaptic alterations remain unclear.</div></div><div><h3>Methods</h3><div><em>C. elegans</em> and neonatal male mice were administered sevoflurane. Subsequently, their learning and memory capabilities were assessed, and the potential mechanisms influencing learning and memory in <em>C. elegans</em> and mice were explored<em>.</em></div></div><div><h3>Results</h3><div>Early developmental exposure to sevoflurane resulted in learning and memory impairment in <em>C. elegans.</em> The eIF3l and ced-3 genes are critical for sevoflurane-induced developmental neurotoxicity in <em>C. elegans</em>. Endoplasmic reticulum stress is a possible mechanism underlying developmental neurotoxicity induced by sevoflurane in <em>C. elegans</em>. In neonatal mice, sevoflurane induced endoplasmic reticulum stress in hippocampal neurons independently of eIF3l, which was mitigated by TUDCA ( tauroursodeoxycholic acid, an ER stress inhibitor). Additionally, mature mice exposed to sevoflurane during the neonatal period exhibited decreased synaptic function in the hippocampus, which was alleviated by TUDCA. Persistent cognitive dysfunction was observed in adult mice exposed to sevoflurane during the neonatal period, which was alleviated by TUDCA.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that early developmental exposure to sevoflurane induces endoplasmic reticulum stress, which may result in a decrease in memory and learning capabilities. TUDCA may alleviate these effects.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103332"},"PeriodicalIF":3.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220441","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 : 2025-09-30DOI: 10.1016/j.neuro.2025.103331
Jingjing Gao , Jinghua Shen , Lu Gao , Dongying Yan , Ying Wang , Jia Meng , Dawei Chen , Hong Li , Jie Wu
Brominated flame retardants polybrominated diphenyl ethers (PBDEs) have posed threat to ecosystems and human health, especially on neurodevelopment, while the mechanisms remain obscure. Here, we assessed recognition memory for new object and spontaneous behavior of adolescent male rats after perinatal BDE-209 exposure. Considering that the miR-34 family is linked to spines morphology and memory formation and mediates neuroprotective role of melatonin through Sirtuin1 (SIRT1), we investigated the role of miR-34 in developmental neurotoxicity of BDE-209 of rats with or without melatonin pretreatment. We analyzed dendritic arborisation and spines density of pyramidal neurons in both prefrontal cortex (PFC) and hippocampal CA1 region via Golgi-staining and Sholl tools; then conducted miRNA sequencing and verified differentially expressed miRNAs and their targets. Our findings indicated that miR-34c and miR-134 were significantly up-regulated in the hippocampus and PFC of maternal BDE-209-exposed rats, as a target of miR-34c simultaneously upstream regulator for miR-134, neuronal SIRT1 level was decreased correspondingly. Furthermore, miR-134 targeted LIMK1/cofilin and CREB/BDNF pathway contributing to changes in dendritic morphology. Melatonin pretreatment restored synaptic morphological plasticity especially spines density in hippocampal and cortical neurons, partially through elevating SIRT1 expression, and alleviated BDE-209-caused memory deficits, providing a potential neuroprotective intervention.
{"title":"Melatonin improves synaptic morphological plasticity of adolescent male rats after perinatal BDE-209 exposure via SIRT1-mediated LIMK1 and CREB signaling","authors":"Jingjing Gao , Jinghua Shen , Lu Gao , Dongying Yan , Ying Wang , Jia Meng , Dawei Chen , Hong Li , Jie Wu","doi":"10.1016/j.neuro.2025.103331","DOIUrl":"10.1016/j.neuro.2025.103331","url":null,"abstract":"<div><div>Brominated flame retardants polybrominated diphenyl ethers (PBDEs) have posed threat to ecosystems and human health, especially on neurodevelopment, while the mechanisms remain obscure. Here, we assessed recognition memory for new object and spontaneous behavior of adolescent male rats after perinatal BDE-209 exposure. Considering that the miR-34 family is linked to spines morphology and memory formation and mediates neuroprotective role of melatonin through Sirtuin1 (SIRT1), we investigated the role of miR-34 in developmental neurotoxicity of BDE-209 of rats with or without melatonin pretreatment. We analyzed dendritic arborisation and spines density of pyramidal neurons in both prefrontal cortex (PFC) and hippocampal CA1 region via Golgi-staining and Sholl tools; then conducted miRNA sequencing and verified differentially expressed miRNAs and their targets. Our findings indicated that miR-34c and miR-134 were significantly up-regulated in the hippocampus and PFC of maternal BDE-209-exposed rats, as a target of miR-34c simultaneously upstream regulator for miR-134, neuronal SIRT1 level was decreased correspondingly. Furthermore, miR-134 targeted LIMK1/cofilin and CREB/BDNF pathway contributing to changes in dendritic morphology. Melatonin pretreatment restored synaptic morphological plasticity especially spines density in hippocampal and cortical neurons, partially through elevating SIRT1 expression, and alleviated BDE-209-caused memory deficits, providing a potential neuroprotective intervention.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103331"},"PeriodicalIF":3.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206976","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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