Pub Date : 2025-08-08DOI: 10.1016/j.neuro.2025.08.001
Dalisa R. Kendricks, Jariatu Stallone, DaNashia S. Thomas, Leslie R. Aksu, Kaylie I. Kirkwood-Donelson, Alan K. Jarmusch, Christopher A. McPherson, Jesse D. Cushman
Chlorpyrifos is an organophosphorus insecticide known to produce severe neurotoxicity following early developmental exposure. So far, little data describes the neurobehavioral and metabolic consequences of low-dose exposures, near the threshold to produce cholinesterase inhibition. The purpose of the current study was to characterize the impact of prenatal exposure to a low dose of chlorpyrifos, at 0.5 mg/kg/day, and compare observed neurobehavioral and metabolic changes to a well-defined daily dose of 5 mg/kg. Pregnant C57BL/6 J dams were exposed to either 0, 0.5, or 5 mg/kg/day chlorpyrifos from gestation day 6.5–17.5. A metabolic profile was determined in dams and pups at the end of exposure and behavior was analyzed in offspring during late adolescence and early adulthood. Exposure to 5 mg/kg chlorpyrifos disrupted metabolites associated with the oxidative stress response and with energy metabolism within the brain and produced long-term impairment in spontaneous behavior and learning in offspring. Exposure to the lower dose of 0.5 mg/kg/day reduced levels of metabolites downstream of ornithine, a process that was also disrupted with exposure to 5 mg/kg/day. Further, 0.5 mg/kg/day chlorpyrifos impaired spontaneous behavior in offspring during adulthood, though no significant effects on learning or reversal were seen. These findings support a conclusion that prenatal low dose chlorpyrifos exposure produces long-term metabolic and neurobehavioral impairment that resemble deficits seen with high dose exposure.
{"title":"Neurobehavioral and metabolic effects of prenatal low-dose chlorpyrifos in C57BL/6J mice","authors":"Dalisa R. Kendricks, Jariatu Stallone, DaNashia S. Thomas, Leslie R. Aksu, Kaylie I. Kirkwood-Donelson, Alan K. Jarmusch, Christopher A. McPherson, Jesse D. Cushman","doi":"10.1016/j.neuro.2025.08.001","DOIUrl":"10.1016/j.neuro.2025.08.001","url":null,"abstract":"<div><div>Chlorpyrifos is an organophosphorus insecticide known to produce severe neurotoxicity following early developmental exposure. So far, little data describes the neurobehavioral and metabolic consequences of low-dose exposures, near the threshold to produce cholinesterase inhibition. The purpose of the current study was to characterize the impact of prenatal exposure to a low dose of chlorpyrifos, at 0.5 mg/kg/day, and compare observed neurobehavioral and metabolic changes to a well-defined daily dose of 5 mg/kg. Pregnant C57BL/6 J dams were exposed to either 0, 0.5, or 5 mg/kg/day chlorpyrifos from gestation day 6.5–17.5. A metabolic profile was determined in dams and pups at the end of exposure and behavior was analyzed in offspring during late adolescence and early adulthood. Exposure to 5 mg/kg chlorpyrifos disrupted metabolites associated with the oxidative stress response and with energy metabolism within the brain and produced long-term impairment in spontaneous behavior and learning in offspring. Exposure to the lower dose of 0.5 mg/kg/day reduced levels of metabolites downstream of ornithine, a process that was also disrupted with exposure to 5 mg/kg/day. Further, 0.5 mg/kg/day chlorpyrifos impaired spontaneous behavior in offspring during adulthood, though no significant effects on learning or reversal were seen. These findings support a conclusion that prenatal low dose chlorpyrifos exposure produces long-term metabolic and neurobehavioral impairment that resemble deficits seen with high dose exposure.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 132-144"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817230","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}
Diesel Exhaust Particles (DEPs) emitted by diesel engines represent a substantial contributor to ambient particulate matter. Extensive research has demonstrated that DEPs pose significant risks to human health. This study seeks to elucidate the molecular mechanisms underlying DEPs-induced dysfunction of the blood-brain barrier (BBB). The research team exposed bEND.3 cells to various concentrations of DEPs for 24 h and evaluated parameters including cell morphology, viability, inflammatory markers, oxidative stress, tight junction protein expression, and modulation of the RhoA/ROCK signaling pathway. The findings revealed that DEPs exposure resulted in morphological and ultrastructural alterations, elevated apoptosis rates, and reduced cell viability. Additionally, DEPs stimulated the release of pro-inflammatory cytokines, induced oxidative stress, disrupted tight junction protein expression, increased BBB permeability, and activated the RhoA/ROCK signaling pathway, thereby amplifying these deleterious effects. Collectively, our results demonstrate that DEPs impair BBB functionality through a cascade of cellular injury mechanisms. These findings highlight the profound impact of air pollution on the central nervous system and underscore the urgent need for stringent regulations on diesel emissions to protect brain health, particularly among populations in urban areas with high exposure to traffic-related emissions.
{"title":"Diesel exhaust particles induced blood-brain barrier dysfunction through inflammation, oxidative stress, and activation of the RhoA/ROCK signaling pathway","authors":"Yanming Lv, Yingying Chen, Zhijian Gao, Siqi Liu, Ya Zhang, Huimin Suo, Shuying Gao","doi":"10.1016/j.neuro.2025.08.002","DOIUrl":"10.1016/j.neuro.2025.08.002","url":null,"abstract":"<div><div>Diesel Exhaust Particles (DEPs) emitted by diesel engines represent a substantial contributor to ambient particulate matter. Extensive research has demonstrated that DEPs pose significant risks to human health. This study seeks to elucidate the molecular mechanisms underlying DEPs-induced dysfunction of the blood-brain barrier (BBB). The research team exposed bEND.3 cells to various concentrations of DEPs for 24 h and evaluated parameters including cell morphology, viability, inflammatory markers, oxidative stress, tight junction protein expression, and modulation of the RhoA/ROCK signaling pathway. The findings revealed that DEPs exposure resulted in morphological and ultrastructural alterations, elevated apoptosis rates, and reduced cell viability. Additionally, DEPs stimulated the release of pro-inflammatory cytokines, induced oxidative stress, disrupted tight junction protein expression, increased BBB permeability, and activated the RhoA/ROCK signaling pathway, thereby amplifying these deleterious effects. Collectively, our results demonstrate that DEPs impair BBB functionality through a cascade of cellular injury mechanisms. These findings highlight the profound impact of air pollution on the central nervous system and underscore the urgent need for stringent regulations on diesel emissions to protect brain health, particularly among populations in urban areas with high exposure to traffic-related emissions.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 122-131"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817228","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 : 2025-08-08DOI: 10.1016/j.neuro.2025.08.003
Klistenes Alves de Lima , Alana Gomes de Souza , Adriano José Maia Chaves Filho , João Victor Souza Oliveira , Michele Albuquerque Jales de Carvalho , Melina Mottin , Camila Nayane de Carvalho Lima , Antonio Eufrásio Vieira-Neto , Iardja Stéfane Lopes Sales , Francisco Josimar Girão Júnior , Carolina Horta Andrade , Marta Maria de França Fonteles
Carbapenems are broad-spectrum β-lactam antibiotics widely used in critical and hospitalized patients. They are usually well tolerated; however, under certain conditions, these drugs are associated with central nervous system toxicity and proconvulsant activity. Here, we investigated the proconvulsant action of different generation carbapenems: imipenem (IMI), meropenem (MERO), and ertapenem (ERTA) in mice through behavioral analysis. We also propose possible molecular mechanisms for this side effect through an integrative experimental and computational approach. For this, male mice received carbapenems at doses of 250 and 500 mg/kg, or saline, subcutaneously, for 7 days. On the last day, the pilocarpine-induced seizure test was performed. On the last day, the pilocarpine-induced seizure test was performed, and latency to the first seizure and latency of death were recorded. Subsequently, oxidative stress markers were measured in brain areas. Additionally, using the three-dimensional structure of the drugs, we performed computational target prediction and molecular docking calculations. IMI and MERO, at both tested doses, reduced seizure latency and death latency compared to pilocarpine group. This effect occurred only with the higher dose of ERTA (500 mg/kg). Furthermore, IMI increased lipid peroxidation in all brain areas, MERO in the hippocampus and prefrontal cortex, and ERTA only in the hippocampus. The three carbapenems increased nitrite/nitrate levels in all brain areas, while only IMI at 500 mg/kg decreased GSH. Computational studies predicted that GABAA receptor, Glutathione S-transferase Pi, Glutathione S-transferase Mu 1, and Glutathione S-transferase A2 could be promising targets for the CNS toxicity of carbapenems, related to their proconvulsant effect. Therefore, our data contribute to the current understanding of CNS toxicity associated with carbapenems and propose the participation of oxidative stress and the interaction with GABA and GSH synthesis systems in the molecular mechanism of their proconvulsant effect.
{"title":"Integrative behavior analysis, oxidative stress markers determination and molecular docking to investigate proconvulsant action of betalactamic carbapenems","authors":"Klistenes Alves de Lima , Alana Gomes de Souza , Adriano José Maia Chaves Filho , João Victor Souza Oliveira , Michele Albuquerque Jales de Carvalho , Melina Mottin , Camila Nayane de Carvalho Lima , Antonio Eufrásio Vieira-Neto , Iardja Stéfane Lopes Sales , Francisco Josimar Girão Júnior , Carolina Horta Andrade , Marta Maria de França Fonteles","doi":"10.1016/j.neuro.2025.08.003","DOIUrl":"10.1016/j.neuro.2025.08.003","url":null,"abstract":"<div><div>Carbapenems are broad-spectrum β-lactam antibiotics widely used in critical and hospitalized patients. They are usually well tolerated; however, under certain conditions, these drugs are associated with central nervous system toxicity and proconvulsant activity. Here, we investigated the proconvulsant action of different generation carbapenems: imipenem (IMI), meropenem (MERO), and ertapenem (ERTA) in mice through behavioral analysis. We also propose possible molecular mechanisms for this side effect through an integrative experimental and computational approach. For this, male mice received carbapenems at doses of 250 and 500 mg/kg, or saline, subcutaneously, for 7 days. On the last day, the pilocarpine-induced seizure test was performed. On the last day, the pilocarpine-induced seizure test was performed, and latency to the first seizure and latency of death were recorded. Subsequently, oxidative stress markers were measured in brain areas. Additionally, using the three-dimensional structure of the drugs, we performed computational target prediction and molecular docking calculations. IMI and MERO, at both tested doses, reduced seizure latency and death latency compared to pilocarpine group. This effect occurred only with the higher dose of ERTA (500 mg/kg). Furthermore, IMI increased lipid peroxidation in all brain areas, MERO in the hippocampus and prefrontal cortex, and ERTA only in the hippocampus. The three carbapenems increased nitrite/nitrate levels in all brain areas, while only IMI at 500 mg/kg decreased GSH. Computational studies predicted that GABA<sub>A</sub> receptor, Glutathione S-transferase Pi, Glutathione S-transferase Mu 1, and Glutathione S-transferase A2 could be promising targets for the CNS toxicity of carbapenems, related to their proconvulsant effect. Therefore, our data contribute to the current understanding of CNS toxicity associated with carbapenems and propose the participation of oxidative stress and the interaction with GABA and GSH synthesis systems in the molecular mechanism of their proconvulsant effect.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 155-167"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817229","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 : 2025-07-29DOI: 10.1016/j.neuro.2025.07.010
Benjamin Hing , Robert Taylor , Samuel Eliasen , Hanna E. Stevens
Pyrethroid insecticides are widely used in agriculture and households, and their exposure can affect neurodevelopment. Few studies have evaluated how preconception parental exposure could also affect this process. To address this knowledge gap, adult C57Bl6/J mice were gavaged daily with α-cypermethrin at a human relevant low (0.3 mg/kg) or high (10 mg/kg) dose in corn oil for four weeks prior to conception. Offspring embryonic day 16 dorsal forebrain was extracted for transcriptomic analysis. In offspring forebrains of exposed compared to unexposed parents, there was increasing number of differentially expressed genes (DEGs) from paternal (least) to maternal to both parent exposure (most). A dose dependent effect was observed in offspring forebrain for paternal and maternal preconceptual exposures. Maternal and both parent exposures led to upregulated genes in offspring brain for biological processes involved in translation with predicted activation of EIF4E, a gene associated with autism. In contrast, paternal exposure upregulated cell cycle related DNA damage signaling processes. After any parent exposure, there was upregulation of biological processes involved in mitochondria function and oxidative stress and a downregulation of neuronal and synaptic processes with predicted inhibition of BDNF signaling. Weighted gene correlation network analysis identified modules associated with different parent exposures that were over-represented with DEGs and had similar functional signatures as DEG-related pathways. Importantly, DEGs in offspring forebrain after any parent exposure were over-represented with genes related to autism spectrum disorder (ASD) and stress vulnerability. The study highlights the potential contribution of preconception parental pyrethroid exposure to aberrant brain functioning.
{"title":"Parental preconceptual α-cypermethrin exposure alters embryonic brain transcriptomics in mice: Implications for autism spectrum disorder and stress vulnerability","authors":"Benjamin Hing , Robert Taylor , Samuel Eliasen , Hanna E. Stevens","doi":"10.1016/j.neuro.2025.07.010","DOIUrl":"10.1016/j.neuro.2025.07.010","url":null,"abstract":"<div><div>Pyrethroid insecticides are widely used in agriculture and households, and their exposure can affect neurodevelopment. Few studies have evaluated how preconception parental exposure could also affect this process. To address this knowledge gap, adult C57Bl6/J mice were gavaged daily with α-cypermethrin at a human relevant low (0.3 mg/kg) or high (10 mg/kg) dose in corn oil for four weeks prior to conception. Offspring embryonic day 16 dorsal forebrain was extracted for transcriptomic analysis. In offspring forebrains of exposed compared to unexposed parents, there was increasing number of differentially expressed genes (DEGs) from paternal (least) to maternal to both parent exposure (most). A dose dependent effect was observed in offspring forebrain for paternal and maternal preconceptual exposures. Maternal and both parent exposures led to upregulated genes in offspring brain for biological processes involved in translation with predicted activation of <em>EIF4E</em>, a gene associated with autism. In contrast, paternal exposure upregulated cell cycle related DNA damage signaling processes. After any parent exposure, there was upregulation of biological processes involved in mitochondria function and oxidative stress and a downregulation of neuronal and synaptic processes with predicted inhibition of <em>BDNF</em> signaling. Weighted gene correlation network analysis identified modules associated with different parent exposures that were over-represented with DEGs and had similar functional signatures as DEG-related pathways. Importantly, DEGs in offspring forebrain after any parent exposure were over-represented with genes related to autism spectrum disorder (ASD) and stress vulnerability. The study highlights the potential contribution of preconception parental pyrethroid exposure to aberrant brain functioning.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 181-196"},"PeriodicalIF":3.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760608","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 : 2025-07-26DOI: 10.1016/j.neuro.2025.07.009
Daniel José Barbosa , Inês C. Santos , Tatiana Moyisyeyenko , Cristina Mendes , Ana Filipa Sobral
The small nematode Caenorhabditis elegans (C. elegans) has emerged as a valuable tool in neurotoxicology due to its well-characterized nervous system, genetic tractability, and high conservation of molecular pathways with humans. These characteristics allow to study cellular and molecular mechanisms triggered by neurotoxic substances. In C. elegans, behavioral, molecular, neurophysiological, and neuronal morphology assays, together with genetic models targeting dopaminergic, glutamatergic, GABAergic, and cholinergic neurons, as well as models for mitochondrial dysfunction and oxidative stress, are valuable for elucidating mechanisms of neurotoxicity. Additionally, C. elegans is widely used for high-throughput neurotoxicity screenings, with automated systems enhancing scalability and accuracy. Despite its advantages, C. elegans has some limitations for translating data to humans, including the absence of a blood-brain barrier and complex brain regions, as well as differences in metabolism. However, it remains a strong model for neurotoxic screening and mechanistic studies. This review offers a broader, updated perspective by addressing not only classical neurotoxicants (e.g., heavy metals, pesticides) but also increasingly relevant substances like microplastics and industrial chemicals, psychotropic medications, and drugs of abuse. It also provides a detailed overview of diverse C. elegans behavioral, molecular, and neurophysiological neurotoxicity assays, and genetic models for neurotransmitter signaling, mitochondrial dysfunction, and oxidative stress. Importantly, it also discusses the relevance of C. elegans within regulatory frameworks such as adverse outcome pathways (AOPs), a connection largely overlooked in prior reviews. These features address gaps in the current literature and distinguish this work from existing reviews on the topic.
{"title":"C. elegans as a powerful model for neurotoxicity assessment","authors":"Daniel José Barbosa , Inês C. Santos , Tatiana Moyisyeyenko , Cristina Mendes , Ana Filipa Sobral","doi":"10.1016/j.neuro.2025.07.009","DOIUrl":"10.1016/j.neuro.2025.07.009","url":null,"abstract":"<div><div>The small nematode <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) has emerged as a valuable tool in neurotoxicology due to its well-characterized nervous system, genetic tractability, and high conservation of molecular pathways with humans. These characteristics allow to study cellular and molecular mechanisms triggered by neurotoxic substances. In <em>C. elegans,</em> behavioral, molecular, neurophysiological, and neuronal morphology assays, together with genetic models targeting dopaminergic, glutamatergic, GABAergic, and cholinergic neurons, as well as models for mitochondrial dysfunction and oxidative stress, are valuable for elucidating mechanisms of neurotoxicity. Additionally, <em>C. elegans</em> is widely used for high-throughput neurotoxicity screenings, with automated systems enhancing scalability and accuracy. Despite its advantages, <em>C. elegans</em> has some limitations for translating data to humans, including the absence of a blood-brain barrier and complex brain regions, as well as differences in metabolism. However, it remains a strong model for neurotoxic screening and mechanistic studies. This review offers a broader, updated perspective by addressing not only classical neurotoxicants (<em>e.g.,</em> heavy metals, pesticides) but also increasingly relevant substances like microplastics and industrial chemicals, psychotropic medications, and drugs of abuse. It also provides a detailed overview of diverse <em>C. elegans</em> behavioral, molecular, and neurophysiological neurotoxicity assays, and genetic models for neurotransmitter signaling, mitochondrial dysfunction, and oxidative stress. Importantly, it also discusses the relevance of <em>C. elegans</em> within regulatory frameworks such as adverse outcome pathways (AOPs), a connection largely overlooked in prior reviews. These features address gaps in the current literature and distinguish this work from existing reviews on the topic.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 85-110"},"PeriodicalIF":3.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724807","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":"2025-07-23","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 : 2025-07-23DOI: 10.1016/j.neuro.2025.07.005
Donna Mergler , Aline Philibert , Jennifer Laura Lee , Myriam Fillion , Judy Da Silva
Prenatal, childhood, and current mercury (Hg) exposure through fish consumption have each been associated with cognitive deficits, but little information exists on the consequences of long-term exposure among adults. Since 1962, Grassy Narrows First Nation has been exposed to Hg from an industrial discharge. Average Hair Hg (HHg) concentrations, initially very high, decreased over time and stabilized in the 1990’s. Montreal Cognitive Assessment (MoCA) test outcomes were analyzed in 85 persons aged 32–75 y (median: 53 y) with respect to retrospective year-based HHg measurements between 1970 and 1997 and current blood Hg. Since the MoCA has not been clinically validated for Indigenous populations, residuals of age- and education-adjusted scores were used (MoCA-r scores). Lower MoCA-r scores were observed among persons in the higher quartile of maximum HHg compared to those in the lower quartile (p = 0.007). Clustering of the test items yielded 3 clusters representing verbal fluency and abstraction, cognitive flexibility and working memory, and visuospatial functioning. To model the evolution of HHg over time, longitudinal mixed effect models (LMEM) were performed with persons with ≥ 10 repeated year-based HHg measurements. Higher long-term past HHg was associated with lower MoCA-r and all cluster scores. No association was observed between MoCA-r or cluster scores and blood Hg, which reflects recent exposure. The findings suggest that legacy exposure can affect cognitive functioning decades later, even when average current concentrations have decreased to below recommended guidelines. Prospective studies could provide information on the rate of decline and the possible future impact of current exposure.
{"title":"Long-term mercury exposure and cognitive functions in a First Nation community in Northern Ontario, Canada","authors":"Donna Mergler , Aline Philibert , Jennifer Laura Lee , Myriam Fillion , Judy Da Silva","doi":"10.1016/j.neuro.2025.07.005","DOIUrl":"10.1016/j.neuro.2025.07.005","url":null,"abstract":"<div><div>Prenatal, childhood, and current mercury (Hg) exposure through fish consumption have each been associated with cognitive deficits, but little information exists on the consequences of long-term exposure among adults. Since 1962, Grassy Narrows First Nation has been exposed to Hg from an industrial discharge. Average Hair Hg (HHg) concentrations, initially very high, decreased over time and stabilized in the 1990’s. Montreal Cognitive Assessment (MoCA) test outcomes were analyzed in 85 persons aged 32–75 y (median: 53 y) with respect to retrospective year-based HHg measurements between 1970 and 1997 and current blood Hg. Since the MoCA has not been clinically validated for Indigenous populations, residuals of age- and education-adjusted scores were used (MoCA-r scores). Lower MoCA-r scores were observed among persons in the higher quartile of maximum HHg compared to those in the lower quartile (p = 0.007). Clustering of the test items yielded 3 clusters representing verbal fluency and abstraction, cognitive flexibility and working memory, and visuospatial functioning. To model the evolution of HHg over time, longitudinal mixed effect models (LMEM) were performed with persons with ≥ 10 repeated year-based HHg measurements. Higher long-term past HHg was associated with lower MoCA-r and all cluster scores. No association was observed between MoCA-r or cluster scores and blood Hg, which reflects recent exposure. The findings suggest that legacy exposure can affect cognitive functioning decades later, even when average current concentrations have decreased to below recommended guidelines. Prospective studies could provide information on the rate of decline and the possible future impact of current exposure.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 145-154"},"PeriodicalIF":3.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718158","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 : 2025-07-23DOI: 10.1016/j.neuro.2025.07.008
Chao Cheng, Dong Xiong, Fengwei Zheng, Tianze Wang, Weixin Li
This study investigated the effects of Kisspeptin-10 (Kp-10) on HIV-1 Tat-induced blood-brain barrier (BBB) permeability and oxidative stress using both in vivo and in vitro models. In vivo, one hour after intraperitoneal administration of 50 nmol/kg (DSS)*6-Kp-10, mice were intravenously injected with HIV-1 Tat (100 μg/kg). Markers of oxidative stress, inflammatory cytokines, and BBB integrity were then evaluated. In vitro, bEnd.3 cells were treated with HIV-1 Tat and Kp-10, and endothelial permeability, Claudin-5 expression, and RhoA/ROCK signaling were assessed. HIV-1 Tat increased oxidative stress in the cortical tissue of mice, as evidenced by elevated malondialdehyde (MDA) and reduced levels of catalase (CAT) activity, glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC). These effects were attenuated by Kp-10 administration. Additionally, Kp-10 suppressed the expression of pro-inflammatory cytokines, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α), in response to HIV-1 Tat. Notably, Kp-10 mitigated HIV-1 Tat-induced BBB dysfunction by upregulating Claudin-5 expression in the cortical tissue of mice. In vitro, bEnd.3 cells were treated with HIV-1 Tat in the presence of Kp-10 at various concentrations. Our results demonstrated that Kp-10 prevented HIV-1 Tat-induced increases in trans-endothelial permeability and reductions in transepithelial electrical resistance (TEER) by upregulating Claudin-5 expression. Furthermore, Kp-10 inhibited the activation of the RhoA/Rho-associated protein kinase (RhoA/ROCK) signaling pathway in bEnd.3 cells. Overexpression of the RhoA-GTP Q63L mutant abolished the protective effects of Kp-10, suggesting that these effects are mediated through the RhoA/ROCK axis. These findings suggest that Kp-10 might be a potential therapeutic agent for HIV-associated neurocognitive disorders (HAND).
{"title":"Kisspeptin-10 protects against HIV-1 Tat-induced blood-brain barrier dysfunction and neuroinflammation via RhoA/ROCK pathway: Implications for HAND therapy","authors":"Chao Cheng, Dong Xiong, Fengwei Zheng, Tianze Wang, Weixin Li","doi":"10.1016/j.neuro.2025.07.008","DOIUrl":"10.1016/j.neuro.2025.07.008","url":null,"abstract":"<div><div>This study investigated the effects of Kisspeptin-10 (Kp-10) on HIV-1 Tat-induced blood-brain barrier (BBB) permeability and oxidative stress using both <em>in vivo</em> and <em>in vitro</em> models. <em>In vivo</em>, one hour after intraperitoneal administration of 50 nmol/kg (DSS)*6-Kp-10, mice were intravenously injected with HIV-1 Tat (100 μg/kg). Markers of oxidative stress, inflammatory cytokines, and BBB integrity were then evaluated. <em>In vitro</em>, bEnd.3 cells were treated with HIV-1 Tat and Kp-10, and endothelial permeability, Claudin-5 expression, and RhoA/ROCK signaling were assessed. HIV-1 Tat increased oxidative stress in the cortical tissue of mice, as evidenced by elevated malondialdehyde (MDA) and reduced levels of catalase (CAT) activity, glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC). These effects were attenuated by Kp-10 administration. Additionally, Kp-10 suppressed the expression of pro-inflammatory cytokines, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α), in response to HIV-1 Tat. Notably, Kp-10 mitigated HIV-1 Tat-induced BBB dysfunction by upregulating Claudin-5 expression in the cortical tissue of mice. <em>In vitro</em>, bEnd.3 cells were treated with HIV-1 Tat in the presence of Kp-10 at various concentrations. Our results demonstrated that Kp-10 prevented HIV-1 Tat-induced increases in trans-endothelial permeability and reductions in transepithelial electrical resistance (TEER) by upregulating Claudin-5 expression. Furthermore, Kp-10 inhibited the activation of the RhoA/Rho-associated protein kinase (RhoA/ROCK) signaling pathway in bEnd.3 cells. Overexpression of the RhoA-GTP Q63L mutant abolished the protective effects of Kp-10, suggesting that these effects are mediated through the RhoA/ROCK axis. These findings suggest that Kp-10 might be a potential therapeutic agent for HIV-associated neurocognitive disorders (HAND).</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 111-121"},"PeriodicalIF":3.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718157","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 : 2025-07-11DOI: 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":"2025-07-11","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}
Pub Date : 2025-07-11DOI: 10.1016/j.neuro.2025.07.002
Bobo Yang , Michael Aschner , Rongzhu Lu
Acrylonitrile (AN) is a toxic, colorless to pale-yellow liquid extensively used in industrial production and has been linked to neurotoxicity. Though our previous study showed a correlation between AN-induced neurotoxicity and gasotransmitter hydrogen sulfide (H2S) in mammalian cells, experimental evidence on overall animal toxicity and specific neurological injury is still limited. We aimed to further explore the molecular association between H2S and AN-induced acute toxicity in Caenorhabditis elegans (C. elegans) by using its genetic advantages, and provide experimental evidence for the validation of H2S donors as AN antidote. In the present study, we demonstrated that acute AN exposure resulted in toxicity as evidenced by changes in death rate, locomotor behavior, brood size, dopaminergic neuron morphology, and oxidative stress. Notably, AN inhibited the H2S content, which was double-examined by methylene blue spectrophotometry and lead acetate paper assay. Furthermore, AN significantly decreased 3-mercaptopyruvate sulphurtransferase (3-MPST)-mediated H2S synthesizing activity and the transcription level of the corresponding coding gene mpst-1 but had no effect on the cystathionine β synthetase (CBS)/cystathionine γ lyase (CSE)-mediated H2S synthesizing activity using L-cysteine as a common substrate and the mRNA levels of H2S oxidative metabolism enzymes. cth-2 and mpst-1 mutations significantly downregulated the H2S content and the corresponding H2S synthesizing activity, and further enhanced the AN-induced toxicity response including lethality, brood size and lifespan. In contrast, H2S donor GYY4137 significantly attenuated the AN-damaged survival rate, body bends, and dopaminergic neuron morphology. Our findings demonstrated that the reduction of H2S mediates the acute toxicity of AN.
{"title":"cth-2/mpst-1-dependent H2S deficiency enhances acrylonitrile acute toxicity in Caenorhabditis elegans","authors":"Bobo Yang , Michael Aschner , Rongzhu Lu","doi":"10.1016/j.neuro.2025.07.002","DOIUrl":"10.1016/j.neuro.2025.07.002","url":null,"abstract":"<div><div>Acrylonitrile (AN) is a toxic, colorless to pale-yellow liquid extensively used in industrial production and has been linked to neurotoxicity. Though our previous study showed a correlation between AN-induced neurotoxicity and gasotransmitter hydrogen sulfide (H<sub>2</sub>S) in mammalian cells, experimental evidence on overall animal toxicity and specific neurological injury is still limited. We aimed to further explore the molecular association between H<sub>2</sub>S and AN-induced acute toxicity in <em>Caenorhabditis elegans (C. elegans)</em> by using its genetic advantages, and provide experimental evidence for the validation of H<sub>2</sub>S donors as AN antidote. In the present study, we demonstrated that acute AN exposure resulted in toxicity as evidenced by changes in death rate, locomotor behavior, brood size, dopaminergic neuron morphology, and oxidative stress. Notably, AN inhibited the H<sub>2</sub>S content, which was double-examined by methylene blue spectrophotometry and lead acetate paper assay. Furthermore, AN significantly decreased 3-mercaptopyruvate sulphurtransferase (3-MPST)-mediated H<sub>2</sub>S synthesizing activity and the transcription level of the corresponding coding gene <em>mpst-1</em> but had no effect on the cystathionine β synthetase (CBS)/cystathionine γ lyase (CSE)-mediated H<sub>2</sub>S synthesizing activity using L-cysteine as a common substrate and the mRNA levels of H<sub>2</sub>S oxidative metabolism enzymes. <em>cth-2</em> and <em>mpst-1</em> mutations significantly downregulated the H<sub>2</sub>S content and the corresponding H<sub>2</sub>S synthesizing activity, and further enhanced the AN-induced toxicity response including lethality, brood size and lifespan. In contrast, H<sub>2</sub>S donor GYY4137 significantly attenuated the AN-damaged survival rate, body bends, and dopaminergic neuron morphology. Our findings demonstrated that the reduction of H<sub>2</sub>S mediates the acute toxicity of AN.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 64-73"},"PeriodicalIF":3.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626784","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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