Pub Date : 2026-01-01Epub Date: 2025-12-18DOI: 10.1016/j.neuro.2025.103369
João Paulo Medeiros Mamede , Maria Clara Galvão-Pereira , Augusto Monteiro de Souza , Silvia Regina Batistuzzo de Medeiros , Ana Carolina Luchiari
Alcohol consumption during pregnancy is a major public health concern, as prenatal exposure to ethanol can disrupt embryonic development and lead to Fetal Alcohol Spectrum Disorders (FASD). These disorders are characterized by a wide range of morphological, behavioral, and cognitive impairments, which variability across individuals is strongly influenced by genetic background and environmental conditions. Animal models, particularly zebrafish, offer a powerful tool to investigate how such factors modulate susceptibility to alcohol. In this study, we examined the effects of embryonic alcohol exposure in three zebrafish populations (AB, TU, and OB), assessing developmental parameters, behavior, and gene expression. Results showed that the OB population exhibited higher mortality and pronounced alterations in genes related to metabolism and neurotransmission; AB displayed reduced body and eye growth, along with increased social cohesion under alcohol exposure; while TU was more vulnerable to behavioral effects despite showing morphological resilience. Furthermore, the expression of key genes such as sox2, th1, drd1b, gabra1, and bdnf varied according to both population and alcohol concentration. These findings emphasize the relevance of genetic differences in modulating alcohol’s impact and reinforce zebrafish as a valuable translational model for FASD research, paving the way for more refined diagnostic and therapeutic approaches.
{"title":"Understanding similarities and differences of FASD in three zebrafish populations","authors":"João Paulo Medeiros Mamede , Maria Clara Galvão-Pereira , Augusto Monteiro de Souza , Silvia Regina Batistuzzo de Medeiros , Ana Carolina Luchiari","doi":"10.1016/j.neuro.2025.103369","DOIUrl":"10.1016/j.neuro.2025.103369","url":null,"abstract":"<div><div>Alcohol consumption during pregnancy is a major public health concern, as prenatal exposure to ethanol can disrupt embryonic development and lead to Fetal Alcohol Spectrum Disorders (FASD). These disorders are characterized by a wide range of morphological, behavioral, and cognitive impairments, which variability across individuals is strongly influenced by genetic background and environmental conditions. Animal models, particularly zebrafish, offer a powerful tool to investigate how such factors modulate susceptibility to alcohol. In this study, we examined the effects of embryonic alcohol exposure in three zebrafish populations (AB, TU, and OB), assessing developmental parameters, behavior, and gene expression. Results showed that the OB population exhibited higher mortality and pronounced alterations in genes related to metabolism and neurotransmission; AB displayed reduced body and eye growth, along with increased social cohesion under alcohol exposure; while TU was more vulnerable to behavioral effects despite showing morphological resilience. Furthermore, the expression of key genes such as <em>sox2, th1, drd1b, gabra1</em><strong>,</strong> and <em>bdnf</em> varied according to both population and alcohol concentration. These findings emphasize the relevance of genetic differences in modulating alcohol’s impact and reinforce zebrafish as a valuable translational model for FASD research, paving the way for more refined diagnostic and therapeutic approaches.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103369"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-23DOI: 10.1016/j.neuro.2025.103371
Kathryn S. Konrad , Katherine Allen-Moyer , Lee Ellis , Ellen Hessel , Oihane Jaka , Arantza Muriana , Beatriz Molina Martínez , Ana del Pozo , Valentina Schiavone , Vincenzo Di Donato , Claudia Miguel Sanz , Lisa Truong , Robyn Tanguay , Keith R. Shockley , Kristen Ryan , Jui-Hua Hsieh
The link between environmental chemical exposures and neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder underscores the need to develop efficient developmental neurotoxicity (DNT) assays for chemical evaluation. The zebrafish Light-Dark Transition Test (LDTT) assesses changes in zebrafish larval behavioral responses to chemical exposure by recording their distance moved under alternating light and dark conditions. To gain confidence in classifying a chemical as having a DNT effect for the LDTT assay, it is important to determine the minimum sample size to obtain a robust behavioral response. We calculated statistical power under common models based on LDTT data collected from four laboratories using standard protocol parameters, where each 96-well plate contained 5–7 test concentrations and 12–16 vehicle control wells (1 larva/well). Power calculations were conducted to identify concentration effects using t-tests, analysis of variance (ANOVA), and repeated measures ANOVA (RMANOVA), with data from four endpoints: Total Distance, Movement Similarity, Distance Change, and Distance Shift. The tests showed the highest power for the Movement Similarity and Distance Change endpoints, which had the lowest intra- and inter-laboratory variability, resulting in a smaller necessary sample size to estimate dose effects. The use of these endpoints more than doubled the power of the statistical tests for the Total Distance endpoints using the same sample size and typically required between 8 and 32 samples to achieve 80 % power at a 20 % effect size. This work demonstrates that the LDTT can be improved for detecting DNT effects by careful consideration of endpoint selection, data transformation, and type of statistical test.
{"title":"Power calculations for larval zebrafish in light-dark transition test for developmental neurotoxicity","authors":"Kathryn S. Konrad , Katherine Allen-Moyer , Lee Ellis , Ellen Hessel , Oihane Jaka , Arantza Muriana , Beatriz Molina Martínez , Ana del Pozo , Valentina Schiavone , Vincenzo Di Donato , Claudia Miguel Sanz , Lisa Truong , Robyn Tanguay , Keith R. Shockley , Kristen Ryan , Jui-Hua Hsieh","doi":"10.1016/j.neuro.2025.103371","DOIUrl":"10.1016/j.neuro.2025.103371","url":null,"abstract":"<div><div>The link between environmental chemical exposures and neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder underscores the need to develop efficient developmental neurotoxicity (DNT) assays for chemical evaluation. The zebrafish Light-Dark Transition Test (LDTT) assesses changes in zebrafish larval behavioral responses to chemical exposure by recording their distance moved under alternating light and dark conditions. To gain confidence in classifying a chemical as having a DNT effect for the LDTT assay, it is important to determine the minimum sample size to obtain a robust behavioral response. We calculated statistical power under common models based on LDTT data collected from four laboratories using standard protocol parameters, where each 96-well plate contained 5–7 test concentrations and 12–16 vehicle control wells (1 larva/well). Power calculations were conducted to identify concentration effects using t-tests, analysis of variance (ANOVA), and repeated measures ANOVA (RMANOVA), with data from four endpoints: Total Distance, Movement Similarity, Distance Change, and Distance Shift. The tests showed the highest power for the Movement Similarity and Distance Change endpoints, which had the lowest intra- and inter-laboratory variability, resulting in a smaller necessary sample size to estimate dose effects. The use of these endpoints more than doubled the power of the statistical tests for the Total Distance endpoints using the same sample size and typically required between 8 and 32 samples to achieve 80 % power at a 20 % effect size. This work demonstrates that the LDTT can be improved for detecting DNT effects by careful consideration of endpoint selection, data transformation, and type of statistical test.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103371"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-16DOI: 10.1016/j.neuro.2025.103368
Yang-Chen Chang , Wan-Hsuan Lin , Horng-Huey Ko , Yi-Ching Lo , Hsun-Shuo Chang , Hui-Ching Lin , Yih-Fung Chen
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger N-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.
{"title":"Formononetin protects against oxaliplatin-induced peripheral neurotoxicity via Nrf2/HO-1 antioxidant pathway without impairing anticancer efficacy","authors":"Yang-Chen Chang , Wan-Hsuan Lin , Horng-Huey Ko , Yi-Ching Lo , Hsun-Shuo Chang , Hui-Ching Lin , Yih-Fung Chen","doi":"10.1016/j.neuro.2025.103368","DOIUrl":"10.1016/j.neuro.2025.103368","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger <em>N</em>-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103368"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-27DOI: 10.1016/j.neuro.2025.103376
Gahyun Lim , Ho Young Lee , Zachery R. Jarrell , Seong Su Kang , Dean P. Jones , Young-Mi Go
Cadmium (Cd) is a neurotoxic metal that accumulates via dietary, environmental, and occupational sources and is closely linked to oxidative stress and neuroinflammation. Little is known about the mechanistic effects of low-dose environmental Cd as found in the human diet on cognition in aged mice. Male aged mice (C57BL/6 J, 20 months old) received water with or without 3.3 mg/L Cd for 12 weeks. Cognitive function was assessed using the Y-maze, thiol/disulfide redox states were analyzed by high-performance liquid chromatography, brain Cd levels were determined by inductively coupled plasma mass spectrometry, hippocampal morphology was examined by histological analysis, and metabolomics was analyzed by high-resolution mass spectrometry. Low-dose environmental Cd exposure led to brain Cd accumulation and impaired cognitive function in aged male mice, accompanied by reduced hippocampal neuronal density in the cornu ammonis 1 region. Cd shifted the plasma redox toward a more oxidizing state, along with elevated hydroxytetradecanoic acid and decreased N-oleoylethanolamine in the brain. Cd decreased bioactive signaling lipids (lysophosphatidic acid, oleamide, sphingomyelin, sphingosine) and selectively acylcarnitine levels in the brain. Increased pyridoxal phosphate and lipoamide and decreased glutamine brain levels suggest potential compensatory responses. Exposure to low environmental levels of Cd in aged male mice disrupts redox homeostasis and systemic lipid metabolism, leading to cognitive decline, accompanied by compensatory responses. The results suggest that environmental Cd at levels found in the human diet could contribute to cognitive decline.
{"title":"Cadmium exposure at low environmental levels induces cognitive decline in aged male mice","authors":"Gahyun Lim , Ho Young Lee , Zachery R. Jarrell , Seong Su Kang , Dean P. Jones , Young-Mi Go","doi":"10.1016/j.neuro.2025.103376","DOIUrl":"10.1016/j.neuro.2025.103376","url":null,"abstract":"<div><div>Cadmium (Cd) is a neurotoxic metal that accumulates via dietary, environmental, and occupational sources and is closely linked to oxidative stress and neuroinflammation. Little is known about the mechanistic effects of low-dose environmental Cd as found in the human diet on cognition in aged mice. Male aged mice (C57BL/6 J, 20 months old) received water with or without 3.3 mg/L Cd for 12 weeks. Cognitive function was assessed using the Y-maze, thiol/disulfide redox states were analyzed by high-performance liquid chromatography, brain Cd levels were determined by inductively coupled plasma mass spectrometry, hippocampal morphology was examined by histological analysis, and metabolomics was analyzed by high-resolution mass spectrometry. Low-dose environmental Cd exposure led to brain Cd accumulation and impaired cognitive function in aged male mice, accompanied by reduced hippocampal neuronal density in the cornu ammonis 1 region. Cd shifted the plasma redox toward a more oxidizing state, along with elevated hydroxytetradecanoic acid and decreased N-oleoylethanolamine in the brain. Cd decreased bioactive signaling lipids (lysophosphatidic acid, oleamide, sphingomyelin, sphingosine) and selectively acylcarnitine levels in the brain. Increased pyridoxal phosphate and lipoamide and decreased glutamine brain levels suggest potential compensatory responses. Exposure to low environmental levels of Cd in aged male mice disrupts redox homeostasis and systemic lipid metabolism, leading to cognitive decline, accompanied by compensatory responses. The results suggest that environmental Cd at levels found in the human diet could contribute to cognitive decline.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103376"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145857364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-31DOI: 10.1016/j.neuro.2025.103379
J. Pepijn Wopken , Jack R. Thornton , Regina G.D.M. van Kleef , Remco H.S. Westerink
The use of novel psychoactive substances (NPS) has been increasing over the last 20 years. Given the coinciding increasing number of health incidents, it is of paramount importance to comprehend the neurotoxic hazards associated with these often potent but poorly characterized designer drugs. The objective of this study was therefore to investigate the neuromodulatory effects of various (designer) drugs, including cannabidiol (CBD), a synthetic cannabinoid receptor agonist (RCS-4), three canonical benzodiazepines (diazepam, oxazepam, and lorazepam) and two designer benzodiazepines (flunitrazolam and fluetizolam). To that aim, we measured changes in spontaneous neuronal activity following acute drug exposure in primary rat cortical cultures grown on microelectrode arrays (MEAs). Acute exposure to ≥ 3 µM CBD resulted in a concentration-dependent decrease of all major activity parameters, such as the number of spikes, the number of bursts, the number of spikes in a burst, burst duration, the number of network bursts, the number of spikes in a network burst, and network burst duration. These effects were comparable to those observed following acute exposure to the synthetic cannabinoid receptor agonist RCS-4, which inhibited neuronal activity at ≥ 1 µM. At the highest concentration, the decrease in neuronal activity was paralleled by an increase in burst duration. The three canonical benzodiazepines (diazepam, oxazepam, and lorazepam) concentration-dependently decreased neuronal activity (number of spikes, number of bursts and number of network bursts) with lowest observed effect concentrations (LOECs) of 0.1 µM, 1 µM and 0.1 µM, respectively. The decrease in neuronal activity was paralleled by an increase in burst duration, which was particularly profound for diazepam. The two designer benzodiazepines (flunitrazolam, and fluetizolam) potently decreased neuronal activity with LOECs of 0.01 µM and 0.03 µM, respectively. Comparable to the canonical benzodiazepines, the decrease in neuronal activity was paralleled by a marked increase in burst duration. Our findings demonstrate the applicability of MEA recordings for neurotoxicity assessment and potency ranking of diverse (designer) drugs. The strong potency of some of these drugs is particularly concerning and underscores the urgent need for better regulation and control of these substances to safeguard public health.
{"title":"Inhibitory effects of (synthetic) cannabinoids and (designer) benzodiazepines on spontaneously active neuronal networks of primary rat cortical cultures in vitro","authors":"J. Pepijn Wopken , Jack R. Thornton , Regina G.D.M. van Kleef , Remco H.S. Westerink","doi":"10.1016/j.neuro.2025.103379","DOIUrl":"10.1016/j.neuro.2025.103379","url":null,"abstract":"<div><div>The use of novel psychoactive substances (NPS) has been increasing over the last 20 years. Given the coinciding increasing number of health incidents, it is of paramount importance to comprehend the neurotoxic hazards associated with these often potent but poorly characterized designer drugs. The objective of this study was therefore to investigate the neuromodulatory effects of various (designer) drugs, including cannabidiol (CBD), a synthetic cannabinoid receptor agonist (RCS-4), three canonical benzodiazepines (diazepam, oxazepam, and lorazepam) and two designer benzodiazepines (flunitrazolam and fluetizolam). To that aim, we measured changes in spontaneous neuronal activity following acute drug exposure in primary rat cortical cultures grown on microelectrode arrays (MEAs). Acute exposure to ≥ 3 µM CBD resulted in a concentration-dependent decrease of all major activity parameters, such as the number of spikes, the number of bursts, the number of spikes in a burst, burst duration, the number of network bursts, the number of spikes in a network burst, and network burst duration. These effects were comparable to those observed following acute exposure to the synthetic cannabinoid receptor agonist RCS-4, which inhibited neuronal activity at ≥ 1 µM. At the highest concentration, the decrease in neuronal activity was paralleled by an increase in burst duration. The three canonical benzodiazepines (diazepam, oxazepam, and lorazepam) concentration-dependently decreased neuronal activity (number of spikes, number of bursts and number of network bursts) with lowest observed effect concentrations (LOECs) of 0.1 µM, 1 µM and 0.1 µM, respectively. The decrease in neuronal activity was paralleled by an increase in burst duration, which was particularly profound for diazepam. The two designer benzodiazepines (flunitrazolam, and fluetizolam) potently decreased neuronal activity with LOECs of 0.01 µM and 0.03 µM, respectively. Comparable to the canonical benzodiazepines, the decrease in neuronal activity was paralleled by a marked increase in burst duration. Our findings demonstrate the applicability of MEA recordings for neurotoxicity assessment and potency ranking of diverse (designer) drugs. The strong potency of some of these drugs is particularly concerning and underscores the urgent need for better regulation and control of these substances to safeguard public health.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103379"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-11DOI: 10.1016/j.neuro.2025.103364
Shengqiang Xie , Shichao Su , Wenxuan Li , Yanteng Li , Fangbin Hao , Gang Cheng , Jianning Zhang
This prospective cohort study quantified the longitudinal associations between long-term exposure to multiple air pollutants and cognitive impairment risk among China's middle-aged and older adults. Leveraging data from 10,584 participants in the China Health and Retirement Longitudinal Study (2011–2020), we assessed high-resolution (1-km) annual exposures to particulate matter (PM1, PM2.5, PM10), nitrogen dioxide (NO2), and ozone (O3) using satellite-based models. Cognitive impairment was defined through education-stratified Chinese Mini-Mental State Examination thresholds. Time-varying Cox proportional hazards models revealed significant dose-response relationships: per 10-μg/m³ increase, PM1 (HR=1.078, 95 % CI:1.022–1.136), PM2.5 (HR=1.042, 1.015–1.070), PM10 (HR=1.038, 1.022–1.054), and NO2 (HR=1.129, 1.061–1.200) elevated cognitive impairment risk, while O3 showed no association (HR=0.878, 0.743–1.038). Three-year exposure windows intensified effects for NO2 (HR=1.053) and PM1 (HR=1.034). Multi-pollutant models demonstrated PM10's exceptional robustness (e.g., PM10+NO2 HR=1.055), whereas NO2 attenuated finer particulate associations. Critical vulnerability emerged among adults with education below junior high (PM1 HR=1.30), rural residents (PM10 HR=1.21), those aged 60–69 years (peak PM1 HR=1.28), and uninsured individuals (PM1 HR=1.22). Strictly linear exposure-response relationships (all Pnonlinear>0.05) indicated no safe thresholds. These findings advocate prioritizing control of PM10 (particles ≤10 μm) alongside mitigation of traffic-related pollutants, while implementing targeted interventions for vulnerable educationally disadvantaged and rural populations to mitigate dementia burden.
{"title":"Long-term air pollution exposure and cognitive impairment risk in Chinese middle-aged and older adults","authors":"Shengqiang Xie , Shichao Su , Wenxuan Li , Yanteng Li , Fangbin Hao , Gang Cheng , Jianning Zhang","doi":"10.1016/j.neuro.2025.103364","DOIUrl":"10.1016/j.neuro.2025.103364","url":null,"abstract":"<div><div>This prospective cohort study quantified the longitudinal associations between long-term exposure to multiple air pollutants and cognitive impairment risk among China's middle-aged and older adults. Leveraging data from 10,584 participants in the China Health and Retirement Longitudinal Study (2011–2020), we assessed high-resolution (1-km) annual exposures to particulate matter (PM<sub>1</sub>, PM<sub>2.5</sub>, PM<sub>10</sub>), nitrogen dioxide (NO<sub>2</sub>), and ozone (O<sub>3</sub>) using satellite-based models. Cognitive impairment was defined through education-stratified Chinese Mini-Mental State Examination thresholds. Time-varying Cox proportional hazards models revealed significant dose-response relationships: per 10-μg/m³ increase, PM<sub>1</sub> (HR=1.078, 95 % CI:1.022–1.136), PM<sub>2.5</sub> (HR=1.042, 1.015–1.070), PM<sub>10</sub> (HR=1.038, 1.022–1.054), and NO<sub>2</sub> (HR=1.129, 1.061–1.200) elevated cognitive impairment risk, while O<sub>3</sub> showed no association (HR=0.878, 0.743–1.038). Three-year exposure windows intensified effects for NO<sub>2</sub> (HR=1.053) and PM<sub>1</sub> (HR=1.034). Multi-pollutant models demonstrated PM<sub>10</sub>'s exceptional robustness (e.g., PM<sub>10</sub>+NO<sub>2</sub> HR=1.055), whereas NO<sub>2</sub> attenuated finer particulate associations. Critical vulnerability emerged among adults with education below junior high (PM<sub>1</sub> HR=1.30), rural residents (PM<sub>10</sub> HR=1.21), those aged 60–69 years (peak PM<sub>1</sub> HR=1.28), and uninsured individuals (PM<sub>1</sub> HR=1.22). Strictly linear exposure-response relationships (all Pnonlinear>0.05) indicated no safe thresholds. These findings advocate prioritizing control of PM<sub>10</sub> (particles ≤10 μm) alongside mitigation of traffic-related pollutants, while implementing targeted interventions for vulnerable educationally disadvantaged and rural populations to mitigate dementia burden.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103364"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-16DOI: 10.1016/j.neuro.2025.103366
Kayla M. Elias, William F. Muliawan, Muriel J. Moon, Gunnar F. Kwakye
Multiple Systems Atrophy (MSA) is a rare, neurodegenerative disorder associated with impaired alpha (α)-synuclein (α-syn) protein function. α-syn can aggregate within oligodendrocytes, activating oxidative stress pathways and ultimately leading to cell death. Point mutations in the α-syn gene (SNCA) are associated with MSA–A53E and G51D, but cases are mainly idiopathic. Methylene Blue (MB) is an organic dye that has been demonstrated to attenuate oxidative stress in cell models of Parkinson’s and Huntington’s disease. We hypothesized that MB would protect α-syn stably transfected oligodendroglial cell models of MSA against hydrogen peroxide (H2O2)-induced cellular stress. We used four α-syn stably transfected OLN-93 rat oligodendroglial cell lines expressing either an empty plasmid (EP), overexpressed humanized wild-type α-syn (WT-α-syn), or humanized α-syn with either point mutation (A53E-α-syn, G51D-α-syn). Upon 3 h (h) pre-treatment of OLN-93 cells with MB, followed by 1 h or 3 h exposure to H2O2, we report that MB does not enact toxic effects but rather substantially improves cell viability and metabolic capability and lowers H2O2-induced cell death in the OLN-93 MSA cell models. MB also significantly reduced H2O2-induced early (1 h) ROS production in the cytosol and mitochondria and the expression of oxidative stress and modified antioxidant-related proteins, including Nuclear factor erythroid 2-related factor 2 (NRF2), affiliated Kelch-like ECH-associated protein 1 (KEAP1), Heme Oxygenase 1 (HO1), and Adenosine Monophosphate-Activated Protein Kinase (AMPK) after 3 h exposure. Our current data suggest a novel glioprotective role for MB in MSA pathology, specifically against H2O2-mediated oxidative injury, and invite future work to investigate MB glioprotection in other in vivo MSA models.
{"title":"Methylene blue protects oligodendroglial cell models of multiple systems atrophy against hydrogen peroxide-mediated oxidative stress","authors":"Kayla M. Elias, William F. Muliawan, Muriel J. Moon, Gunnar F. Kwakye","doi":"10.1016/j.neuro.2025.103366","DOIUrl":"10.1016/j.neuro.2025.103366","url":null,"abstract":"<div><div>Multiple Systems Atrophy (MSA) is a rare, neurodegenerative disorder associated with impaired alpha (α)-synuclein (α-syn) protein function. α-syn can aggregate within oligodendrocytes, activating oxidative stress pathways and ultimately leading to cell death. Point mutations in the α-syn gene (<em>SNCA</em>) are associated with MSA–A53E and G51D, but cases are mainly idiopathic. Methylene Blue (MB) is an organic dye that has been demonstrated to attenuate oxidative stress in cell models of Parkinson’s and Huntington’s disease. We hypothesized that MB would protect α-syn stably transfected oligodendroglial cell models of MSA against hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced cellular stress. We used four α-syn stably transfected OLN-93 rat oligodendroglial cell lines expressing either an empty plasmid (EP), overexpressed humanized wild-type α-syn (WT-α-syn), or humanized α-syn with either point mutation (A53E-α-syn, G51D-α-syn). Upon 3 h (h) pre-treatment of OLN-93 cells with MB, followed by 1 h or 3 h exposure to H<sub>2</sub>O<sub>2</sub>, we report that MB does not enact toxic effects but rather substantially improves cell viability and metabolic capability and lowers H<sub>2</sub>O<sub>2</sub>-induced cell death in the OLN-93 MSA cell models. MB also significantly reduced H<sub>2</sub>O<sub>2</sub>-induced early (1 h) ROS production in the cytosol and mitochondria and the expression of oxidative stress and modified antioxidant-related proteins, including Nuclear factor erythroid 2-related factor 2 (NRF2), affiliated Kelch-like ECH-associated protein 1 (KEAP1), Heme Oxygenase 1 (HO1), and Adenosine Monophosphate-Activated Protein Kinase (AMPK) after 3 h exposure. Our current data suggest a novel glioprotective role for MB in MSA pathology, specifically against H<sub>2</sub>O<sub>2</sub>-mediated oxidative injury, and invite future work to investigate MB glioprotection in other <em>in vivo</em> MSA models.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103366"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-30DOI: 10.1016/j.neuro.2025.103377
Hualong Zhen , Linlin Zhu , Xuemei Hao , Jingru Lu , Yufan Guo , Chunmei Liang , Juan Tong , Fangbiao Tao , Jiong Li , Kun Huang
Purpose
To explore the interaction effects of children's plasma copper (Cu) levels and socioeconomic status (SES) on cognitive function in preschoolers.
Methods
This study utilized follow-up data from the China National Birth Cohort conducted at Ma’anshan Maternal and Child Health Center between May 2017 and September 2018. Cognitive development in 3-year-old children was assessed by trained professionals using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Plasma Cu concentrations were measured by inductively coupled plasma mass spectrometry. Family SES was assessed as a composite index derived from a baseline parental questionnaire. Restricted cubic spline plots and Poisson regression models were applied respectively to analyze the independent and interactive effects of children’s Cu exposure and SES on preschoolers’ cognitive development.
Results
The median plasma Cu concentration was 1062.8 µg/L (IQR: 931.9–1229.3 µg/L). Compared to high SES, low SES was associated with an increased risk of abnormalities in cognitive function (OR=2.56, 95 % CI: 1.27–5.14), receptive communication (OR=2.87, 95 % CI: 1.22–6.80), expressive communication (OR=1.77, 95 % CI: 1.23–2.54), and fine motor (OR=2.57, 95 % CI: 1.19–5.56). A medium or high concentration of Cu was associated with an increased risk of abnormalities in cognition and expressive communication compared to a low concentration of Cu. Children with medium Cu level and low SES had an increased risk of abnormalities in cognition (OR=9.88, 95 % CI: 1.26–77.47) and expressive communication (OR=2.85, 95 % CI: 1.33–6.10) compared to low Cu/high SES. Similarly, the combination of high Cu level and low SES was associated with an increased risk of abnormalities in cognition (OR=14.35, 95 % CI: 1.81–113.52) and expressive communication (OR=3.87, 95 % CI: 1.84–8.17).
Conclusions
Our findings revealed that low SES and children’s high concentrations of Cu were associated with preschoolers’ cognitive development both independently and interactively.
{"title":"Interactive effect of children’s copper exposure and socioeconomic status on preschoolers’ cognitive development","authors":"Hualong Zhen , Linlin Zhu , Xuemei Hao , Jingru Lu , Yufan Guo , Chunmei Liang , Juan Tong , Fangbiao Tao , Jiong Li , Kun Huang","doi":"10.1016/j.neuro.2025.103377","DOIUrl":"10.1016/j.neuro.2025.103377","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the interaction effects of children's plasma copper (Cu) levels and socioeconomic status (SES) on cognitive function in preschoolers.</div></div><div><h3>Methods</h3><div>This study utilized follow-up data from the China National Birth Cohort conducted at Ma’anshan Maternal and Child Health Center between May 2017 and September 2018. Cognitive development in 3-year-old children was assessed by trained professionals using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Plasma Cu concentrations were measured by inductively coupled plasma mass spectrometry. Family SES was assessed as a composite index derived from a baseline parental questionnaire. Restricted cubic spline plots and Poisson regression models were applied respectively to analyze the independent and interactive effects of children’s Cu exposure and SES on preschoolers’ cognitive development.</div></div><div><h3>Results</h3><div>The median plasma Cu concentration was 1062.8 µg/L (IQR: 931.9–1229.3 µg/L). Compared to high SES, low SES was associated with an increased risk of abnormalities in cognitive function (OR=2.56, 95 % CI: 1.27–5.14), receptive communication (OR=2.87, 95 % CI: 1.22–6.80), expressive communication (OR=1.77, 95 % CI: 1.23–2.54), and fine motor (OR=2.57, 95 % CI: 1.19–5.56). A medium or high concentration of Cu was associated with an increased risk of abnormalities in cognition and expressive communication compared to a low concentration of Cu. Children with medium Cu level and low SES had an increased risk of abnormalities in cognition (OR=9.88, 95 % CI: 1.26–77.47) and expressive communication (OR=2.85, 95 % CI: 1.33–6.10) compared to low Cu/high SES. Similarly, the combination of high Cu level and low SES was associated with an increased risk of abnormalities in cognition (OR=14.35, 95 % CI: 1.81–113.52) and expressive communication (OR=3.87, 95 % CI: 1.84–8.17).</div></div><div><h3>Conclusions</h3><div>Our findings revealed that low SES and children’s high concentrations of Cu were associated with preschoolers’ cognitive development both independently and interactively.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103377"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-31DOI: 10.1016/j.neuro.2025.103378
Xinhui Wang , Lauren E. Salminen , Andrew J. Petkus , Ira Frahmand , Joshua Millstein , Daniel P. Beavers , Mark A. Espeland , Guray Erus , Meredith N. Braskie , Paul M. Thompson , Margaret Gatz , Helena C. Chui , Susan M. Resnick , Joel D. Kaufman , Stephen R. Rapp , Sally Shumaker , Mark Brown , Diana Younan , Jiu-Chiuan Chen
Ambient air pollution exposures increase risk for Alzheimer’s disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, previous MRI studies examining exposure effects on the MTL were cross-sectional and mostly focused on the hippocampus, yielding mixed results. We addressed these limitations using longitudinal data collected from 653 cognitively unimpaired community-dwelling women from the Women’s Health Initiative Memory Study with two MRI scans (Mage at MRI-1 =77.3 ± 3.5years). We used linear regressions to examine relationships between 3-year annual average exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1, and 5-year volume changes in the bilateral hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC), which were summed to operationalize MTL volume. Covariates included intracranial volume, sociodemographic, lifestyle, and clinical characteristics. For each interquartile increase of PM2.5 (3.26 µg/m3) and NO2 (6.77 ppb), adjusted MTL volume had greater shrinkage by 0.32 cm3 (95 %CI=[-0.43,-0.21]) and 0.12 cm3 (95 %CI=[-0.22,-0.01]), respectively. Exposure effects did not differ by APOE ε4 genotype, sociodemographic, or cardiovascular risk factors. Subregionally, higher PM2.5 was associated with greater PHG and ERC atrophy, and higher NO2 was associated with greater PHG atrophy. Brain associations with PM2.5 were not significant among women residing in locations that met air quality standards (PM2.5<9 µg/m3). Collectively, late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy in cognitively unimpaired older women, especially in the PHG and ERC. These cortical MTL subregions are among the earliest affected by AD neuropathology – and may be preferentially vulnerable to air pollution neurotoxicity.
{"title":"Association between late-life air pollution exposure and medial temporal lobe atrophy in older women","authors":"Xinhui Wang , Lauren E. Salminen , Andrew J. Petkus , Ira Frahmand , Joshua Millstein , Daniel P. Beavers , Mark A. Espeland , Guray Erus , Meredith N. Braskie , Paul M. Thompson , Margaret Gatz , Helena C. Chui , Susan M. Resnick , Joel D. Kaufman , Stephen R. Rapp , Sally Shumaker , Mark Brown , Diana Younan , Jiu-Chiuan Chen","doi":"10.1016/j.neuro.2025.103378","DOIUrl":"10.1016/j.neuro.2025.103378","url":null,"abstract":"<div><div>Ambient air pollution exposures increase risk for Alzheimer’s disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, previous MRI studies examining exposure effects on the MTL were cross-sectional and mostly focused on the hippocampus, yielding mixed results. We addressed these limitations using longitudinal data collected from 653 cognitively unimpaired community-dwelling women from the Women’s Health Initiative Memory Study with two MRI scans (M<sub>age</sub> at MRI-1 =77.3 ± 3.5years). We used linear regressions to examine relationships between 3-year annual average exposures to fine particulate matter (PM<sub>2.5</sub>) and nitrogen dioxide (NO<sub>2</sub>) prior to MRI-1, and 5-year volume changes in the bilateral hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC), which were summed to operationalize MTL volume. Covariates included intracranial volume, sociodemographic, lifestyle, and clinical characteristics. For each interquartile increase of PM<sub>2.5</sub> (3.26 µg/m<sup>3</sup>) and NO<sub>2</sub> (6.77 ppb), adjusted MTL volume had greater shrinkage by 0.32 cm<sup>3</sup> (95 %CI=[-0.43,-0.21]) and 0.12 cm<sup>3</sup> (95 %CI=[-0.22,-0.01]), respectively. Exposure effects did not differ by <em>APOE</em> ε4 genotype, sociodemographic, or cardiovascular risk factors. Subregionally, higher PM<sub>2.5</sub> was associated with greater PHG and ERC atrophy, and higher NO<sub>2</sub> was associated with greater PHG atrophy. Brain associations with PM<sub>2.5</sub> were not significant among women residing in locations that met air quality standards (PM<sub>2.5</sub><9 µg/m<sup>3</sup>). Collectively, late-life PM<sub>2.5</sub> and NO<sub>2</sub> exposures were associated with greater MTL atrophy in cognitively unimpaired older women, especially in the PHG and ERC. These cortical MTL subregions are among the earliest affected by AD neuropathology – and may be preferentially vulnerable to air pollution neurotoxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103378"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-23DOI: 10.1016/j.neuro.2025.103372
Niki Tagkalidou , Ouwais Aljabasini , Sergi Pujol , Eva Prats , Josep Maria Porta , Carlos Barata , Demetrio Raldúa
The acoustic startle response (ASR) is a conserved sensorimotor reflex widely used to investigate neural plasticity, sensorimotor gating, and neurotoxicity. While zebrafish is an established vertebrate model for ASR analysis, most existing platforms were originally optimized for 6 dpf larvae, which constrains applications requiring reliable assessment of earlier developmental stages. Here, we introduce Zebra_K⁺, a modular extension of the previously developed Zebra_K platform, designed for high-throughput kinematic analysis of ASR in zebrafish embryos (5 days post-fertilization, dpf) and early larvae (6–7 dpf). The system enables simultaneous quantification of ASR kinematics, sensitivity, short-term habituation, and prepulse inhibition (PPI) in up to 25 individuals. Using the NMDA receptor antagonist ketamine, the dopamine receptor agonist apomorphine, and the D₂ receptor antagonist haloperidol, we validated the platform’s ability to detect pharmacologically induced and developmentally specific alterations in startle plasticity. Ketamine reduced habituation and PPI at all developmental stages, whereas apomorphine selectively impaired PPI, an effect that was reversed by haloperidol only at 7 dpf. These results demonstrate the neurodevelopmental progression of glutamatergic and dopaminergic modulation of sensorimotor gating and establish Zebra_K⁺ as a modular technological platform that supports the development of New Approach Methods (NAMs) for neurotoxicological screening and developmental neuropharmacology.
{"title":"Zebra_K+ : High-throughput analysis of acoustic startle response plasticity in zebrafish embryos and larvae in neurotoxicity testing","authors":"Niki Tagkalidou , Ouwais Aljabasini , Sergi Pujol , Eva Prats , Josep Maria Porta , Carlos Barata , Demetrio Raldúa","doi":"10.1016/j.neuro.2025.103372","DOIUrl":"10.1016/j.neuro.2025.103372","url":null,"abstract":"<div><div>The acoustic startle response (ASR) is a conserved sensorimotor reflex widely used to investigate neural plasticity, sensorimotor gating, and neurotoxicity. While zebrafish is an established vertebrate model for ASR analysis, most existing platforms were originally optimized for 6 dpf larvae, which constrains applications requiring reliable assessment of earlier developmental stages. Here, we introduce Zebra_K⁺, a modular extension of the previously developed Zebra_K platform, designed for high-throughput kinematic analysis of ASR in zebrafish embryos (5 days post-fertilization, dpf) and early larvae (6–7 dpf). The system enables simultaneous quantification of ASR kinematics, sensitivity, short-term habituation, and prepulse inhibition (PPI) in up to 25 individuals. Using the NMDA receptor antagonist ketamine, the dopamine receptor agonist apomorphine, and the D₂ receptor antagonist haloperidol, we validated the platform’s ability to detect pharmacologically induced and developmentally specific alterations in startle plasticity. Ketamine reduced habituation and PPI at all developmental stages, whereas apomorphine selectively impaired PPI, an effect that was reversed by haloperidol only at 7 dpf. These results demonstrate the neurodevelopmental progression of glutamatergic and dopaminergic modulation of sensorimotor gating and establish Zebra_K⁺ as a modular technological platform that supports the development of New Approach Methods (NAMs) for neurotoxicological screening and developmental neuropharmacology.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103372"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834368","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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