Pub Date : 2025-12-01Epub Date: 2025-11-06DOI: 10.1016/j.neuro.2025.103348
Abeer M. Shaheen , Rabab H. Sayed , Gouda K. Helal , Mohammed F. El-Yamany , Mohamed I. Fahmy
Cisplatin is a well-known, highly potent, and efficient anticancer drug frequently used for the treatment of a range of malignant tumors; nevertheless, it is associated with an undefined phenomenon termed chemobrain. Chemobrain is an extensive impairment in memory, learning abilities, and cognitive functions brought on by inflammation, apoptosis, and oxidative stress in the brain tissue, which negatively affects cancer survivors’ quality of life. Dapagliflozin (DAPA), a sodium-glucose transporter-2 inhibitor, has shown remarkable neuroprotective effects in different preclinical studies; nonetheless, it has not been studied in a chemobrain model. The current research aimed to assess the potential neuroprotective effect of DAPA in mitigating the cognitive impairment induced by cisplatin and the possible underlying mechanism of action. Forty male Wistar albino rats were allocated into four groups and treated for 4 weeks as follows: control, DAPA (1 mg/kg/day, p.o) group, cisplatin (5 mg/kg/week, i.p.) group, and cisplatin + DAPA group. The results proved that DAPA treatment alleviates cognitive dysfunction induced by cisplatin, as evidenced by behavioral tests, namely novel object recognition, Morris water maze, and Y-maze tests. Moreover, DAPA attenuated oxidative stress, inflammation, and apoptotic pathways. DAPA also downregulated the expression of miRNA-2, extracellular regulated kinase (p-ERK), and p-38 mitogen-activated protein kinase (p-38 MAPK). Along with that, DAPA restored neurogenesis and neuronal survival via promoting the wingless-related integration site (Wnt), β-catenin, accompanied by a reduction in glycogen synthase kinase-3 beta (GSK-3β). In conclusion, our findings postulated that DAPA may have a promising neuroprotective activity against cisplatin-induced cognitive impairments.
{"title":"Dapagliflozin ameliorates cisplatin-induced cognitive impairments in rats: Cross-talk between miRNA-21/p-ERK/p-38 MAPK and wnt/β-catenin signaling pathways","authors":"Abeer M. Shaheen , Rabab H. Sayed , Gouda K. Helal , Mohammed F. El-Yamany , Mohamed I. Fahmy","doi":"10.1016/j.neuro.2025.103348","DOIUrl":"10.1016/j.neuro.2025.103348","url":null,"abstract":"<div><div>Cisplatin is a well-known, highly potent, and efficient anticancer drug frequently used for the treatment of a range of malignant tumors; nevertheless, it is associated with an undefined phenomenon termed chemobrain. Chemobrain is an extensive impairment in memory, learning abilities, and cognitive functions brought on by inflammation, apoptosis, and oxidative stress in the brain tissue, which negatively affects cancer survivors’ quality of life. Dapagliflozin (DAPA), a sodium-glucose transporter-2 inhibitor, has shown remarkable neuroprotective effects in different preclinical studies; nonetheless, it has not been studied in a chemobrain model. The current research aimed to assess the potential neuroprotective effect of DAPA in mitigating the cognitive impairment induced by cisplatin and the possible underlying mechanism of action. Forty male Wistar albino rats were allocated into four groups and treated for 4 weeks as follows: control, DAPA (1 mg/kg/day, p.o) group, cisplatin (5 mg/kg/week, i.p.) group, and cisplatin + DAPA group. The results proved that DAPA treatment alleviates cognitive dysfunction induced by cisplatin, as evidenced by behavioral tests, namely novel object recognition, Morris water maze, and Y-maze tests. Moreover, DAPA attenuated oxidative stress, inflammation, and apoptotic pathways. DAPA also downregulated the expression of miRNA-2, extracellular regulated kinase (p-ERK), and p-38 mitogen-activated protein kinase (p-38 MAPK). Along with that, DAPA restored neurogenesis and neuronal survival via promoting the wingless-related integration site (Wnt), β-catenin, accompanied by a reduction in glycogen synthase kinase-3 beta (GSK-3β). In conclusion, our findings postulated that DAPA may have a promising neuroprotective activity against cisplatin-induced cognitive impairments.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103348"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465585","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 : 2025-12-01Epub Date: 2025-09-19DOI: 10.1016/j.neuro.2025.103325
Samuel T. Vielee , Pan Chen , Romina Deza-Ponzio , Idoia Meaza , Shreesh Raj Sammi , Michael Aschner , John P. Wise Jr.
Hexavalent chromium [Cr(VI)] is a ubiquitous environmental pollutant and potent toxicant. Cr(VI) exposure impacts millions of people around the world, primarily through inhalation or ingestion. Such exposures are best known for contributing to cancers of the lung, sinus, and nasal passage, damage to kidneys and liver, and contact dermatitis. Growing evidence indicates exposure contributes to neurological conditions, but knowledge gaps persist regarding Cr(VI) neurotoxicity. Human studies report Cr(VI) contributes to autism spectrum disorders, motor neuron disease, olfactory dysfunction, and impaired memory. However, knowledge of specific targets for Cr(VI) in the brain is limited to reports of regional accumulation (greatest effects reported in the rodent hippocampus, hypothalamus, and pituitary gland), while cell-specific effects remain unknown. Caenorhabditis elegans is a useful high-throughput model, frequently used for metals neurotoxicity. Here, we characterize a C. elegans model to address knowledge gaps in Cr(VI) neurotoxicity. All Cr(VI) concentrations tested were sublethal, and we estimate bioaccumulation of Cr in worms was ∼1e10−8% of the administered dose after a 24-hour exposure. Cr(VI) initially targeted GABAergic neurons after a 6-hour exposure, while cholinergic, dopaminergic, and GABAergic neurons were affected following a 24-hour exposure. Impacts on behaviors were consistent with neurodegeneration. Further, Cr(VI) exacerbated gut autofluorescence in worms, indicative of accelerated biological aging. These data collectively address key knowledge gaps, identifying key neuronal targets and informing potential mechanisms of neurotoxicity.
{"title":"Hexavalent chromium neurotoxicity in Caenorhabditis elegans targeted GABAergic, cholinergic, and dopaminergic neurons, and contributed to an aged phenotype","authors":"Samuel T. Vielee , Pan Chen , Romina Deza-Ponzio , Idoia Meaza , Shreesh Raj Sammi , Michael Aschner , John P. Wise Jr.","doi":"10.1016/j.neuro.2025.103325","DOIUrl":"10.1016/j.neuro.2025.103325","url":null,"abstract":"<div><div>Hexavalent chromium [Cr(VI)] is a ubiquitous environmental pollutant and potent toxicant. Cr(VI) exposure impacts millions of people around the world, primarily through inhalation or ingestion. Such exposures are best known for contributing to cancers of the lung, sinus, and nasal passage, damage to kidneys and liver, and contact dermatitis. Growing evidence indicates exposure contributes to neurological conditions, but knowledge gaps persist regarding Cr(VI) neurotoxicity. Human studies report Cr(VI) contributes to autism spectrum disorders, motor neuron disease, olfactory dysfunction, and impaired memory. However, knowledge of specific targets for Cr(VI) in the brain is limited to reports of regional accumulation (greatest effects reported in the rodent hippocampus, hypothalamus, and pituitary gland), while cell-specific effects remain unknown. <em>Caenorhabditis elegans</em> is a useful high-throughput model, frequently used for metals neurotoxicity. Here, we characterize a <em>C. elegans</em> model to address knowledge gaps in Cr(VI) neurotoxicity. All Cr(VI) concentrations tested were sublethal, and we estimate bioaccumulation of Cr in worms was ∼1e10<sup>−8</sup>% of the administered dose after a 24-hour exposure. Cr(VI) initially targeted GABAergic neurons after a 6-hour exposure, while cholinergic, dopaminergic, and GABAergic neurons were affected following a 24-hour exposure. Impacts on behaviors were consistent with neurodegeneration. Further, Cr(VI) exacerbated gut autofluorescence in worms, indicative of accelerated biological aging. These data collectively address key knowledge gaps, identifying key neuronal targets and informing potential mechanisms of neurotoxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103325"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113803","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-11-21DOI: 10.1016/j.neuro.2025.103352
Gustavo Axel Elizalde-Velázquez , Selene Elizabeth Herrera-Vázquez , Leobardo Manuel Gómez-Oliván , Nely SanJuan-Reyes , José Manuel Orozco-Hernández , Ana María Téllez-López , Sandra García-Medina , Marcela Galar-Martínez
Imatinib mesylate (IM), a first-generation tyrosine kinase inhibitor (TKI), remains a global standard in leukemia treatment. However, its environmental persistence and structural homology with conserved kinase domains in aquatic vertebrates raise concerns about potential off-target effects in non-target organisms. This study investigates, for the first time, the neurotoxic impact of IM on adult zebrafish (Danio rerio), employing a multidisciplinary approach that integrates behavioral assays, enzymatic analysis, oxidative stress biomarkers, and gene expression profiling. Exposure to IM induced a distinct anxiety-like behavioral phenotype in zebrafish, characterized by increased bottom-dwelling, heightened locomotor activity, and delayed exploration of upper tank zones in the Novel Tank Test. Concurrently, IM elicited a concentration-dependent inhibition of brain acetylcholinesterase (AChE) activity without classical active-site interaction, suggesting an indirect mechanism potentially linked to oxidative stress. Biochemical analyses confirmed increased lipid and protein oxidation, decreased antioxidant enzyme activities (SOD, CAT), and transcriptional upregulation of pro-apoptotic markers (bax, p53, casp3), alongside suppression of oxidative defense and energy-regulatory genes (nrf1, nrf2, prkaa1). The downregulation of prkaa1, encoding the catalytic subunit of AMP-activated protein kinase (AMPK), implicates disrupted metabolic adaptation and redox homeostasis as central features of IM-induced toxicity. Together, these findings suggest that IM provokes neurobehavioral disturbances in zebrafish through mitochondrial dysfunction, impaired AMPK signaling, oxidative stress, and secondary inhibition of AChE, ultimately leading to cholinergic dysregulation and anxiety-like responses.
{"title":"Neurotoxic potential of imatinib in aquatic vertebrates: Behavioral and biochemical disruptions in zebrafish","authors":"Gustavo Axel Elizalde-Velázquez , Selene Elizabeth Herrera-Vázquez , Leobardo Manuel Gómez-Oliván , Nely SanJuan-Reyes , José Manuel Orozco-Hernández , Ana María Téllez-López , Sandra García-Medina , Marcela Galar-Martínez","doi":"10.1016/j.neuro.2025.103352","DOIUrl":"10.1016/j.neuro.2025.103352","url":null,"abstract":"<div><div>Imatinib mesylate (IM), a first-generation tyrosine kinase inhibitor (TKI), remains a global standard in leukemia treatment. However, its environmental persistence and structural homology with conserved kinase domains in aquatic vertebrates raise concerns about potential off-target effects in non-target organisms. This study investigates, for the first time, the neurotoxic impact of IM on adult zebrafish (<em>Danio rerio</em>), employing a multidisciplinary approach that integrates behavioral assays, enzymatic analysis, oxidative stress biomarkers, and gene expression profiling. Exposure to IM induced a distinct anxiety-like behavioral phenotype in zebrafish, characterized by increased bottom-dwelling, heightened locomotor activity, and delayed exploration of upper tank zones in the Novel Tank Test. Concurrently, IM elicited a concentration-dependent inhibition of brain acetylcholinesterase (AChE) activity without classical active-site interaction, suggesting an indirect mechanism potentially linked to oxidative stress. Biochemical analyses confirmed increased lipid and protein oxidation, decreased antioxidant enzyme activities (SOD, CAT), and transcriptional upregulation of pro-apoptotic markers (bax, p53, casp3), alongside suppression of oxidative defense and energy-regulatory genes (nrf1, nrf2, prkaa1). The downregulation of prkaa1, encoding the catalytic subunit of AMP-activated protein kinase (AMPK), implicates disrupted metabolic adaptation and redox homeostasis as central features of IM-induced toxicity. Together, these findings suggest that IM provokes neurobehavioral disturbances in zebrafish through mitochondrial dysfunction, impaired AMPK signaling, oxidative stress, and secondary inhibition of AChE, ultimately leading to cholinergic dysregulation and anxiety-like responses.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103352"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588165","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 : 2025-12-01Epub Date: 2025-08-24DOI: 10.1016/j.neuro.2025.08.005
Sorour Ghotbinasab , Ali Akbar Oroojan , Mohammad Amin Behmanesh , Neda Amirgholamy , Amir Hossein Nasiri , Soheila Alboghobeish
Environmental cadmium (Cd) contamination has increased in recent years, coinciding with the expansion of industrial activities and the global consumption of high-fat diets (HFD). Both are recognized as independent risk factors for neurodegenerative processes, yet their combined effects on brain function remain poorly characterized. This study is the first to investigate the interactive neurotoxicity of chronic Cd exposure and HFD, and to assess the potential protective effects of naringin, a flavonoid with known antioxidant and anti-inflammatory properties. Eighty female NMRI mice were assigned to eight groups receiving low- or high-fat diets, with or without Cd (0.5 or 5 ppm) in drinking water for 12 weeks. Two groups co-exposed to Cd and HFD received naringin (50 or 100 mg/kg). Behavioral assessments (Y-maze, shuttle box) were conducted, along with evaluations of oxidative stress markers, mitochondrial function, acetylcholinesterase activity, DNA fragmentation, histopathology, and proinflammatory cytokines. Cd and HFD individually induced cognitive deficits, oxidative imbalance, mitochondrial dysfunction, inflammation, and cholinergic disruption, which were more pronounced when both insults were combined. Naringin, particularly at a dose of 100 mg/kg, effectively reversed these alterations, restoring redox homeostasis and neuronal integrity without reducing Cadmium accumulation in brain tissue. These findings demonstrate, for the first time, that naringin mitigates the synergistic neurotoxic effects of Cd and HFD, highlighting its therapeutic potential against modern environmental and dietary challenges.
{"title":"Severe neurotoxicity induced by the combined exposure to cadmium and high-fat diet: Protective role of naringin against oxidative, mitochondrial, and inflammatory brain damage","authors":"Sorour Ghotbinasab , Ali Akbar Oroojan , Mohammad Amin Behmanesh , Neda Amirgholamy , Amir Hossein Nasiri , Soheila Alboghobeish","doi":"10.1016/j.neuro.2025.08.005","DOIUrl":"10.1016/j.neuro.2025.08.005","url":null,"abstract":"<div><div>Environmental cadmium (Cd) contamination has increased in recent years, coinciding with the expansion of industrial activities and the global consumption of high-fat diets (HFD). Both are recognized as independent risk factors for neurodegenerative processes, yet their combined effects on brain function remain poorly characterized. This study is the first to investigate the interactive neurotoxicity of chronic Cd exposure and HFD, and to assess the potential protective effects of <em>naringin</em>, a flavonoid with known antioxidant and anti-inflammatory properties. Eighty female NMRI mice were assigned to eight groups receiving low- or high-fat diets, with or without Cd (0.5 or 5 ppm) in drinking water for 12 weeks. Two groups co-exposed to Cd and HFD received naringin (50 or 100 mg/kg). Behavioral assessments (Y-maze, shuttle box) were conducted, along with evaluations of oxidative stress markers, mitochondrial function, acetylcholinesterase activity, DNA fragmentation, histopathology, and proinflammatory cytokines. Cd and HFD individually induced cognitive deficits, oxidative imbalance, mitochondrial dysfunction, inflammation, and cholinergic disruption, which were more pronounced when both insults were combined. Naringin, particularly at a dose of 100 mg/kg, effectively reversed these alterations, restoring redox homeostasis and neuronal integrity without reducing Cadmium accumulation in brain tissue. These findings demonstrate, for the first time, that naringin mitigates the synergistic neurotoxic effects of Cd and HFD, highlighting its therapeutic potential against modern environmental and dietary challenges.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103306"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912218","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-09-01Epub Date: 2025-07-08DOI: 10.1016/j.neuro.2025.07.001
E. Bernal Meléndez , T. Venet , A. Thomas , S. Boucard , L. Guenot , L. Merlen , S. Grossmann , E. Joubert , M. Mascherin , S. Viton , L. Wathier , F. Cosnier , B. Pouyatos
Exposure to volatile organic solvents, in both industrial workers and animal models, has a depressant effect on the central nervous system and alters behavior. However, the specific impact on brain activity during acute exposure has not been extensively studied. Here, we assessed how acute exposure to three common industrial solvents - toluene, styrene and methyl-ethyl-ketone (MEK) - affected the power of brain oscillations in rats. Rats (n = 14/group) were implanted with cortical electrodes which were connected to a removable headstage during exposure, to wirelessly transmit digitized electrocorticographic (ECoG) signals. Signals were continuously recorded while the rats inhaled solvent vapors (1000 ppm) for 6 h, with a 1-h control period before and after (breathing filtered air). Experiments were repeated for four successive days. In addition to brain oscillations, post-rotatory nystagmus (PRN) and sensory-motor coordination were tested following air/solvent exposure. MEK had no significant effects on the parameters tested. Styrene decreased the power of overall brain activity, but had no effect on motor activity. Toluene increased the power of fast oscillations (30–90 Hz) within minutes and further over time; concomitantly, the power of slow waves (2–12 Hz) decreased. Motor activity was slightly increased by toluene. Both toluene and styrene increased the number and duration of saccades measured by PRN. Dose-response experiments with styrene (n = 16 rats) revealed significant changes in oscillation power even at 50 ppm. These findings suggest that ECoG can be used to assess solvent effects on brain activity in real-time, surpassing the sensitivity of traditional sensorimotor tests.
{"title":"Toluene, styrene and methyl-ethyl-ketone inhalation: Effects on the power of cortical oscillations in rats","authors":"E. Bernal Meléndez , T. Venet , A. Thomas , S. Boucard , L. Guenot , L. Merlen , S. Grossmann , E. Joubert , M. Mascherin , S. Viton , L. Wathier , F. Cosnier , B. Pouyatos","doi":"10.1016/j.neuro.2025.07.001","DOIUrl":"10.1016/j.neuro.2025.07.001","url":null,"abstract":"<div><div>Exposure to volatile organic solvents, in both industrial workers and animal models, has a depressant effect on the central nervous system and alters behavior. However, the specific impact on brain activity during acute exposure has not been extensively studied. Here, we assessed how acute exposure to three common industrial solvents - toluene, styrene and methyl-ethyl-ketone (MEK) - affected the power of brain oscillations in rats. Rats (n = 14/group) were implanted with cortical electrodes which were connected to a removable headstage during exposure, to wirelessly transmit digitized electrocorticographic (ECoG) signals. Signals were continuously recorded while the rats inhaled solvent vapors (1000 ppm) for 6 h, with a 1-h control period before and after (breathing filtered air). Experiments were repeated for four successive days. In addition to brain oscillations, post-rotatory nystagmus (PRN) and sensory-motor coordination were tested following air/solvent exposure. MEK had no significant effects on the parameters tested. Styrene decreased the power of overall brain activity, but had no effect on motor activity. Toluene increased the power of fast oscillations (30–90 Hz) within minutes and further over time; concomitantly, the power of slow waves (2–12 Hz) decreased. Motor activity was slightly increased by toluene. Both toluene and styrene increased the number and duration of saccades measured by PRN. Dose-response experiments with styrene (n = 16 rats) revealed significant changes in oscillation power even at 50 ppm. These findings suggest that ECoG can be used to assess solvent effects on brain activity in real-time, surpassing the sensitivity of traditional sensorimotor tests.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 31-41"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605952","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}
<div><h3>Background</h3><div>Increased prevalence of neurodevelopmental syndromes raises concerns regarding risks from environmental exposures. Phthalates are a class of chemicals widely used in daily products. It has been suggested that prenatal and early childhood exposure to phthalates are associated with disruption of developmental outcomes, cognitive and psychomotor functions.</div></div><div><h3>Aims</h3><div>To estimate the association between prenatal and early childhood exposure to phthalates and neurodevelopmental outcomes.</div></div><div><h3>Methods</h3><div>Women were recruited at 11–18 weeks of gestation and provided spot urine samples, analyzed for phthalate metabolites (DEHP, DiNP, MBzBP). Children (n = 102) were examined at 42 months of age, using a broad developmental assessment and standard maternal reports, regarding cognitive, developmental and behavioral problems (WPPSI-III, NIH-toolbox, NEPSY-II, CBCL, ASQ-3 questionnaires), and provided spot urine samples (n = 47). To explore the associations between tertiles or continuous levels of metabolites and developmental outcomes, multivariate general linear models (GLM) were used.</div></div><div><h3>Results</h3><div>DEHP and DiNP metabolites were above the level of detection (>LOD) in more than 97 % of maternal specimens and MBzBP was detected in 88 % of maternal specimens. Increased DEHP levels were associated with problem solving scores among boys (scores: 53.24 <u>+</u> 2.34, 54<u>.</u>29 <u>+</u> 2.45, and 43.54 <u>+</u> 3.26 for low, medium and high DEHP tertiles, respectively; p = 0.029), and fine motor problems (47.58 <u>+</u> 2.93, 49<u>.</u>75 <u>+</u> 3.07, and 32.01 <u>+</u> 4.07 for low, medium and high DEHP tertiles, respectively; p = 0.003) and attention problems among girls (Flanker scores: 112.53 <u>+</u> 14.28, 110<u>.</u>3 <u>+</u> 12.93, and 98.83 <u>+</u> 12.65 for low, medium and high DEHP tertiles, respectively; p = 0.007). Moreover, in girls, a potential U-shaped association was found between levels of exposure to MBzBP and problem solving (54.55 <u>+</u> 6.87, 44<u>.</u>69 <u>+</u> 14.88, and 54.62 <u>+</u> 6.60 for low, medium and high MBzBP tertiles, respectively; p = 0.015), fine motor problems (56.36 <u>+</u> 5.04, 42<u>.</u>50 <u>+</u> 15.49, and 51.92 <u>+</u> 8.04 for low, medium and high MBzBP tertiles, respectively; p = 0.007), and verbal abilities (Vocabulary scores: 11.46 <u>+</u> 3.01, 8.25 <u>+</u> 3.43, and 11.53 <u>+</u> 2.69 for low, medium and high MBzBP tertiles, respectively; p = 0.007). Early childhood exposure was associated with fine motor scores and DEHP and MBzBP postnatal exposure (DEHP: β = −0.010, Cl: −0.016, −0.004, p = 0.003; MBzBP: β = −0.321, Cl: −0.499, −0.144, p = 0.001). Most associations became nonsignificant after FDR correction for multiple comparisons.</div></div><div><h3>Conclusion</h3><div>This study suggests associations between prenatal exposure to phthalates and early childhood motor and cognitive abilities, wi
{"title":"Prenatal and early childhood exposure to phthalates and neurodevelopment in 42 months old children","authors":"Liron Cohen-Eliraz , Asher Ornoy , Eliana Ein-Mor , Moriah Bar-Nitsan , Ronit Calderon-Margalit , Tammy Pilowsky-Peleg","doi":"10.1016/j.neuro.2025.07.007","DOIUrl":"10.1016/j.neuro.2025.07.007","url":null,"abstract":"<div><h3>Background</h3><div>Increased prevalence of neurodevelopmental syndromes raises concerns regarding risks from environmental exposures. Phthalates are a class of chemicals widely used in daily products. It has been suggested that prenatal and early childhood exposure to phthalates are associated with disruption of developmental outcomes, cognitive and psychomotor functions.</div></div><div><h3>Aims</h3><div>To estimate the association between prenatal and early childhood exposure to phthalates and neurodevelopmental outcomes.</div></div><div><h3>Methods</h3><div>Women were recruited at 11–18 weeks of gestation and provided spot urine samples, analyzed for phthalate metabolites (DEHP, DiNP, MBzBP). Children (n = 102) were examined at 42 months of age, using a broad developmental assessment and standard maternal reports, regarding cognitive, developmental and behavioral problems (WPPSI-III, NIH-toolbox, NEPSY-II, CBCL, ASQ-3 questionnaires), and provided spot urine samples (n = 47). To explore the associations between tertiles or continuous levels of metabolites and developmental outcomes, multivariate general linear models (GLM) were used.</div></div><div><h3>Results</h3><div>DEHP and DiNP metabolites were above the level of detection (>LOD) in more than 97 % of maternal specimens and MBzBP was detected in 88 % of maternal specimens. Increased DEHP levels were associated with problem solving scores among boys (scores: 53.24 <u>+</u> 2.34, 54<u>.</u>29 <u>+</u> 2.45, and 43.54 <u>+</u> 3.26 for low, medium and high DEHP tertiles, respectively; p = 0.029), and fine motor problems (47.58 <u>+</u> 2.93, 49<u>.</u>75 <u>+</u> 3.07, and 32.01 <u>+</u> 4.07 for low, medium and high DEHP tertiles, respectively; p = 0.003) and attention problems among girls (Flanker scores: 112.53 <u>+</u> 14.28, 110<u>.</u>3 <u>+</u> 12.93, and 98.83 <u>+</u> 12.65 for low, medium and high DEHP tertiles, respectively; p = 0.007). Moreover, in girls, a potential U-shaped association was found between levels of exposure to MBzBP and problem solving (54.55 <u>+</u> 6.87, 44<u>.</u>69 <u>+</u> 14.88, and 54.62 <u>+</u> 6.60 for low, medium and high MBzBP tertiles, respectively; p = 0.015), fine motor problems (56.36 <u>+</u> 5.04, 42<u>.</u>50 <u>+</u> 15.49, and 51.92 <u>+</u> 8.04 for low, medium and high MBzBP tertiles, respectively; p = 0.007), and verbal abilities (Vocabulary scores: 11.46 <u>+</u> 3.01, 8.25 <u>+</u> 3.43, and 11.53 <u>+</u> 2.69 for low, medium and high MBzBP tertiles, respectively; p = 0.007). Early childhood exposure was associated with fine motor scores and DEHP and MBzBP postnatal exposure (DEHP: β = −0.010, Cl: −0.016, −0.004, p = 0.003; MBzBP: β = −0.321, Cl: −0.499, −0.144, p = 0.001). Most associations became nonsignificant after FDR correction for multiple comparisons.</div></div><div><h3>Conclusion</h3><div>This study suggests associations between prenatal exposure to phthalates and early childhood motor and cognitive abilities, wi","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 74-84"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704597","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 : 2025-09-01Epub Date: 2025-07-11DOI: 10.1016/j.neuro.2025.07.004
Laia Guardia-Escote , Judit Biosca-Brull , Jordi Blanco , Maria Cabré , Pia Basaure , Cristian Pérez-Fernández , Fernando Sánchez-Santed , José L. Domingo , Maria Teresa Colomina
Environmental factors, such as exposure to neurotoxicants and diet, play a critical role in shaping cognitive function, particularly in genetically susceptible individuals. Chlorpyrifos (CPF), an organophosphate pesticide, and high-fat diets (HFD) have been independently associated with cognitive impairment, yet their combined effects remain poorly understood. Apolipoprotein E (APOE) genotype influences vulnerability to cognitive decline, with the ε4 allele being a major risk factor for neurodegenerative diseases. This study assessed the interplay between APOE genotype, sex, early-life CPF exposure, and HFD on spatial learning and memory. Male and female C57BL/6, apoE3- and apoE4-targeted replacement (TR) mice were orally exposed to CPF during postnatal days 10–15 and subsequently subjected to a HFD for 8 weeks. At the end of the HFD challenge, body weight gain was calculated, and spatial learning and memory assessed using the Morris Water Maze test. Results indicate that HFD-driven weight gain was influenced by sex and APOE genotype. All groups acquired the spatial learning task, but postnatal CPF exposure affected performance in certain groups. Retention was more variable in females, suggesting increased susceptibility to environmental exposures. Notably, apoE4-TR females showed improved memory retention following either CPF exposure or HFD, whereas apoE4-TR males exhibited impaired long-term memory after HFD exposure. These findings highlight the complex interactions between genetic and environmental factors. Understanding these dynamics is essential for developing targeted nutritional and public health strategies to mitigate cognitive decline. Importantly, dietary recommendations should not be generalized but tailored to individual profiles to optimize cognitive health and disease prevention.
{"title":"Impact of a high-fat diet on spatial learning and memory: The role of sex, APOE genotype, and postnatal chlorpyrifos exposure","authors":"Laia Guardia-Escote , Judit Biosca-Brull , Jordi Blanco , Maria Cabré , Pia Basaure , Cristian Pérez-Fernández , Fernando Sánchez-Santed , José L. Domingo , Maria Teresa Colomina","doi":"10.1016/j.neuro.2025.07.004","DOIUrl":"10.1016/j.neuro.2025.07.004","url":null,"abstract":"<div><div>Environmental factors, such as exposure to neurotoxicants and diet, play a critical role in shaping cognitive function, particularly in genetically susceptible individuals. Chlorpyrifos (CPF), an organophosphate pesticide, and high-fat diets (HFD) have been independently associated with cognitive impairment, yet their combined effects remain poorly understood. Apolipoprotein E (<em>APOE)</em> genotype influences vulnerability to cognitive decline, with the <em>ε4</em> allele being a major risk factor for neurodegenerative diseases. This study assessed the interplay between <em>APOE</em> genotype, sex, early-life CPF exposure, and HFD on spatial learning and memory. Male and female C57BL/6, apoE3- and apoE4-targeted replacement (TR) mice were orally exposed to CPF during postnatal days 10–15 and subsequently subjected to a HFD for 8 weeks. At the end of the HFD challenge, body weight gain was calculated, and spatial learning and memory assessed using the Morris Water Maze test. Results indicate that HFD-driven weight gain was influenced by sex and <em>APOE</em> genotype. All groups acquired the spatial learning task, but postnatal CPF exposure affected performance in certain groups. Retention was more variable in females, suggesting increased susceptibility to environmental exposures. Notably, apoE4-TR females showed improved memory retention following either CPF exposure or HFD, whereas apoE4-TR males exhibited impaired long-term memory after HFD exposure. These findings highlight the complex interactions between genetic and environmental factors. Understanding these dynamics is essential for developing targeted nutritional and public health strategies to mitigate cognitive decline. Importantly, dietary recommendations should not be generalized but tailored to individual profiles to optimize cognitive health and disease prevention.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 42-52"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626785","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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