Pub 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":"2025-08-12","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 : 2025-08-11DOI: 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":"2025-08-11","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 : 2025-07-01DOI: 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 : 2025-07-01DOI: 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}
Pub Date : 2025-07-01DOI: 10.1016/j.ntt.2025.107519
Ju-Feng Ma , Jing Zhang , Rui He , Ju-Hui Niu , Shen Yang
Background
Local anesthetics have been associated with spinal neurotoxicity, including the risk of persistent neurological injury. Pregnancy is known to increase the sensitivity of nervous tissue to local anesthetics, potentially elevating the risk of neurological deficits in obstetric patients following spinal block. This study aimed to investigate the effects of pregnancy on the neurotoxicity of intrathecal bupivacaine.
Methods
Pregnant and non-pregnant rabbits were administered three injections of either 0.375 % or 0.75 % bupivacaine, or normal saline, at 48-h intervals (average volume: 200 μl). Seven days after the first injection, electron microscopic scores (EMS), spinal neuronal apoptotic rates, intracellular Ca2+ concentrations, and mitochondrial membrane potential were evaluated.
Results
The EMS indicated more severe neurotoxicity in non-pregnant rabbits compared to pregnant rabbits in the bupivacaine-treated groups (median [Q1-Q3]: 23 [21–26] vs. 21 [18.5–24], P = 0.045). Pregnant rabbits exhibited significantly lower apoptosis rates and intracellular Ca2+ concentrations, along with a higher mitochondrial membrane potential compared to their non-pregnant counterparts (0.99 % ± 1.33 % vs. 2.03 % ± 2.09 %, P < 0.01; 240 ± 104 vs. 257 ± 112, P < 0.01; 84.1 % ± 6.1 % vs. 69.9 % ± 15.4 %, P < 0.01).
Conclusion
These findings indicated that pregnancy protects nervous tissue against the toxicity of intrathecal bupivacaine.
Conclusion: These findings suggest that pregnancy confers a protective effect on nervous tissue against the neurotoxicity induced by intrathecal bupivacaine.
{"title":"Pregnancy protects nervous tissues against the neurotoxicity of intrathecal bupivacaine in rabbits","authors":"Ju-Feng Ma , Jing Zhang , Rui He , Ju-Hui Niu , Shen Yang","doi":"10.1016/j.ntt.2025.107519","DOIUrl":"10.1016/j.ntt.2025.107519","url":null,"abstract":"<div><h3>Background</h3><div>Local anesthetics have been associated with spinal neurotoxicity, including the risk of persistent neurological injury. Pregnancy is known to increase the sensitivity of nervous tissue to local anesthetics, potentially elevating the risk of neurological deficits in obstetric patients following spinal block. This study aimed to investigate the effects of pregnancy on the neurotoxicity of intrathecal bupivacaine.</div></div><div><h3>Methods</h3><div>Pregnant and non-pregnant rabbits were administered three injections of either 0.375 % or 0.75 % bupivacaine, or normal saline, at 48-h intervals (average volume: 200 μl). Seven days after the first injection, electron microscopic scores (EMS), spinal neuronal apoptotic rates, intracellular Ca<sup>2+</sup> concentrations, and mitochondrial membrane potential were evaluated.</div></div><div><h3>Results</h3><div>The EMS indicated more severe neurotoxicity in non-pregnant rabbits compared to pregnant rabbits in the bupivacaine-treated groups (median [Q1-Q3]: 23 [21–26] vs. 21 [18.5–24], <em>P</em> = 0.045). Pregnant rabbits exhibited significantly lower apoptosis rates and intracellular Ca<sup>2+</sup> concentrations, along with a higher mitochondrial membrane potential compared to their non-pregnant counterparts (0.99 % ± 1.33 % vs. 2.03 % ± 2.09 %, <em>P</em> < 0.01; 240 ± 104 vs. 257 ± 112, <em>P</em> < 0.01; 84.1 % ± 6.1 % vs. 69.9 % ± 15.4 %, <em>P</em> < 0.01).</div></div><div><h3>Conclusion</h3><div>These findings indicated that pregnancy protects nervous tissue against the toxicity of intrathecal bupivacaine.</div><div><strong>Conclusion:</strong> These findings suggest that pregnancy confers a protective effect on nervous tissue against the neurotoxicity induced by intrathecal bupivacaine.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107519"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529022","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 : 2025-07-01DOI: 10.1016/j.ntt.2025.107524
Nusret Uysal , Baris Karadas , Secil Karaca Kurtulmus , Merve Tor , Ismail Yilmaz , Nihal Olgac Dundar , Yusuf C. Kaplan
Objective
To assess pregnancy outcomes following maternal favipiravir exposure, with a particular focus on congenital malformations and neonatal development.
Methods
A case series, including data from pregnancies with favipiravir exposure between 2020 and 2021, was conducted at Izmir Katip Celebi University Teratology Information Center. Pregnant women and their infants were evaluated through structured interviews, ultrasonography, neonatal follow-ups, and developmental assessments. Congenital malformations were classified per EUROCAT criteria, and development was assessed using the Denver Developmental Screening Test-III.
Results
Of 45 pregnancies, 37 resulted in live births (including 1 set of twins), seven were electively terminated, and one ended in intrauterine death. Among the 28 infants with first-trimester exposure, 7.1 % (n = 2) had major malformations (congenital ichthyosis and hydronephrosis) and an additional 7.1 % (n = 2) had minor malformations (pleural effusion, patent foramen ovale). A review of exposure windows relative to critical developmental periods did not indicate a consistent or conclusive temporal association with the observed anomalies. Preterm birth and low birth weight rates were 9.6 % and 6.4 %, respectively. Neonatal jaundice occurred in 32.2 % of neonates. Developmental screening was normal in most cases, with one infant—who did not have any congenital malformations—exhibiting mild language delay.
Conclusion
Our study does not indicate a major teratogenic signal regarding favipiravir exposure in pregnancy, though the higher elective termination rate suggests increased risk perception. While study limitations prevent definitive conclusions, our findings may be of value to clinicians in counseling pregnant women regarding favipiravir exposure.
{"title":"Pregnancy outcomes following maternal exposure to favipiravir: A Terafar case series","authors":"Nusret Uysal , Baris Karadas , Secil Karaca Kurtulmus , Merve Tor , Ismail Yilmaz , Nihal Olgac Dundar , Yusuf C. Kaplan","doi":"10.1016/j.ntt.2025.107524","DOIUrl":"10.1016/j.ntt.2025.107524","url":null,"abstract":"<div><h3>Objective</h3><div>To assess pregnancy outcomes following maternal favipiravir exposure, with a particular focus on congenital malformations and neonatal development.</div></div><div><h3>Methods</h3><div>A case series, including data from pregnancies with favipiravir exposure between 2020 and 2021, was conducted at Izmir Katip Celebi University Teratology Information Center. Pregnant women and their infants were evaluated through structured interviews, ultrasonography, neonatal follow-ups, and developmental assessments. Congenital malformations were classified per EUROCAT criteria, and development was assessed using the Denver Developmental Screening Test-III.</div></div><div><h3>Results</h3><div>Of 45 pregnancies, 37 resulted in live births (including 1 set of twins), seven were electively terminated, and one ended in intrauterine death. Among the 28 infants with first-trimester exposure, 7.1 % (<em>n</em> = 2) had major malformations (congenital ichthyosis and hydronephrosis) and an additional 7.1 % (n = 2) had minor malformations (pleural effusion, patent foramen ovale). A review of exposure windows relative to critical developmental periods did not indicate a consistent or conclusive temporal association with the observed anomalies. Preterm birth and low birth weight rates were 9.6 % and 6.4 %, respectively. Neonatal jaundice occurred in 32.2 % of neonates. Developmental screening was normal in most cases, with one infant—who did not have any congenital malformations—exhibiting mild language delay.</div></div><div><h3>Conclusion</h3><div>Our study does not indicate a major teratogenic signal regarding favipiravir exposure in pregnancy, though the higher elective termination rate suggests increased risk perception. While study limitations prevent definitive conclusions, our findings may be of value to clinicians in counseling pregnant women regarding favipiravir exposure.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107524"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656127","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 : 2025-07-01DOI: 10.1016/j.ntt.2025.107520
Jerrold S. Meyer , Sonya Sobrian , Gregg D. Stanwood
{"title":"Introduction to “Effects of stress exposure during development on neurobehavioral and neuroendocrine function”","authors":"Jerrold S. Meyer , Sonya Sobrian , Gregg D. Stanwood","doi":"10.1016/j.ntt.2025.107520","DOIUrl":"10.1016/j.ntt.2025.107520","url":null,"abstract":"","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107520"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560607","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 : 2025-07-01DOI: 10.1016/j.ntt.2025.107534
Nusret Uysal , Baris Karadas , Secil Karaca Kurtulmus , Merve Tor , Ismail Yilmaz , Nihal Olgac Dundar , Yusuf C. Kaplan
{"title":"Corrigendum to: “Pregnancy outcomes following maternal exposure to Favipiravir: A Terafar case series” [Neurotoxicology and Teratology 110 (2025) 107524]","authors":"Nusret Uysal , Baris Karadas , Secil Karaca Kurtulmus , Merve Tor , Ismail Yilmaz , Nihal Olgac Dundar , Yusuf C. Kaplan","doi":"10.1016/j.ntt.2025.107534","DOIUrl":"10.1016/j.ntt.2025.107534","url":null,"abstract":"","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107534"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775881","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}
As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.
{"title":"Micro(nano)plastics in the brain: Epigenetic perturbations in progression to neurodegenerative diseases","authors":"Mou Mondal , Apoorva Chouksey , Vikas Gurjar , Rajnarayan Tiwari , Rupesh K. Srivasatava , Pradyumna Kumar Mishra","doi":"10.1016/j.ntt.2025.107521","DOIUrl":"10.1016/j.ntt.2025.107521","url":null,"abstract":"<div><div>As global plastic production escalates, micro(nano)plastics (MNPs) have become pressing ecological and biomedical concerns. These pollutants are increasingly implicated in the pathogenesis of neurodegenerative diseases. Due to their nanoscale size and surface reactivity, MNPs can cross the blood-brain barrier, accumulating in neural tissues. Once internalized, they disrupt neuronal homeostasis by inducing oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, key processes in neurodegenerative progression. Mitochondria, central to neuronal energy and redox regulation, are particularly vulnerable, leading to impaired ATP production, elevated ROS, and pro-apoptotic signaling. Recent studies reveal that MNPs also induce epigenetic changes, including aberrant DNA methylation, histone modifications, and dysregulation of non-coding RNAs. These alterations can result in synaptic instability, persistent transcriptional reprogramming, and heightened susceptibility to diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. The mitochondrial epigenome is a vital target of MNP-induced disruption, offering potential biomarkers like methylated mtDNA and microRNAs for early diagnosis and prognosis. Understanding the molecular mechanisms behind these epigenetic alterations is essential for developing practical diagnostic tools and therapies. This review provides a comprehensive overview of MNP-induced neurodegeneration, focusing on mitochondrial and epigenetic disruptions. Moreover, it explores emerging biosensing technologies for detecting MNP-induced epigenetic alterations, highlighting the urgent need for further investigation to fully understand the neurotoxic potential of MNPs and develop preventive and therapeutic strategies for mitigating their effects on brain health.</div></div>","PeriodicalId":19144,"journal":{"name":"Neurotoxicology and teratology","volume":"110 ","pages":"Article 107521"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595585","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号