Pub Date : 2025-09-01Epub Date: 2025-08-12DOI: 10.1016/j.ntt.2025.107543
Fangfei Li , Jie Zhang , Xiaoli Ma , Hao Chen , Guiqiang Liang , Yunfeng Zou
Excessive accumulation of manganese (Mn) can cause neuroinflammation, impairing cognitive function. SPON1, a secreted glycoprotein in the extracellular matrix, is implicated in neuroinflammation, but its role in activating pro-inflammatory pathways in Mn-induced neuroinflammation remains unclear. This study employed in vivo and in vitro models to investigate Mn neuroinflammation. The expression levels of SPON1 and the ERK1/2/NF-κB pathway associated with inflammation were measured in male C57BL/6 mice after gavage of Mn at different doses (0, 25, 50, 100 mg/kg) for 12 weeks. SPON1 levels were measured after primary hippocampal neurons, primary cortical neurons, neuroblastoma cells (N2a), and microglial cells (BV2) were exposed to various concentrations of Mn for 24 h. We observed that in vivo Mn exposure significantly decreased SPON1 expression in the cortex but not in the hippocampus. Similarly, in vitro experiments demonstrated that Mn exposure significantly reduced SPON1 levels in primary cortical neurons, N2a, and BV2. In addition, Mn exposure increased the expression levels of ERK1/2 and NF-κB pathway proteins in the mouse cortex. Because BV2 cells are susceptible to inflammatory signals, they were chosen to elucidate how SPON1 induces neuroinflammation during Mn exposure. SPON1 knockdown increases the expression of inflammatory factors, whereas SPON1 overexpression inhibits the activation of the ERK1/2/NF-κB pathway and reduces inflammatory factor levels. In summary, these results suggest that Mn may affect the activation of ERK1/2/NF-κB pathway and the expression of inflammatory factors by inhibiting SPON1, ultimately promoting neuroinflammation.
{"title":"Manganese induces neuroinflammation through SPON1-mediated activation of ERK1/2/NF-κB pathway","authors":"Fangfei Li , Jie Zhang , Xiaoli Ma , Hao Chen , Guiqiang Liang , Yunfeng Zou","doi":"10.1016/j.ntt.2025.107543","DOIUrl":"10.1016/j.ntt.2025.107543","url":null,"abstract":"<div><div>Excessive accumulation of manganese (Mn) can cause neuroinflammation, impairing cognitive function. SPON1, a secreted glycoprotein in the extracellular matrix, is implicated in neuroinflammation, but its role in activating pro-inflammatory pathways in Mn-induced neuroinflammation remains unclear. This study employed <em>in vivo</em> and <em>in vitro</em> models to investigate Mn neuroinflammation. The expression levels of SPON1 and the ERK1/2/NF-κB pathway associated with inflammation were measured in male C57BL/6 mice after gavage of Mn at different doses (0, 25, 50, 100 mg/kg) for 12 weeks. SPON1 levels were measured after primary hippocampal neurons, primary cortical neurons, neuroblastoma cells (N2a), and microglial cells (BV2) were exposed to various concentrations of Mn for 24 h. We observed that <em>in vivo</em> Mn exposure significantly decreased SPON1 expression in the cortex but not in the hippocampus. Similarly, <em>in vitro</em> experiments demonstrated that Mn exposure significantly reduced SPON1 levels in primary cortical neurons, N2a, and BV2. In addition, Mn exposure increased the expression levels of ERK1/2 and NF-κB pathway proteins in the mouse cortex. Because BV2 cells are susceptible to inflammatory signals, they were chosen to elucidate how SPON1 induces neuroinflammation during Mn exposure. SPON1 knockdown increases the expression of inflammatory factors, whereas SPON1 overexpression inhibits the activation of the ERK1/2/NF-κB pathway and reduces inflammatory factor levels. In summary, these results suggest that Mn may affect the activation of ERK1/2/NF-κB pathway and the expression of inflammatory factors by inhibiting SPON1, ultimately promoting neuroinflammation.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"111 ","pages":"Article 107543"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855826","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: 2025-08-22DOI: 10.1016/j.ntt.2025.107548
Shayla Victoria, Courtney Roper
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that can impact communication and social behaviors. Evidence suggests that the causes of ASD are likely a combination of genetic and environmental factors, such as air pollution. Particulate matter (PM) is the solid and liquid portion of air pollution that can vary in size and has been associated with many health impacts, including cardiorespiratory impacts, and has more recently been found to be associated with the prevalence of ASD. However, little is known about the phenotypic presentations of this association between PM and ASD, therefore, the zebrafish (Danio rerio) model was employed to study behaviors often associated with ASD as a result of PM exposure. Zebrafish larvae were exposed for a total of 5 days to PM standard reference material (SRM1649b) and a commonly used home remedy, melatonin, beginning at 6 h post-fertilization and various behavioral assays were performed on subsequent days for a total of 13 days. Observed and quantified behaviors were compared to a positive control, valproic acid (VPA). Generally, PM exposure did not elicit behavior resembling that of VPA exposure and the interactions between PM and VPA did not induce additive or synergistic behavioral patterns, as expected. Melatonin supplementation did not ameliorate most of the observed behavioral impacts of PM or VPA exposure. These results have prompted additional questions about the phenotypic presentations of ASD as a result of PM exposure and contribute to growing knowledge about disease-environment interactions.
{"title":"Autism spectrum disorder-like behaviors in developing zebrafish exposed to particulate matter","authors":"Shayla Victoria, Courtney Roper","doi":"10.1016/j.ntt.2025.107548","DOIUrl":"10.1016/j.ntt.2025.107548","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that can impact communication and social behaviors. Evidence suggests that the causes of ASD are likely a combination of genetic and environmental factors, such as air pollution. Particulate matter (PM) is the solid and liquid portion of air pollution that can vary in size and has been associated with many health impacts, including cardiorespiratory impacts, and has more recently been found to be associated with the prevalence of ASD. However, little is known about the phenotypic presentations of this association between PM and ASD, therefore, the zebrafish (<em>Danio rerio</em>) model was employed to study behaviors often associated with ASD as a result of PM exposure. Zebrafish larvae were exposed for a total of 5 days to PM standard reference material (SRM1649b) and a commonly used home remedy, melatonin, beginning at 6 h post-fertilization and various behavioral assays were performed on subsequent days for a total of 13 days. Observed and quantified behaviors were compared to a positive control, valproic acid (VPA). Generally, PM exposure did not elicit behavior resembling that of VPA exposure and the interactions between PM and VPA did not induce additive or synergistic behavioral patterns, as expected. Melatonin supplementation did not ameliorate most of the observed behavioral impacts of PM or VPA exposure. These results have prompted additional questions about the phenotypic presentations of ASD as a result of PM exposure and contribute to growing knowledge about disease-environment interactions.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"111 ","pages":"Article 107548"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908918","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: 2025-08-18DOI: 10.1016/j.ntt.2025.107547
Liliana Ataides Silva Barichello , Rafaela Ribeiro de Brito , Wesley Rodrigues Soares , Aline Sueli de Lima Rodrigues , Alex Rodrigues Gomes , Bruno da Cruz Pádua , Bruna de Oliveira Mendes , Ariane Guimarães , Raíssa de Oliveira Ferreira , Thiarlen Marinho da Luz , Guilherme Malafaia
Despite the growing recognition of the impacts of microplastics (MPs) and the intensification of extreme weather events, recent investigations have focused mainly on the consequences of global warming, while overlooking the potential impacts of extreme low-temperature (ELT) events and their interaction with these pollutants. Accordingly, the aim of this study was to assess the integrated effects of co-exposure to environmentally aged polystyrene microplastics (PS-MPs) and ELTs on behavioral, neuroendocrine, metabolic, and histomorphometric biomarkers in female Swiss mice. To this end, animals were orally exposed to environmentally aged PS-MPs (10 mg/kg/day) and maintained in a climate-controlled chamber at 4 °C for 21 days, whereas control groups were kept at 25 °C. In the behavioral domain, co-exposed animals exhibited increased locomotor disorganization, anxiety-like behavior, reduced exploratory efficiency, and impairments in memory and social discrimination, associated with neuroendocrine alterations involving dopamine, serotonin, epinephrine, and corticosterone, depending on the response evaluated. The retention of PS-MPs in the interscapular brown adipose tissue (iBAT) was confirmed by epifluorescence microscopy. It was associated with oxidative stress, decreased antioxidant defenses, and metabolic dysfunction in iBAT, effects exacerbated by ELT exposure. Multivariate analyses, including principal component analysis (PCA), Random Forest, and structural equation modeling (PLS-PM), revealed distinct phenotypic patterns among groups, as well as integrated causal trajectories linking neuroendocrine dysfunction to systemic phenotypic alterations. In conclusion, our study confirms the initial hypothesis by demonstrating that the combination of ELT and PS-MP ingestion amplifies systemic physiological dysfunctions beyond the effects of each individual stressor, highlighting the vulnerability of homeothermic mammals under multiple environmental pressures, and opening new perspectives for ecotoxicology to consider not only the impacts of global warming, but also the deleterious effects of ELTs in interaction with emerging pollutants.
{"title":"Extreme low-temperature exacerbates polystyrene microplastic-induced neuroendocrine and behavioral dysfunctions in female mice","authors":"Liliana Ataides Silva Barichello , Rafaela Ribeiro de Brito , Wesley Rodrigues Soares , Aline Sueli de Lima Rodrigues , Alex Rodrigues Gomes , Bruno da Cruz Pádua , Bruna de Oliveira Mendes , Ariane Guimarães , Raíssa de Oliveira Ferreira , Thiarlen Marinho da Luz , Guilherme Malafaia","doi":"10.1016/j.ntt.2025.107547","DOIUrl":"10.1016/j.ntt.2025.107547","url":null,"abstract":"<div><div>Despite the growing recognition of the impacts of microplastics (MPs) and the intensification of extreme weather events, recent investigations have focused mainly on the consequences of global warming, while overlooking the potential impacts of extreme low-temperature (ELT) events and their interaction with these pollutants. Accordingly, the aim of this study was to assess the integrated effects of <em>co</em>-exposure to environmentally aged polystyrene microplastics (PS-MPs) and ELTs on behavioral, neuroendocrine, metabolic, and histomorphometric biomarkers in female Swiss mice. To this end, animals were orally exposed to environmentally aged PS-MPs (10 mg/kg/day) and maintained in a climate-controlled chamber at 4 °C for 21 days, whereas control groups were kept at 25 °C. In the behavioral domain, co-exposed animals exhibited increased locomotor disorganization, anxiety-like behavior, reduced exploratory efficiency, and impairments in memory and social discrimination, associated with neuroendocrine alterations involving dopamine, serotonin, epinephrine, and corticosterone, depending on the response evaluated. The retention of PS-MPs in the interscapular brown adipose tissue (iBAT) was confirmed by epifluorescence microscopy. It was associated with oxidative stress, decreased antioxidant defenses, and metabolic dysfunction in iBAT, effects exacerbated by ELT exposure. Multivariate analyses, including principal component analysis (PCA), Random Forest, and structural equation modeling (PLS-PM), revealed distinct phenotypic patterns among groups, as well as integrated causal trajectories linking neuroendocrine dysfunction to systemic phenotypic alterations. In conclusion, our study confirms the initial hypothesis by demonstrating that the combination of ELT and PS-MP ingestion amplifies systemic physiological dysfunctions beyond the effects of each individual stressor, highlighting the vulnerability of homeothermic mammals under multiple environmental pressures, and opening new perspectives for ecotoxicology to consider not only the impacts of global warming, but also the deleterious effects of ELTs in interaction with emerging pollutants.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"111 ","pages":"Article 107547"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879844","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: 2025-08-25DOI: 10.1016/j.ntt.2025.107549
Mohamed Ahmed
Neurodegenerative diseases and cognitive impairments represent significant global health challenges, necessitating the exploration of alternative and complementary therapeutic options. Herbal remedies, known for their bioactive compounds, have garnered attention for their potential neuroprotective and cognitive-enhancing effects. This review focuses on three widely studied herbal agents, including St. John's Wort (Hypericum perforatum), Green Tea (Camellia sinensis), and Ashwagandha (Withania somnifera) and evaluates their mechanisms in promoting brain health. St. John's Wort has demonstrated potential in alleviating symptoms of depression and anxiety, which are often linked to cognitive decline. Green Tea, rich in polyphenols such as epigallocatechin gallate (EGCG), has shown promise in improving memory function and providing antioxidant protection against neurotoxicity. Ashwagandha, an adaptogenic herb, is recognized for its neuroprotective properties, including reducing stress-induced cognitive deficits and promoting neuronal regeneration. The neuroprotective and cognitive-enhancing effects of these herbs are attributed to their antioxidative, anti-inflammatory, and neurotrophic properties, which collectively may support brain function and mitigate age-related cognitive decline.
{"title":"Neuroprotective and cognitive-enhancing potentials of herbal remedies: Focus on St. John's wort, green tea, and Ashwagandha","authors":"Mohamed Ahmed","doi":"10.1016/j.ntt.2025.107549","DOIUrl":"10.1016/j.ntt.2025.107549","url":null,"abstract":"<div><div>Neurodegenerative diseases and cognitive impairments represent significant global health challenges, necessitating the exploration of alternative and complementary therapeutic options. Herbal remedies, known for their bioactive compounds, have garnered attention for their potential neuroprotective and cognitive-enhancing effects. This review focuses on three widely studied herbal agents, including St. John's Wort (<em>Hypericum perforatum</em>), Green Tea (<em>Camellia sinensis</em>), and Ashwagandha (<em>Withania somnifera</em>) and evaluates their mechanisms in promoting brain health. St. John's Wort has demonstrated potential in alleviating symptoms of depression and anxiety, which are often linked to cognitive decline. Green Tea, rich in polyphenols such as epigallocatechin gallate (EGCG), has shown promise in improving memory function and providing antioxidant protection against neurotoxicity. Ashwagandha, an adaptogenic herb, is recognized for its neuroprotective properties, including reducing stress-induced cognitive deficits and promoting neuronal regeneration. The neuroprotective and cognitive-enhancing effects of these herbs are attributed to their antioxidative, anti-inflammatory, and neurotrophic properties, which collectively may support brain function and mitigate age-related cognitive decline.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"111 ","pages":"Article 107549"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932619","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: 2025-08-11DOI: 10.1016/j.ntt.2025.107546
Andrew B. Hawkey , Rongxi Fan , Kala Nwachukwu , Shutong Liu , Anas Gondal , Sarabesh Natarajan , Jade Porter , Melissa Marchese , Giuliana Mesarick , Megan Stout , Corinne Wells , Amir H. Rezvani , Edward D. Levin
Neurotoxic risks in the environment come from many toxicants, which are often found together in complex mixtures. However, nearly all experimental studies evaluate one chemical at a time. Neurobehavioral effects of developmental exposure to heavy metals such as cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) have been well-studied, however their potential for non-additive or interactive effects are not well known. We recently reported that, in zebrafish, embryonic exposure to the PAH benzo[a]pyrene (BaP) and/or the heavy metal cadmium chloride (CdCl2) led to selective sub-additive effects on behavior. The current study was performed in rats, to determine whether such interactions translate to mammals and to better account for characteristics like biological sex. In this study, we exposed female rats to BAP (0.03 mg/kg/day), the metal salt CdCl2 (0.3 mg/kg/day) or both via osmotic minipumps throughout gestation. Male and female offspring were assessed for bodily and reflex development, and locomotor, emotional and cognitive function. Cd treatment was associated with impaired sex differences in neonatal anogenital distance, enhanced negative geotaxis performance on PND7, reduced body weight at weaning, increased open-arm exploration in the elevated plus maze (females only), and reductions in sex differences in novel object recognition. Co-treatment with BaP attenuated those CdCl-effects on negative geotaxis and elevated plus maze. BaP was also associated with reduced metrics of food consumption in the novel environment suppressed feeding task, and with increases in errors during the initial phase of radial arm maze training (males only). As in zebrafish, persisting neurobehavioral effects are seen in rats after chronic developmental exposure to BaP and CdCl. However, these effects can differ between single-exposures and mixtures, which indicates a need for greater clarity on interactions within such mixtures.
{"title":"Persisting neurobehavioral consequences of gestational exposure to cadmium and benzo[a]pyrene in rats","authors":"Andrew B. Hawkey , Rongxi Fan , Kala Nwachukwu , Shutong Liu , Anas Gondal , Sarabesh Natarajan , Jade Porter , Melissa Marchese , Giuliana Mesarick , Megan Stout , Corinne Wells , Amir H. Rezvani , Edward D. Levin","doi":"10.1016/j.ntt.2025.107546","DOIUrl":"10.1016/j.ntt.2025.107546","url":null,"abstract":"<div><div>Neurotoxic risks in the environment come from many toxicants, which are often found together in complex mixtures. However, nearly all experimental studies evaluate one chemical at a time. Neurobehavioral effects of developmental exposure to heavy metals such as cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) such as benzo[<em>a</em>]pyrene (BaP) have been well-studied, however their potential for non-additive or interactive effects are not well known. We recently reported that, in zebrafish, embryonic exposure to the PAH benzo[<em>a</em>]pyrene (BaP) and/or the heavy metal cadmium chloride (CdCl<sub>2</sub>) led to selective sub-additive effects on behavior. The current study was performed in rats, to determine whether such interactions translate to mammals and to better account for characteristics like biological sex. In this study, we exposed female rats to BAP (0.03 mg/kg/day), the metal salt CdCl<sub>2</sub> (0.3 mg/kg/day) or both via osmotic minipumps throughout gestation. Male and female offspring were assessed for bodily and reflex development, and locomotor, emotional and cognitive function. Cd treatment was associated with impaired sex differences in neonatal anogenital distance, enhanced negative geotaxis performance on PND7, reduced body weight at weaning, increased open-arm exploration in the elevated plus maze (females only), and reductions in sex differences in novel object recognition. Co-treatment with BaP attenuated those CdCl-effects on negative geotaxis and elevated plus maze. BaP was also associated with reduced metrics of food consumption in the novel environment suppressed feeding task, and with increases in errors during the initial phase of radial arm maze training (males only). As in zebrafish, persisting neurobehavioral effects are seen in rats after chronic developmental exposure to BaP and CdCl. However, these effects can differ between single-exposures and mixtures, which indicates a need for greater clarity on interactions within such mixtures.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"111 ","pages":"Article 107546"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841892","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 : 2025-07-01Epub Date: 2025-05-31DOI: 10.1016/j.ntt.2025.107500
Wenwen Jiang , Xixin Fan , Hui Wu , Jiankang Song , Chunhe Yang , Zhanzhi Zhao
Neuroinflammation is a critical factor in the pathogenesis of postoperative cognitive dysfunction (POCD). Maintaining microglial homeostasis is vital for regulating neuroinflammation, as microglial cell death can trigger an inflammatory response within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in supporting cell survival and modulating microglial-driven neuroinflammation. Our previous study indicated that TREM2 overexpression exerts protective effects against neuroinflammation and cognitive deficits in aged mice. However, the precise mechanisms by which TREM2 functions in microglia remain unclear. Consequently, this study aimed to examine the role of TREM2 in lipopolysaccharide (LPS)-induced cell death and neuroinflammation in BV2 cells. This research showed that TREM2 reduces LPS-induced nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis and the subsequent release of inflammatory factors through western blot analysis, flow cytometry, and enzyme-linked immunosorbent assay. Recent research has suggested that the loss of spleen tyrosine kinase (SYK), a downstream receptor kinase of TREM2 in microglia, results in exacerbated neuroinflammatory disease. This study further demonstrated that SYK activation via TREM2 treatment exerts neuroprotective effects by mitigating LPS-induced mitochondrial membrane potential damage, facilitating mitophagy, and inhibiting NLRP3-mediated pyroptosis in BV2 cells. Conversely, SYK inhibition by R406 led to microglial cell death and aggravated neuroinflammation, thereby reducing the neuroprotective effects of TREM2. Our findings indicate that TREM2 and SYK mitigate the inflammatory response in LPS-induced BV2 microglia and interfere with pyroptosis by enhancing mitophagy. These findings suggest that TREM2 and SYK may be valuable therapeutic targets for neuroinflammation.
{"title":"TREM2 inhibits LPS-induced pyroptosis and inflammation by promoting mitophagy via SYK in BV2 cells","authors":"Wenwen Jiang , Xixin Fan , Hui Wu , Jiankang Song , Chunhe Yang , Zhanzhi Zhao","doi":"10.1016/j.ntt.2025.107500","DOIUrl":"10.1016/j.ntt.2025.107500","url":null,"abstract":"<div><div>Neuroinflammation is a critical factor in the pathogenesis of postoperative cognitive dysfunction (POCD). Maintaining microglial homeostasis is vital for regulating neuroinflammation, as microglial cell death can trigger an inflammatory response within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in supporting cell survival and modulating microglial-driven neuroinflammation. Our previous study indicated that TREM2 overexpression exerts protective effects against neuroinflammation and cognitive deficits in aged mice. However, the precise mechanisms by which TREM2 functions in microglia remain unclear. Consequently, this study aimed to examine the role of TREM2 in lipopolysaccharide (LPS)-induced cell death and neuroinflammation in BV2 cells. This research showed that TREM2 reduces LPS-induced nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis and the subsequent release of inflammatory factors through western blot analysis, flow cytometry, and enzyme-linked immunosorbent assay. Recent research has suggested that the loss of spleen tyrosine kinase (SYK), a downstream receptor kinase of TREM2 in microglia, results in exacerbated neuroinflammatory disease. This study further demonstrated that SYK activation via TREM2 treatment exerts neuroprotective effects by mitigating LPS-induced mitochondrial membrane potential damage, facilitating mitophagy, and inhibiting NLRP3-mediated pyroptosis in BV2 cells. Conversely, SYK inhibition by R406 led to microglial cell death and aggravated neuroinflammation, thereby reducing the neuroprotective effects of TREM2. Our findings indicate that TREM2 and SYK mitigate the inflammatory response in LPS-induced BV2 microglia and interfere with pyroptosis by enhancing mitophagy. These findings suggest that TREM2 and SYK may be valuable therapeutic targets for neuroinflammation.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107500"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208961","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 : 2025-07-01Epub Date: 2025-06-27DOI: 10.1016/j.ntt.2025.107518
Khoa Duc Le , Jeffrey Albert , June-Yung Kim , Sonia Minnes , Meeyoung O. Min , Lynn T. Singer
Introduction
Prenatal cocaine exposure (PCE) can alter the monoaminergic neurotransmitter system in the fetal brain related to emotional and behavioral regulation. PCE has been associated with high rates of aggression and delinquency, risk for victimization, and multiple environmental stressors associated with a disadvantaged environment, including postnatal lead exposure. While postnatal lead exposure has also been linked to aggressive behavior/delinquency, little is known about the combined impacts of PCE and lead on behavior, nor how they interact with environmental stressors such as victimization.
Objectives
Assess the relationships of PCE, postnatal lead levels, and victimization to adolescent self-report of aggressive behavior/delinquency, controlling for other prenatal drug exposures and the quality of the caregiving environment.
Methods
At age 17, 336 adolescents (50 % PCE, 46 % male) reported their aggressive behavior/delinquency (AGG) on the Problem-Oriented Screening Instrument for Teenagers, and type of lifetime victimization on the Juvenile Victimization Questionnaire. Blood lead levels were measured at 2–4 years, and the Home Observation for the Measurement of the Environment – Early Adolescence at 15 years. Binomial logistic, multiple regression and mediation analyses examined group differences and relationships among variables.
Results
PCE, victimization (child maltreatment and peer/sibling victimization), and postnatal lead levels were each associated with higher AGG. Girls with PCE reported higher AGG than non-exposed girls while boys did not differ, and all adolescents with PCE reported more child maltreatment and peer/sibling victimization. Child maltreatment partially mediated the relationship between PCE and aggressive behavior/delinquency.
Conclusions
Recognition of the higher rates of maltreatment and peer/sibling victimization with PCE is important for intervention efforts, as each contributes to higher AGG. As PCE may be associated differentially with higher AGG in girls, gender-focused interventions should be considered while addressing the increased impact of victimization and postnatal lead levels on AGG in both PCE and NCE boys and girls.
{"title":"The relationships of prenatal cocaine exposure, postnatal lead exposure, and victimization to aggressive behavior/delinquency in adolescence","authors":"Khoa Duc Le , Jeffrey Albert , June-Yung Kim , Sonia Minnes , Meeyoung O. Min , Lynn T. Singer","doi":"10.1016/j.ntt.2025.107518","DOIUrl":"10.1016/j.ntt.2025.107518","url":null,"abstract":"<div><h3>Introduction</h3><div>Prenatal cocaine exposure (PCE) can alter the monoaminergic neurotransmitter system in the fetal brain related to emotional and behavioral regulation. PCE has been associated with high rates of aggression and delinquency, risk for victimization, and multiple environmental stressors associated with a disadvantaged environment, including postnatal lead exposure. While postnatal lead exposure has also been linked to aggressive behavior/delinquency, little is known about the combined impacts of PCE and lead on behavior, nor how they interact with environmental stressors such as victimization.</div></div><div><h3>Objectives</h3><div>Assess the relationships of PCE, postnatal lead levels, and victimization to adolescent self-report of aggressive behavior/delinquency, controlling for other prenatal drug exposures and the quality of the caregiving environment.</div></div><div><h3>Methods</h3><div>At age 17, 336 adolescents (50 % PCE, 46 % male) reported their aggressive behavior/delinquency (AGG) on the Problem-Oriented Screening Instrument for Teenagers, and type of lifetime victimization on the Juvenile Victimization Questionnaire. Blood lead levels were measured at 2–4 years, and the Home Observation for the Measurement of the Environment – Early Adolescence at 15 years. Binomial logistic, multiple regression and mediation analyses examined group differences and relationships among variables.</div></div><div><h3>Results</h3><div>PCE, victimization (child maltreatment and peer/sibling victimization), and postnatal lead levels were each associated with higher AGG. Girls with PCE reported higher AGG than non-exposed girls while boys did not differ, and all adolescents with PCE reported more child maltreatment and peer/sibling victimization. Child maltreatment partially mediated the relationship between PCE and aggressive behavior/delinquency.</div></div><div><h3>Conclusions</h3><div>Recognition of the higher rates of maltreatment and peer/sibling victimization with PCE is important for intervention efforts, as each contributes to higher AGG. As PCE may be associated differentially with higher AGG in girls, gender-focused interventions should be considered while addressing the increased impact of victimization and postnatal lead levels on AGG in both PCE and NCE boys and girls.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107518"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529023","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 : 2025-07-01Epub Date: 2025-06-25DOI: 10.1016/j.ntt.2025.107517
Imam Hossen Rakib , Mohd Shahnawaz Khan , Arusha Ayub , Md. Sakib Al Hasan , Mohammed Alfaifi , Md. Shimul Bhuia , Emon Mia , Noshin Tasnim Yana , Md. Nasimul Haque Shipon , Muhammad Torequl Islam
Salvianolic acid A (SAL A), a polyphenolic compound derived from Salvia miltiorrhiza, exhibits several neuroprotective effects, but its sedative potential is unexamined. This study explores the sedative effects of SAL A and its potential to modulate the impacts of diazepam (DZP) in a thiopental sodium (TS)-induced sleep model in Swiss albino mice. Mice received intraperitoneal (i.p.) doses of SAL A (5 and 10 mg/kg) and DZP (2 mg/kg), followed by TS (20 mg/kg), with sleep latency and duration recorded. Molecular docking and in silico analyses evaluated SAL A’s interaction with the GABAA receptor (α1 and β2 subunits) (PDB ID: 6X3X) and its pharmacokinetic properties. Results revealed that SAL A significantly (p < 0.05) reduced sleep latency and prolonged sleep duration dose-dependently, with 10 mg/kg showing the strongest effect (latency: 14.29 ± 3.09 min; duration: 175.71 ± 18.97 min; Cohen's d = 4.37 and 1.60, respectively). Combined therapy with SAL A-10 and DZP-2 synergistically enhanced sleep duration, with the highest effect sizes observed (d = 5.45 for latency; 4.36 for duration). Molecular docking studies revealed that SAL A showed similar binding affinity (−8.7 kcal/mol) with 6X3X, comparable to DZP. SAL A also exhibited favorable pharmacokinetic properties and low toxicity. These findings suggest SAL A as a potential novel sedative agent with synergistic effects alongside DZP. However, SAL A's poor blood-brain barrier permeability and need for structural optimization highlight the necessity for future mechanistic studies, enhanced delivery methods, and clinical validation to confirm its therapeutic potential for sleep disorders.
{"title":"Salvianolic acid A enhances sedative effect of diazepam through the GABAergic pathway: In vivo, molecular docking, and pharmacokinetics approaches","authors":"Imam Hossen Rakib , Mohd Shahnawaz Khan , Arusha Ayub , Md. Sakib Al Hasan , Mohammed Alfaifi , Md. Shimul Bhuia , Emon Mia , Noshin Tasnim Yana , Md. Nasimul Haque Shipon , Muhammad Torequl Islam","doi":"10.1016/j.ntt.2025.107517","DOIUrl":"10.1016/j.ntt.2025.107517","url":null,"abstract":"<div><div>Salvianolic acid A (SAL A), a polyphenolic compound derived from <em>Salvia miltiorrhiza</em>, exhibits several neuroprotective effects, but its sedative potential is unexamined. This study explores the sedative effects of SAL A and its potential to modulate the impacts of diazepam (DZP) in a thiopental sodium (TS)-induced sleep model in <em>Swiss</em> albino mice. Mice received intraperitoneal (i.p.) doses of SAL A (5 and 10 mg/kg) and DZP (2 mg/kg), followed by TS (20 mg/kg), with sleep latency and duration recorded. Molecular docking and in silico analyses evaluated SAL A’s interaction with the GABA<sub>A</sub> receptor (α1 and β2 subunits) (PDB ID: <span><span>6X3X</span><svg><path></path></svg></span>) and its pharmacokinetic properties. Results revealed that SAL A significantly (<em>p</em> < 0.05) reduced sleep latency and prolonged sleep duration dose-dependently, with 10 mg/kg showing the strongest effect (latency: 14.29 ± 3.09 min; duration: 175.71 ± 18.97 min; Cohen's d = 4.37 and 1.60, respectively). Combined therapy with SAL A-10 and DZP-2 synergistically enhanced sleep duration, with the highest effect sizes observed (<em>d</em> = 5.45 for latency; 4.36 for duration). Molecular docking studies revealed that SAL A showed similar binding affinity (−8.7 kcal/mol) with 6X3X, comparable to DZP. SAL A also exhibited favorable pharmacokinetic properties and low toxicity. These findings suggest SAL A as a potential novel sedative agent with synergistic effects alongside DZP. However, SAL A's poor blood-brain barrier permeability and need for structural optimization highlight the necessity for future mechanistic studies, enhanced delivery methods, and clinical validation to confirm its therapeutic potential for sleep disorders.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107517"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502314","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 : 2025-07-01Epub Date: 2025-08-05DOI: 10.1016/j.ntt.2025.107535
Greena Kim , Kaitlyn Love , Fawn Connor-Stroud , Mark G. Baxter , Maria Alvarado , Jessica Raper
Animal models and human studies suggest that general anesthesia exposure during infancy results in long-lasting neurocognitive impairments. Because millions of children each year undergo procedures that require anesthesia, it is important to investigate the mechanism of anesthesia induced neurotoxicity to ultimately develop ways to protect the vulnerable developing brain. Animal models have played a key role in this investigation and have shown that neonatal general anesthesia exposure results in neuronal apoptosis, long-term mitochondrial dysfunction, and astrogliosis. The current study involved a rhesus macaque model of repeated sevoflurane exposure that has been shown to produce cognitive deficits, behavioral changes, and mitochondrial damage. This study sought to investigate whether prolonged sevoflurane exposure induced inflammation as measured in peripheral blood samples. Results found that sevoflurane exposure resulted in changing levels of inflammatory markers in the periphery. Specifically, interleukin 6 (IL-6) was increased immediately following sevoflurane exposure, but not at 24-h post-exposure. Plasma samples collected 24-h after exposure revealed increased granulocyte macrophage colony-stimulating factor (GM-CSF), but decreased monocyte chemoattractant protein-4 (MCP-4) and interferon gamma-induced protein 10 (IP-10) levels. Changes in these markers have been linked to cognitive impairment, and together these data suggest that plasma levels of cytokines and chemokines are a good potential medium to investigate anesthesia-induced inflammation in clinical populations.
{"title":"Neonatal sevoflurane exposure induces plasma biomarkers of inflammation in infant rhesus macaques","authors":"Greena Kim , Kaitlyn Love , Fawn Connor-Stroud , Mark G. Baxter , Maria Alvarado , Jessica Raper","doi":"10.1016/j.ntt.2025.107535","DOIUrl":"10.1016/j.ntt.2025.107535","url":null,"abstract":"<div><div>Animal models and human studies suggest that general anesthesia exposure during infancy results in long-lasting neurocognitive impairments. Because millions of children each year undergo procedures that require anesthesia, it is important to investigate the mechanism of anesthesia induced neurotoxicity to ultimately develop ways to protect the vulnerable developing brain. Animal models have played a key role in this investigation and have shown that neonatal general anesthesia exposure results in neuronal apoptosis, long-term mitochondrial dysfunction, and astrogliosis. The current study involved a rhesus macaque model of repeated sevoflurane exposure that has been shown to produce cognitive deficits, behavioral changes, and mitochondrial damage. This study sought to investigate whether prolonged sevoflurane exposure induced inflammation as measured in peripheral blood samples. Results found that sevoflurane exposure resulted in changing levels of inflammatory markers in the periphery. Specifically, interleukin 6 (IL-6) was increased immediately following sevoflurane exposure, but not at 24-h post-exposure. Plasma samples collected 24-h after exposure revealed increased granulocyte macrophage colony-stimulating factor (GM-CSF), but decreased monocyte chemoattractant protein-4 (MCP-4) and interferon gamma-induced protein 10 (IP-10) levels. Changes in these markers have been linked to cognitive impairment, and together these data suggest that plasma levels of cytokines and chemokines are a good potential medium to investigate anesthesia-induced inflammation in clinical populations.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107535"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775882","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}
The safety of antenatal corticosteroid administration during the late preterm period is currently questioned. This experimental study conducted in a CD-1 mouse model aimed to determine if exposure to betamethasone in the late preterm period 1) induces behavioral changes in adulthood and 2) alters cerebral anatomy. In the prenatal group, four gravid mice were randomly assigned to receive 0.1 mg of betamethasone (around 1.82 mg/kg based on an average body weight of 55 g) or an equivalent volume of phosphate buffered saline (PBS) on gestation day 18, and yielded a total of 43 pups. This model was selected to test the impact of cumulative exposure to exogenous and endogenous steroids. In the postnatal group, six gravid mice yielded a total of 69 pups which were randomly assigned to receive betamethasone or PBS. Pups in the intervention group received 0.03 mg of betamethasone subcutaneously on postnatal day 5, at which time mouse brain development is equivalent to that of humans at 34–36 weeks' gestation. To evaluate objective 1, pups were subjected to behavioral tests on postnatal days 21–50. On postnatal day 60, structural magnetic resonance imaging (MRI) was performed to assess objective 2. Outcomes were compared between treatment groups using linear mixed models including random effects for litter and a fixed term for the interaction of treatment and sex. We used a statistical significance threshold of p < 0.05. Male mice exposed to betamethasone ante- or postnatally engaged in more social contact than those exposed to PBS (interaction of betamethasone and male sex: prenatal β = 0.09, 95 % CI (0.02, 0.17), p = 0.02; postnatal β = 0.08, 95 %CI (0.01, 0.14), p = 0.03), while female mice engaged in less social contact. MRI showed that male mice exposed to betamethasone prenatally had larger habenulas and smaller amygdala than those exposed to PBS (interaction of betamethasone and male sex: habenula β = 0.01, 95 %CI (0.004, 0.02), p = 0.01, amygdala β = −1.43, 95 %CI (−2.67, −0.21), p = 0.03), while female mice had larger amygdala and smaller habenulas. Postnatal exposure to betamethasone was associated with lower combined volume of the parietal cortex and hypothalamus (interaction of betamethasone and male sex: β = −0.32, 95 %CI (−0.58, −0.03), p = 0.04). No other significant differences in behavioral outcomes or brain volumes were identified. These results suggest that exposure to betamethasone in the late preterm period is associated with small but significant sex-specific disruptions of the limbic system, associated with social behavior disturbances.
{"title":"Neurodevelopmental impacts of betamethasone administered in the late preterm period: An experimental study in CD-1 mice","authors":"Isabelle Hardy , Anthony Gagnon , Erika-Kate Croft , Luc Tremblay , Réjean Lebel , Marie-Ève Roy-Lacroix , Larissa Takser , Annie Ouellet , Denis Gris","doi":"10.1016/j.ntt.2025.107523","DOIUrl":"10.1016/j.ntt.2025.107523","url":null,"abstract":"<div><div>The safety of antenatal corticosteroid administration during the late preterm period is currently questioned. This experimental study conducted in a CD-1 mouse model aimed to determine if exposure to betamethasone in the late preterm period 1) induces behavioral changes in adulthood and 2) alters cerebral anatomy. In the prenatal group, four gravid mice were randomly assigned to receive 0.1 mg of betamethasone (around 1.82 mg/kg based on an average body weight of 55 g) or an equivalent volume of phosphate buffered saline (PBS) on gestation day 18, and yielded a total of 43 pups. This model was selected to test the impact of cumulative exposure to exogenous and endogenous steroids. In the postnatal group, six gravid mice yielded a total of 69 pups which were randomly assigned to receive betamethasone or PBS. Pups in the intervention group received 0.03 mg of betamethasone subcutaneously on postnatal day 5, at which time mouse brain development is equivalent to that of humans at 34–36 weeks' gestation. To evaluate objective 1, pups were subjected to behavioral tests on postnatal days 21–50. On postnatal day 60, structural magnetic resonance imaging (MRI) was performed to assess objective 2. Outcomes were compared between treatment groups using linear mixed models including random effects for litter and a fixed term for the interaction of treatment and sex. We used a statistical significance threshold of <em>p</em> < 0.05. Male mice exposed to betamethasone ante- or postnatally engaged in more social contact than those exposed to PBS (interaction of betamethasone and male sex: prenatal β = 0.09, 95 % CI (0.02, 0.17), <em>p</em> = 0.02; postnatal β = 0.08, 95 %CI (0.01, 0.14), <em>p</em> = 0.03), while female mice engaged in less social contact. MRI showed that male mice exposed to betamethasone prenatally had larger habenulas and smaller amygdala than those exposed to PBS (interaction of betamethasone and male sex: habenula β = 0.01, 95 %CI (0.004, 0.02), <em>p</em> = 0.01, amygdala β = −1.43, 95 %CI (−2.67, −0.21), <em>p</em> = 0.03), while female mice had larger amygdala and smaller habenulas. Postnatal exposure to betamethasone was associated with lower combined volume of the parietal cortex and hypothalamus (interaction of betamethasone and male sex: β = −0.32, 95 %CI (−0.58, −0.03), <em>p</em> = 0.04). No other significant differences in behavioral outcomes or brain volumes were identified. These results suggest that exposure to betamethasone in the late preterm period is associated with small but significant sex-specific disruptions of the limbic system, associated with social behavior disturbances.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107523"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626778","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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