Pub Date : 2025-11-01Epub Date: 2025-09-26DOI: 10.1016/j.ntt.2025.107561
Kim N. Cajachagua-Torres , Olga D. Boer , Anneke Louwerse , Akhgar Ghassabian , Irwin K.M. Reiss , Vincent W.V. Jaddoe , Hanan El Marroun
Prenatal cannabis and tobacco exposure is associated with attention and behavior problems in children, while associations with autism symptoms remain unclear. We prospectively examined whether parental cannabis and tobacco use during pregnancy were associated with childhood autism symptoms. Information on parental cannabis and tobacco use was assessed using questionnaires, and maternal cannabis metabolites were detected via urinalysis. We measured autistic symptoms using two mother-reported instruments: Child Behavior Checklist (CBCL) at ages 1.5, 3, and 6; and Social Responsiveness Scale (SRS) at 6 years (n = 4380). Linear mixed models were used to examine the association between parental cannabis and tobacco use and CBCL autism symptoms across childhood. Linear regression was used for SRS autism symptoms. Maternal cannabis use before, but not during, pregnancy was associated with higher CBCL autism symptoms across childhood (β: 0.33, 95 % CI: 0.02, 0.63). Paternal cannabis use was linked to higher CBCL autism symptoms across childhood (β: 0.27, 95 % CI: 0.05, 0.50), explained by maternal psychopathology; no association was found with SRS autism symptoms. Excluding cannabis users, children whose mothers used tobacco throughout pregnancy had more SRS autism symptoms (β: 0.03, 95 % CI: 0.003, 0.05), not CBCL; no association was found with paternal tobacco use.
Our results suggest that maternal and paternal cannabis use is not associated with offspring autism symptoms, although preconception use is associated with autism symptoms across childhood. In contrast, maternal continued tobacco use during pregnancy was associated with autism symptoms, but not paternal use, suggesting possible intrauterine programming rather than family-based factors.
{"title":"The association of preconception and prenatal cannabis and tobacco exposure with autism symptoms in offspring: A population-based longitudinal study","authors":"Kim N. Cajachagua-Torres , Olga D. Boer , Anneke Louwerse , Akhgar Ghassabian , Irwin K.M. Reiss , Vincent W.V. Jaddoe , Hanan El Marroun","doi":"10.1016/j.ntt.2025.107561","DOIUrl":"10.1016/j.ntt.2025.107561","url":null,"abstract":"<div><div>Prenatal cannabis and tobacco exposure is associated with attention and behavior problems in children, while associations with autism symptoms remain unclear. We prospectively examined whether parental cannabis and tobacco use during pregnancy were associated with childhood autism symptoms. Information on parental cannabis and tobacco use was assessed using questionnaires, and maternal cannabis metabolites were detected via urinalysis. We measured autistic symptoms using two mother-reported instruments: Child Behavior Checklist (CBCL) at ages 1.5, 3, and 6; and Social Responsiveness Scale (SRS) at 6 years (<em>n</em> = 4380). Linear mixed models were used to examine the association between parental cannabis and tobacco use and CBCL autism symptoms across childhood. Linear regression was used for SRS autism symptoms. Maternal cannabis use before, but not during, pregnancy was associated with higher CBCL autism symptoms across childhood (β: 0.33, 95 % CI: 0.02, 0.63). Paternal cannabis use was linked to higher CBCL autism symptoms across childhood (β: 0.27, 95 % CI: 0.05, 0.50), explained by maternal psychopathology; no association was found with SRS autism symptoms. Excluding cannabis users, children whose mothers used tobacco throughout pregnancy had more SRS autism symptoms (β: 0.03, 95 % CI: 0.003, 0.05), not CBCL; no association was found with paternal tobacco use.</div><div>Our results suggest that maternal and paternal cannabis use is not associated with offspring autism symptoms, although preconception use is associated with autism symptoms across childhood. In contrast, maternal continued tobacco use during pregnancy was associated with autism symptoms, but not paternal use, suggesting possible intrauterine programming rather than family-based factors.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107561"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183780","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 : 2025-11-01Epub Date: 2025-10-06DOI: 10.1016/j.ntt.2025.107560
Ming Li , Bo Ma , Si Liang , Xuanyi Pan , Jingyi Xie , Hongjie Wang , Jiguang Guo
The demand for surgical and anesthetic care in patients with Parkinson's disease (PD) is projected to increase, because PD is the fastest-growing neurological disorder. Sevoflurane, the most commonly used volatile anesthetic, is neurotoxic to human and animal neonatal brains. Moreover, sevoflurane-based anesthesia can induce postoperative delirium (POD) in patients with PD. Therefore, our study was aimed at finding an effective treatment for sevoflurane-induced neurotoxicity in patients with PD by using a PD-POD Drosophila model. The small gas, hydrogen (H2), was found to ameliorate learning and memory impairment, and increase the lifespan of PD flies, after long-term sevoflurane exposure. The performance index of the PD-POD flies increased by 30 % after H2 inhalation. Moreover, H2 inhalation decreased oxidative stress levels in PD fly brains, and increased electron transport chain and OXPHOS efficiency, as well as ATP synthesis, thus indicating enhanced mitochondrial function. In addition, PD flies with H2 inhalation after sevoflurane exposure showed increased nuclear levels of Nrf2 and expression of its downstream target HO. Therefore, H2 might exert antioxidant effects by activating the Nrf2/HO pathway, thereby decreasing oxidative stress levels and apoptosis in PD fly brains after long-term sevoflurane treatment. Inhalation of H2 is likely to be an effective and convenient method to alleviate the neurotoxicity effects or POD caused by long-term sevoflurane exposure.
{"title":"Hydrogen activated the Nrf2/HO pathway to alleviate the cognitive decline in PD Drosophila after long-term sevoflurane exposure","authors":"Ming Li , Bo Ma , Si Liang , Xuanyi Pan , Jingyi Xie , Hongjie Wang , Jiguang Guo","doi":"10.1016/j.ntt.2025.107560","DOIUrl":"10.1016/j.ntt.2025.107560","url":null,"abstract":"<div><div>The demand for surgical and anesthetic care in patients with Parkinson's disease (PD) is projected to increase, because PD is the fastest-growing neurological disorder. Sevoflurane, the most commonly used volatile anesthetic, is neurotoxic to human and animal neonatal brains. Moreover, sevoflurane-based anesthesia can induce postoperative delirium (POD) in patients with PD. Therefore, our study was aimed at finding an effective treatment for sevoflurane-induced neurotoxicity in patients with PD by using a PD-POD <em>Drosophila</em> model. The small gas, hydrogen (H<sub>2</sub>), was found to ameliorate learning and memory impairment, and increase the lifespan of PD flies, after long-term sevoflurane exposure. The performance index of the PD-POD flies increased by 30 % after H<sub>2</sub> inhalation. Moreover, H<sub>2</sub> inhalation decreased oxidative stress levels in PD fly brains, and increased electron transport chain and OXPHOS efficiency, as well as ATP synthesis, thus indicating enhanced mitochondrial function. In addition, PD flies with H<sub>2</sub> inhalation after sevoflurane exposure showed increased nuclear levels of Nrf2 and expression of its downstream target HO. Therefore, H<sub>2</sub> might exert antioxidant effects by activating the Nrf2/HO pathway, thereby decreasing oxidative stress levels and apoptosis in PD fly brains after long-term sevoflurane treatment. Inhalation of H<sub>2</sub> is likely to be an effective and convenient method to alleviate the neurotoxicity effects or POD caused by long-term sevoflurane exposure.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107560"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252292","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 : 2025-11-01Epub Date: 2025-09-30DOI: 10.1016/j.ntt.2025.107563
Eugenio Aztiria , Carlos Javier Baier
This article reviews the use, toxicology, and neurological effects of organophosphates (OPs) used as pharmacological agents. OPs, a versatile chemical family, have been applied in many sectors but pose significant risks, particularly to the nervous system. In the first part of this review, we discuss the toxicological effects of OPs, particularly their inhibition of the acetylcholinesterase (AChE) enzyme, leading to severe neurological impairments. Indeed, prolonged exposure to these chemicals can trigger neuroinflammation, oxidative stress, and changes in neurotransmitter systems, resulting in cognitive deficits, neuropsychiatric disorders, and, potentially, neurodegeneration. In the second part, we address the therapeutic potential of these chemicals, focusing mainly on their effects on the central nervous system (CNS). Some naturally occurring compounds, like citicoline, have shown neuroprotective properties, while synthetic OPs such as bisphosphonates and their derivatives are being explored to treat some mental conditions. However, the high toxicity and side effects of some of them, whether in the short or long term, may limit their use in clinical settings. Overall, there is a call for better animal models and continued research to develop safer therapeutic options.
{"title":"Organophosphorus compounds and neurological conditions: Dr. Jekyll and Mr. Hyde","authors":"Eugenio Aztiria , Carlos Javier Baier","doi":"10.1016/j.ntt.2025.107563","DOIUrl":"10.1016/j.ntt.2025.107563","url":null,"abstract":"<div><div>This article reviews the use, toxicology, and neurological effects of organophosphates (OPs) used as pharmacological agents. OPs, a versatile chemical family, have been applied in many sectors but pose significant risks, particularly to the nervous system. In the first part of this review, we discuss the toxicological effects of OPs, particularly their inhibition of the acetylcholinesterase (AChE) enzyme, leading to severe neurological impairments. Indeed, prolonged exposure to these chemicals can trigger neuroinflammation, oxidative stress, and changes in neurotransmitter systems, resulting in cognitive deficits, neuropsychiatric disorders, and, potentially, neurodegeneration. In the second part, we address the therapeutic potential of these chemicals, focusing mainly on their effects on the central nervous system (CNS). Some naturally occurring compounds, like citicoline, have shown neuroprotective properties, while synthetic OPs such as bisphosphonates and their derivatives are being explored to treat some mental conditions. However, the high toxicity and side effects of some of them, whether in the short or long term, may limit their use in clinical settings. Overall, there is a call for better animal models and continued research to develop safer therapeutic options.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107563"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213141","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 : 2025-11-01Epub Date: 2025-10-19DOI: 10.1016/j.ntt.2025.107565
Gabriel Gavazza Noé , Larissa de Jesus Corrêa , Janne Ketly da Silva Oliveira , Karoline de Oliveira Sant'Anna , Vitor Sampaio Minassa , Andrew Vieira Aitken , Karla Nivea Sampaio , Vanessa Beijamini
Clinical and preclinical evidence points to a bilateral association between cardiovascular diseases (CVD) and mental disorders such as anxiety and depression. We previously reported that exposure to organophosphate (OP) compounds, such as chlorpyrifos (CPF), promotes cardiovascular damage and behavioral alterations in normotensive rats. Also, spontaneously hypertensive rats (SHR), a well-established rodent model of hypertension, exhibit more severe symptoms of acute CPF toxicosis and higher mortality rates, likely due to lower plasma butyrylcholinesterase (BuChE) activity. The potential role of pre-existing hypertension in increasing susceptibility to acute OP toxicity, particularly in relation to psychiatric disorders, remains an open question. Given this, we investigated whether SHR are more susceptible than normotensive Wistar rats to the damage caused by acute CPF exposure on innate (elevated plus maze, EPM; light-dark transition, LDT; and open field tests) and learned (contextual fear conditioning) anxiety-like behaviors. A single dose of CPF (20 mg/kg) induced an anxiolytic-like behavior in SHR exposed to the EPM and no effect in Wistar rats. CPF acute intoxication increased fear expression in both strains, but impaired memory extinction only in Wistar rats. CPF inhibited BuChE in Wistar at all tested doses (10, 20 and 30 mg/kg), whereas inhibition occurred only at the highest dose in SHR. CPF also decreased acetylcholinesterase (AChE) activity in the hippocampus and prefrontal cortex of both strains. In summary, acute intoxication with CPF induces strain-dependent behavioral changes. SHRs intoxicated with CPF may not be the most suitable model for studying anxiety susceptibility to OP intoxication in previously hypertensive rats.
{"title":"Differential cognitive, behavioral, and neurochemical responses to acute chlorpyrifos exposure in normotensive compared to hypertensive adult rats","authors":"Gabriel Gavazza Noé , Larissa de Jesus Corrêa , Janne Ketly da Silva Oliveira , Karoline de Oliveira Sant'Anna , Vitor Sampaio Minassa , Andrew Vieira Aitken , Karla Nivea Sampaio , Vanessa Beijamini","doi":"10.1016/j.ntt.2025.107565","DOIUrl":"10.1016/j.ntt.2025.107565","url":null,"abstract":"<div><div>Clinical and preclinical evidence points to a bilateral association between cardiovascular diseases (CVD) and mental disorders such as anxiety and depression. We previously reported that exposure to organophosphate (OP) compounds, such as chlorpyrifos (CPF), promotes cardiovascular damage and behavioral alterations in normotensive rats. Also, spontaneously hypertensive rats (SHR), a well-established rodent model of hypertension, exhibit more severe symptoms of acute CPF toxicosis and higher mortality rates, likely due to lower plasma butyrylcholinesterase (BuChE) activity. The potential role of pre-existing hypertension in increasing susceptibility to acute OP toxicity, particularly in relation to psychiatric disorders, remains an open question. Given this, we investigated whether SHR are more susceptible than normotensive Wistar rats to the damage caused by acute CPF exposure on innate (elevated plus maze, EPM; light-dark transition, LDT; and open field tests) and learned (contextual fear conditioning) anxiety-like behaviors. A single dose of CPF (20 mg/kg) induced an anxiolytic-like behavior in SHR exposed to the EPM and no effect in Wistar rats. CPF acute intoxication increased fear expression in both strains, but impaired memory extinction only in Wistar rats. CPF inhibited BuChE in Wistar at all tested doses (10, 20 and 30 mg/kg), whereas inhibition occurred only at the highest dose in SHR. CPF also decreased acetylcholinesterase (AChE) activity in the hippocampus and prefrontal cortex of both strains. In summary, acute intoxication with CPF induces strain-dependent behavioral changes. SHRs intoxicated with CPF may not be the most suitable model for studying anxiety susceptibility to OP intoxication in previously hypertensive rats.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107565"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346303","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 : 2025-11-01Epub Date: 2025-10-24DOI: 10.1016/j.ntt.2025.107566
Laura M. Carlson , G. Jean Harry , Kelly Carstens
{"title":"Introduction to developmental outcomes of neuroinflammatory insults","authors":"Laura M. Carlson , G. Jean Harry , Kelly Carstens","doi":"10.1016/j.ntt.2025.107566","DOIUrl":"10.1016/j.ntt.2025.107566","url":null,"abstract":"","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107566"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459216","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 : 2025-11-01Epub Date: 2025-09-26DOI: 10.1016/j.ntt.2025.107562
Kathryn S. Konrad , Laura Betz , Sandra McBride , Keith R. Shockley , Georgia Roberts , Helen Cunny , G. Jean Harry
Behavioral assays are critical in evaluating impacts on nervous system function in rodents due to genetic or environmental factors and are frequently incorporated into regulatory decision-making studies. Despite numerous sources of guidance for such studies, results across behavioral assays are reputed to be highly variable with questionable replicability. Behavioral data obtained from control rats within four contract laboratory studies were used to evaluate replicability across studies, calculate the level of statistical power, and estimate the number of animals required for a specific effect size. For the three behaviors evaluated here (motor activity, acoustic startle response, and learning and memory), control rats from all studies showed the expected pattern of behavior, e.g., open field acclimation, startle habituation, % prepulse inhibition (PPI) over pre-pulse intensities, and acquisition and goal quadrant preference in the Morris Water Maze (MWM). For selected representative individual endpoints, power analyses were conducted to evaluate sample size requirements. Across all endpoints, a drop in power occurred as differences between two groups became smaller. Power analysis of multiple representative endpoints suggested that a sample size of 20 may detect a 30 % effect with 80 % power. Sample size requirements changed with the effect size, and achieving 80 % power with a 20 % effect size generally required a sample size of 30 rats. While the behavioral performance was replicated over the Study Cohorts, power analyses suggested a need for moderation of expectations regarding detectable differences if decisions relied on single endpoints or small effect sizes. Reporting results from a low powered study can have significant and wide-ranging impacts, including undermining confidence in data interpretation, misleading future research, and failing to adhere to the ethical framework of the 3 R's.
{"title":"Assessing replicability and power estimates of behavioral performance of control rats across standardized pre-clinical and toxicology studies","authors":"Kathryn S. Konrad , Laura Betz , Sandra McBride , Keith R. Shockley , Georgia Roberts , Helen Cunny , G. Jean Harry","doi":"10.1016/j.ntt.2025.107562","DOIUrl":"10.1016/j.ntt.2025.107562","url":null,"abstract":"<div><div>Behavioral assays are critical in evaluating impacts on nervous system function in rodents due to genetic or environmental factors and are frequently incorporated into regulatory decision-making studies. Despite numerous sources of guidance for such studies, results across behavioral assays are reputed to be highly variable with questionable replicability. Behavioral data obtained from control rats within four contract laboratory studies were used to evaluate replicability across studies, calculate the level of statistical power, and estimate the number of animals required for a specific effect size. For the three behaviors evaluated here (motor activity, acoustic startle response, and learning and memory), control rats from all studies showed the expected pattern of behavior, e.g., open field acclimation, startle habituation, % prepulse inhibition (PPI) over pre-pulse intensities, and acquisition and goal quadrant preference in the Morris Water Maze (MWM). For selected representative individual endpoints, power analyses were conducted to evaluate sample size requirements. Across all endpoints, a drop in power occurred as differences between two groups became smaller. Power analysis of multiple representative endpoints suggested that a sample size of 20 may detect a 30 % effect with 80 % power. Sample size requirements changed with the effect size, and achieving 80 % power with a 20 % effect size generally required a sample size of 30 rats. While the behavioral performance was replicated over the Study Cohorts, power analyses suggested a need for moderation of expectations regarding detectable differences if decisions relied on single endpoints or small effect sizes. Reporting results from a low powered study can have significant and wide-ranging impacts, including undermining confidence in data interpretation, misleading future research, and failing to adhere to the ethical framework of the 3 R's.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107562"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186615","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 : 2025-11-01Epub Date: 2025-10-20DOI: 10.1016/j.ntt.2025.107564
Yun Yan , Junyi Wang , Xiaoping Lei
Prenatal use of synthetic corticosteroids has been widely applied in preventing respiratory distress syndrome in preterm infants. In recent years, research has begun to focus on the effects of Antenatal Corticosteroids(ACS) on the short-term and long-term neurological development of offspring. This review summarizes the direct and potential effects of ACS on offspring neurological outcomes, including cognitive function, behavioral problems, and neurodevelopmental disorders. Studies have shown that prenatal corticosteroid exposure may be associated with improved short-term neurological outcomes in extremely preterm infants. However, the benefits on near- and long-term outcomes in late preterm and full-term infants remain inconclusive and controversial due to a lack of robust evidence. This article explores the potential effects of exposure timing and different dosages on offspring neurological outcomes, and emphasizes the need for further research to optimize the indications for ACS use. This will ensure its benefits in preterm complications while minimizing its potential negative impact on offspring neurodevelopment.
{"title":"Prenatal corticosteroid use and offspring neurological outcomes","authors":"Yun Yan , Junyi Wang , Xiaoping Lei","doi":"10.1016/j.ntt.2025.107564","DOIUrl":"10.1016/j.ntt.2025.107564","url":null,"abstract":"<div><div>Prenatal use of synthetic corticosteroids has been widely applied in preventing respiratory distress syndrome in preterm infants. In recent years, research has begun to focus on the effects of Antenatal Corticosteroids(ACS) on the short-term and long-term neurological development of offspring. This review summarizes the direct and potential effects of ACS on offspring neurological outcomes, including cognitive function, behavioral problems, and neurodevelopmental disorders. Studies have shown that prenatal corticosteroid exposure may be associated with improved short-term neurological outcomes in extremely preterm infants. However, the benefits on near- and long-term outcomes in late preterm and full-term infants remain inconclusive and controversial due to a lack of robust evidence. This article explores the potential effects of exposure timing and different dosages on offspring neurological outcomes, and emphasizes the need for further research to optimize the indications for ACS use. This will ensure its benefits in preterm complications while minimizing its potential negative impact on offspring neurodevelopment.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107564"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337338","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 : 2025-11-01Epub Date: 2025-11-19DOI: 10.1016/j.ntt.2025.107568
Miles T. Wiley , Adrian H. Courville , Hayden Northcutt , Iva Durdanovic , Kawsar U. Chowdhury , Vishnu Suppiramaniam , Miranda N. Reed
Cannabis is the most widely used illicit drug among pregnant women, and its use has been linked to higher risks of hyperactivity, attention issues, anxiety, depression, and reduced cognitive abilities in children. Cannabinoids cross the placenta and affect the fetal endocannabinoid (eCB) system, which is crucial for neurodevelopment and interacts with other key neurotransmitter systems, such as GABA, that regulate the proliferation, migration, differentiation, and plasticity of developing neurons. This review discusses the effects of exogenous cannabinoids on the eCB and GABAergic systems during neurodevelopment, including recent findings that exposure to exogenous cannabinoids can delay the developmental transition of GABA from a depolarizing to a hyperpolarizing state. This paper also examines the consequences of delayed GABA switching during early postnatal development and considers its potential long-term effects on brain function. These findings expand our understanding of maternal cannabis use and highlight the need for further research to clarify mechanisms, identify potential treatment targets, and evaluate public health impacts as cannabis use during pregnancy rises.
{"title":"Neurodevelopmental effects of exogenous cannabinoids on endocannabinoid and GABAergic neurotransmission","authors":"Miles T. Wiley , Adrian H. Courville , Hayden Northcutt , Iva Durdanovic , Kawsar U. Chowdhury , Vishnu Suppiramaniam , Miranda N. Reed","doi":"10.1016/j.ntt.2025.107568","DOIUrl":"10.1016/j.ntt.2025.107568","url":null,"abstract":"<div><div>Cannabis is the most widely used illicit drug among pregnant women, and its use has been linked to higher risks of hyperactivity, attention issues, anxiety, depression, and reduced cognitive abilities in children. Cannabinoids cross the placenta and affect the fetal endocannabinoid (eCB) system, which is crucial for neurodevelopment and interacts with other key neurotransmitter systems, such as GABA, that regulate the proliferation, migration, differentiation, and plasticity of developing neurons. This review discusses the effects of exogenous cannabinoids on the eCB and GABAergic systems during neurodevelopment, including recent findings that exposure to exogenous cannabinoids can delay the developmental transition of GABA from a depolarizing to a hyperpolarizing state. This paper also examines the consequences of delayed GABA switching during early postnatal development and considers its potential long-term effects on brain function. These findings expand our understanding of maternal cannabis use and highlight the need for further research to clarify mechanisms, identify potential treatment targets, and evaluate public health impacts as cannabis use during pregnancy rises.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"112 ","pages":"Article 107568"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573987","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: 2025-08-05DOI: 10.1016/j.ntt.2025.107536
Neha Sehgal, Patricia A Brennan, Anne L Dunlop, Donghai Liang, Elizabeth J Corwin, Youran Tan, Todd M Everson, W Michael Caudle, Parinya Panuwet, Priya E D'Souza, Volha Yakimavets, Grace E Lee, Dana Boyd Barr, Stephanie M Eick
Background: Cannabis and tobacco are contaminated with insecticides and used during pregnancy in the U.S., raising concerns for co-exposures and compounded neurodevelopmental effects. However, these cumulative effects remain unexplored. We examine the associations of prenatal cannabis, tobacco, pyrethroid, and organophosphate insecticides co-exposures with early childhood neurobehaviors.
Methods: Among 197 mother-child pairs from a birth cohort in Atlanta, Georgia, cannabis (THCCOOH), tobacco (COT and 3OH-COT), pyrethroids (3PBA), and organophosphates (TCPY) metabolite levels were quantified in maternal urine sampled at 8-14 and 24-30 weeks' gestation. Infant arousal and attention were evaluated 2 weeks postnatally using the NICU Network Neurobehavioral Assessment Scale. Externalizing and internalizing behaviors were assessed annually using the Child Behavior Checklist and averaged across ages 2-5 years. We examined individual associations using linear regression; cumulative associations using quantile g-computation and Bayesian kernel machine regression (BKMR); and whether THCCOOH modified the cumulative effect of tobacco and insecticides.
Results: Of the prenatal exposures, only insecticides were associated with child neurobehavior. For example, a doubling in 3PBA was positively related to internalizing behaviors (β = 18.1 %; 95 % confidence interval [CI] = 0.0 %, 39.5 %), and TCPY was negatively associated with externalizing behaviors (β = -12.9 %; 95 % CI = -27.8 %, 5.0 %). These were modified by THCCOOH and sex. The prenatal 3PBA, TCPY, COT, and 3OH-COT mixture was associated with lower externalizing behaviors among females with detectable THCCOOH (quantile g-computation β = -46.8 %; 95 % CI = -70.4 %, -4.1 %). BKMR showed no interactions and dose-responses.
Discussion: Prenatally, 3PBA and TCPY were associated with child neurobehaviors, and effects differed by THCCOOH and sex. Further studies on the neurodevelopmental burden of cannabis, tobacco, and insecticide co-exposures are needed.
{"title":"Associations of prenatal tobacco and insecticide co-exposures with neurobehavioral responses among children born to pregnant women exposed to cannabis.","authors":"Neha Sehgal, Patricia A Brennan, Anne L Dunlop, Donghai Liang, Elizabeth J Corwin, Youran Tan, Todd M Everson, W Michael Caudle, Parinya Panuwet, Priya E D'Souza, Volha Yakimavets, Grace E Lee, Dana Boyd Barr, Stephanie M Eick","doi":"10.1016/j.ntt.2025.107536","DOIUrl":"10.1016/j.ntt.2025.107536","url":null,"abstract":"<p><strong>Background: </strong>Cannabis and tobacco are contaminated with insecticides and used during pregnancy in the U.S., raising concerns for co-exposures and compounded neurodevelopmental effects. However, these cumulative effects remain unexplored. We examine the associations of prenatal cannabis, tobacco, pyrethroid, and organophosphate insecticides co-exposures with early childhood neurobehaviors.</p><p><strong>Methods: </strong>Among 197 mother-child pairs from a birth cohort in Atlanta, Georgia, cannabis (THCCOOH), tobacco (COT and 3OH-COT), pyrethroids (3PBA), and organophosphates (TCPY) metabolite levels were quantified in maternal urine sampled at 8-14 and 24-30 weeks' gestation. Infant arousal and attention were evaluated 2 weeks postnatally using the NICU Network Neurobehavioral Assessment Scale. Externalizing and internalizing behaviors were assessed annually using the Child Behavior Checklist and averaged across ages 2-5 years. We examined individual associations using linear regression; cumulative associations using quantile g-computation and Bayesian kernel machine regression (BKMR); and whether THCCOOH modified the cumulative effect of tobacco and insecticides.</p><p><strong>Results: </strong>Of the prenatal exposures, only insecticides were associated with child neurobehavior. For example, a doubling in 3PBA was positively related to internalizing behaviors (β = 18.1 %; 95 % confidence interval [CI] = 0.0 %, 39.5 %), and TCPY was negatively associated with externalizing behaviors (β = -12.9 %; 95 % CI = -27.8 %, 5.0 %). These were modified by THCCOOH and sex. The prenatal 3PBA, TCPY, COT, and 3OH-COT mixture was associated with lower externalizing behaviors among females with detectable THCCOOH (quantile g-computation β = -46.8 %; 95 % CI = -70.4 %, -4.1 %). BKMR showed no interactions and dose-responses.</p><p><strong>Discussion: </strong>Prenatally, 3PBA and TCPY were associated with child neurobehaviors, and effects differed by THCCOOH and sex. Further studies on the neurodevelopmental burden of cannabis, tobacco, and insecticide co-exposures are needed.</p>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":" ","pages":"107536"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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}
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