Pub Date : 2025-08-30DOI: 10.1016/j.neuro.2025.103310
Pratham Gautam , Varinder Singh , Navjot Kanwar , Richa Shri , Tanveer Singh , Manjinder Singh , Thakur Gurjeet Singh , Amarjot Kaur Grewal , Amit Kumar , Ravinder Singh , Sheikh F. Ahmad , Haneen A. Al-Mazroua
Lead (Pb) neurotoxicity remains a global concern, causing irreversible cognitive and motor impairments through mechanisms like mitochondrial dysfunction, oxidative stress and inflammation. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy that also coordinates mitochondrial function, has emerged as a novel target in neuroprotection. This study evaluated the neuroprotective potential of hesperidin (natural flavonoid) against Pb-induced neurotoxicity, with a focus on the role of TFEB. Rats were orally administered lead acetate (100 mg/kg) once daily for 30 days to induce neurotoxicity, followed by hesperidin (50 and 100 mg/kg, p.o.) treatment. Cognitive and motor functions were assessed through Morris Water Maze and rotarod tests, while biochemical analyses measured oxidative stress markers (TBARS, GSH), inflammatory cytokines (TNF-α, IL-6, NF-κB), and mitochondrial complex I–III activities. Pb exposure significantly impaired learning, memory, and motor coordination, increased oxidative and inflammatory markers, and reduced mitochondrial function. Hesperidin treatment improved behavioral outcomes and restored redox balance, inflammatory markers and mitochondrial enzyme activity. However, co-treatment with eltrombopag, a TFEB inhibitor, abolished these protective effects, confirming TFEB’s involvement. These findings highlight hesperidin’s ability to mitigate Pb neurotoxicity through TFEB-mediated restoration of mitochondrial function and suppression of oxidative stress and inflammation. Targeting TFEB may offer a novel therapeutic strategy for heavy metal-induced neurodegeneration.
{"title":"Hesperidin mitigates lead-induced neurotoxicity via TFEB-dependent restoration of mitochondrial function, oxidative balance, and neuroinflammation in rats","authors":"Pratham Gautam , Varinder Singh , Navjot Kanwar , Richa Shri , Tanveer Singh , Manjinder Singh , Thakur Gurjeet Singh , Amarjot Kaur Grewal , Amit Kumar , Ravinder Singh , Sheikh F. Ahmad , Haneen A. Al-Mazroua","doi":"10.1016/j.neuro.2025.103310","DOIUrl":"10.1016/j.neuro.2025.103310","url":null,"abstract":"<div><div>Lead (Pb) neurotoxicity remains a global concern, causing irreversible cognitive and motor impairments through mechanisms like mitochondrial dysfunction, oxidative stress and inflammation. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy that also coordinates mitochondrial function, has emerged as a novel target in neuroprotection. This study evaluated the neuroprotective potential of hesperidin (natural flavonoid) against Pb-induced neurotoxicity, with a focus on the role of TFEB. Rats were orally administered lead acetate (100 mg/kg) once daily for 30 days to induce neurotoxicity, followed by hesperidin (50 and 100 mg/kg, p.o.) treatment. Cognitive and motor functions were assessed through Morris Water Maze and rotarod tests, while biochemical analyses measured oxidative stress markers (TBARS, GSH), inflammatory cytokines (TNF-α, IL-6, NF-κB), and mitochondrial complex I–III activities. Pb exposure significantly impaired learning, memory, and motor coordination, increased oxidative and inflammatory markers, and reduced mitochondrial function. Hesperidin treatment improved behavioral outcomes and restored redox balance, inflammatory markers and mitochondrial enzyme activity. However, co-treatment with eltrombopag, a TFEB inhibitor, abolished these protective effects, confirming TFEB’s involvement. These findings highlight hesperidin’s ability to mitigate Pb neurotoxicity through TFEB-mediated restoration of mitochondrial function and suppression of oxidative stress and inflammation. Targeting TFEB may offer a novel therapeutic strategy for heavy metal-induced neurodegeneration.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103310"},"PeriodicalIF":3.9,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922518","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 : 2025-08-26DOI: 10.1016/j.neuro.2025.103308
Lennart V.J. van Melis, Teije Bak, Anneloes M. Peerdeman, Regina G.D.M. van Kleef, J. Pepijn Wopken, Remco H.S. Westerink
Organochlorine insecticide exposure has been associated with neurodevelopmental and neurodegenerative disorders. Moreover, both in vitro and in vivo studies have shown that exposure to organochlorine insecticides causes hyperactivity in the nervous system, and negatively affects calcium homeostasis, neurite outgrowth, and neurotransmitter (receptor) levels. Some of the in vivo effects and associations from epidemiological studies were sex-specific, highlighting the importance of investigating the effects of organochlorine exposure in both sexes. It is therefore of great importance to investigate the effects of prolonged, developmental exposure to organochlorines on the development of neuronal network activity. Here, we examined the effects of acute (30 min), prolonged (up to 48 h), and chronic (21 days) exposure to DDT, its metabolite DDE, endosulfan, dieldrin, and lindane on neuronal activity and network development in sex-separated rat primary cortical cultures using micro-electrode array (MEA) recordings. Our study showed that acute exposure to all tested organochlorines evoked a hyperexcitation, sometimes at concentrations ≤ 1 µM. Exposure to DDT, DDE, endosulfan, and dieldrin inhibited neuronal activity after prolonged exposure, while exposure to lindane had no clear effects after 24 and 48 h. Chronic exposure to all tested organochlorines inhibited neuronal network development at high micromolar concentrations. Most of these effects were observed at non-cytotoxic concentrations, except for exposure to 100 µM endosulfan. Some of the effects found in this study differed between male and female cultures, but no clear sex-specific patterns could be determined across exposure scenarios or between compounds. Together, these results show that acute, prolonged, and chronic exposure to organochlorine insecticides evoke differential effects on neuronal activity and network development. The effects found after acute exposure to DDT, endosulfan, dieldrin, and lindane occur at concentrations close to, or even below human internal exposure levels, highlighting the importance of further monitoring human exposure to organochlorine insecticides.
{"title":"Acute, prolonged, and chronic exposure to organochlorine insecticides evoke differential effects on in vitro neuronal activity and network development","authors":"Lennart V.J. van Melis, Teije Bak, Anneloes M. Peerdeman, Regina G.D.M. van Kleef, J. Pepijn Wopken, Remco H.S. Westerink","doi":"10.1016/j.neuro.2025.103308","DOIUrl":"10.1016/j.neuro.2025.103308","url":null,"abstract":"<div><div>Organochlorine insecticide exposure has been associated with neurodevelopmental and neurodegenerative disorders. Moreover, both <em>in vitro</em> and <em>in vivo</em> studies have shown that exposure to organochlorine insecticides causes hyperactivity in the nervous system, and negatively affects calcium homeostasis, neurite outgrowth, and neurotransmitter (receptor) levels. Some of the <em>in vivo</em> effects and associations from epidemiological studies were sex-specific, highlighting the importance of investigating the effects of organochlorine exposure in both sexes. It is therefore of great importance to investigate the effects of prolonged, developmental exposure to organochlorines on the development of neuronal network activity. Here, we examined the effects of acute (30 min), prolonged (up to 48 h), and chronic (21 days) exposure to DDT, its metabolite DDE, endosulfan, dieldrin, and lindane on neuronal activity and network development in sex-separated rat primary cortical cultures using micro-electrode array (MEA) recordings. Our study showed that acute exposure to all tested organochlorines evoked a hyperexcitation, sometimes at concentrations ≤ 1 µM. Exposure to DDT, DDE, endosulfan, and dieldrin inhibited neuronal activity after prolonged exposure, while exposure to lindane had no clear effects after 24 and 48 h. Chronic exposure to all tested organochlorines inhibited neuronal network development at high micromolar concentrations. Most of these effects were observed at non-cytotoxic concentrations, except for exposure to 100 µM endosulfan. Some of the effects found in this study differed between male and female cultures, but no clear sex-specific patterns could be determined across exposure scenarios or between compounds. Together, these results show that acute, prolonged, and chronic exposure to organochlorine insecticides evoke differential effects on neuronal activity and network development. The effects found after acute exposure to DDT, endosulfan, dieldrin, and lindane occur at concentrations close to, or even below human internal exposure levels, highlighting the importance of further monitoring human exposure to organochlorine insecticides.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103308"},"PeriodicalIF":3.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912217","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 : 2025-08-26DOI: 10.1016/j.neuro.2025.08.006
Kyungtae Hyun , Yunkyoung Lee , Sumin Hong , Eunjung Han , Saemi Park , Hyun woo Baek , Hwee-Jin Kim , Yoon Chan Rah , June Choi
Osthole, a coumarin derivative with potent antioxidant and anti-inflammatory properties, has demonstrated promising therapeutic potential in protecting against ototoxicity. This study investigated the protective effects of osthole through both in vitro and in vivo experimental models. A high-content screening of 1505 natural compounds in HEI-OC1 cells identified osthole as the most effective compound in alleviating gentamicin-induced cellular damage. Our results indicate that osthole confers protection by restoring autophagic flux and reducing the accumulation of reactive oxygen species (ROS). In HEI-OC1 cells, cell viability was significantly improved following co-treatment with gentamicin and osthole. Western blot analysis revealed that osthole modulates key signaling pathways involved in cell survival and autophagy. Furthermore, LysoTracker staining in zebrafish larvae confirmed that osthole preserved autophagic activity compromised by gentamicin exposure. In vivo experiments using wild-type and Tg(Brn3c:EGFP) zebrafish lines assessed neuromast hair cell survival in the lateral line system. Compared with the gentamicin-only group, the osthole co-treated group exhibited increased hair cell counts, a reduced number of TUNEL-positive apoptotic cells, decreased ROS levels, and enhanced autophagy. These outcomes collectively demonstrate the potential protective effects of osthole against gentamicin-induced ototoxicity in both cellular and zebrafish models. Taken together, these findings highlight osthole as a promising candidate for therapeutic development against aminoglycoside-induced hearing loss, offering a multi-targeted mechanism involving oxidative stress reduction, autophagy restoration, and inhibition of apoptosis.
{"title":"In vivo and in vitro evaluation of the protective effects of osthole against ototoxicity using the zebrafish model and HEI-OC1 cell line","authors":"Kyungtae Hyun , Yunkyoung Lee , Sumin Hong , Eunjung Han , Saemi Park , Hyun woo Baek , Hwee-Jin Kim , Yoon Chan Rah , June Choi","doi":"10.1016/j.neuro.2025.08.006","DOIUrl":"10.1016/j.neuro.2025.08.006","url":null,"abstract":"<div><div>Osthole, a coumarin derivative with potent antioxidant and anti-inflammatory properties, has demonstrated promising therapeutic potential in protecting against ototoxicity. This study investigated the protective effects of osthole through both <em>in vitro</em> and <em>in vivo</em> experimental models. A high-content screening of 1505 natural compounds in HEI-OC1 cells identified osthole as the most effective compound in alleviating gentamicin-induced cellular damage. Our results indicate that osthole confers protection by restoring autophagic flux and reducing the accumulation of reactive oxygen species (ROS). In HEI-OC1 cells, cell viability was significantly improved following co-treatment with gentamicin and osthole. Western blot analysis revealed that osthole modulates key signaling pathways involved in cell survival and autophagy. Furthermore, LysoTracker staining in zebrafish larvae confirmed that osthole preserved autophagic activity compromised by gentamicin exposure. <em>In vivo</em> experiments using wild-type and Tg(Brn3c:EGFP) zebrafish lines assessed neuromast hair cell survival in the lateral line system. Compared with the gentamicin-only group, the osthole co-treated group exhibited increased hair cell counts, a reduced number of TUNEL-positive apoptotic cells, decreased ROS levels, and enhanced autophagy. These outcomes collectively demonstrate the potential protective effects of osthole against gentamicin-induced ototoxicity in both cellular and zebrafish models. Taken together, these findings highlight osthole as a promising candidate for therapeutic development against aminoglycoside-induced hearing loss, offering a multi-targeted mechanism involving oxidative stress reduction, autophagy restoration, and inhibition of apoptosis.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 197-208"},"PeriodicalIF":3.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907780","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 : 2025-08-24DOI: 10.1016/j.neuro.2025.08.005
Sorour Ghotbinasab , Ali Akbar Oroojan , Mohammad Amin Behmanesh , Neda Amirgholamy , Amir Hossein Nasiri , Soheila Alboghobeish
Environmental cadmium (Cd) contamination has increased in recent years, coinciding with the expansion of industrial activities and the global consumption of high-fat diets (HFD). Both are recognized as independent risk factors for neurodegenerative processes, yet their combined effects on brain function remain poorly characterized. This study is the first to investigate the interactive neurotoxicity of chronic Cd exposure and HFD, and to assess the potential protective effects of naringin, a flavonoid with known antioxidant and anti-inflammatory properties. Eighty female NMRI mice were assigned to eight groups receiving low- or high-fat diets, with or without Cd (0.5 or 5 ppm) in drinking water for 12 weeks. Two groups co-exposed to Cd and HFD received naringin (50 or 100 mg/kg). Behavioral assessments (Y-maze, shuttle box) were conducted, along with evaluations of oxidative stress markers, mitochondrial function, acetylcholinesterase activity, DNA fragmentation, histopathology, and proinflammatory cytokines. Cd and HFD individually induced cognitive deficits, oxidative imbalance, mitochondrial dysfunction, inflammation, and cholinergic disruption, which were more pronounced when both insults were combined. Naringin, particularly at a dose of 100 mg/kg, effectively reversed these alterations, restoring redox homeostasis and neuronal integrity without reducing Cadmium accumulation in brain tissue. These findings demonstrate, for the first time, that naringin mitigates the synergistic neurotoxic effects of Cd and HFD, highlighting its therapeutic potential against modern environmental and dietary challenges.
{"title":"Severe neurotoxicity induced by the combined exposure to cadmium and high-fat diet: Protective role of naringin against oxidative, mitochondrial, and inflammatory brain damage","authors":"Sorour Ghotbinasab , Ali Akbar Oroojan , Mohammad Amin Behmanesh , Neda Amirgholamy , Amir Hossein Nasiri , Soheila Alboghobeish","doi":"10.1016/j.neuro.2025.08.005","DOIUrl":"10.1016/j.neuro.2025.08.005","url":null,"abstract":"<div><div>Environmental cadmium (Cd) contamination has increased in recent years, coinciding with the expansion of industrial activities and the global consumption of high-fat diets (HFD). Both are recognized as independent risk factors for neurodegenerative processes, yet their combined effects on brain function remain poorly characterized. This study is the first to investigate the interactive neurotoxicity of chronic Cd exposure and HFD, and to assess the potential protective effects of <em>naringin</em>, a flavonoid with known antioxidant and anti-inflammatory properties. Eighty female NMRI mice were assigned to eight groups receiving low- or high-fat diets, with or without Cd (0.5 or 5 ppm) in drinking water for 12 weeks. Two groups co-exposed to Cd and HFD received naringin (50 or 100 mg/kg). Behavioral assessments (Y-maze, shuttle box) were conducted, along with evaluations of oxidative stress markers, mitochondrial function, acetylcholinesterase activity, DNA fragmentation, histopathology, and proinflammatory cytokines. Cd and HFD individually induced cognitive deficits, oxidative imbalance, mitochondrial dysfunction, inflammation, and cholinergic disruption, which were more pronounced when both insults were combined. Naringin, particularly at a dose of 100 mg/kg, effectively reversed these alterations, restoring redox homeostasis and neuronal integrity without reducing Cadmium accumulation in brain tissue. These findings demonstrate, for the first time, that naringin mitigates the synergistic neurotoxic effects of Cd and HFD, highlighting its therapeutic potential against modern environmental and dietary challenges.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103306"},"PeriodicalIF":3.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1016/j.neuro.2025.08.004
Jessie R. Badley , Peter M. Andrew , Hans-Joachim Lehmler , Pamela J. Lein
Higher-chlorinated (HC) polychlorinated biphenyls (PCBs) are known developmental neurotoxicants. In contrast, there are limited data regarding the developmental neurotoxicity of lower-chlorinated (LC) PCBs despite the increasing environmental prevalence and detection of LC-PCBs in contemporary human tissues, including the perinatal brain. This study characterized the neurotoxic effects of the LC-PCB congener PCB 37 in primary male and female rat cortical neuron-glia co-cultures. Cultures were exposed to varying concentrations of PCB 37 for 48 h beginning on day in vitro 0 or 7. Cell viability was assessed by measuring lactate dehydrogenase release into the culture medium and the percentage of live cells identified using Calcein-AM and Hoechst staining. Apoptosis was measured using fluorometric assays of caspase 3/7 activity and Annexin V binding. Axonal and dendritic growth were quantified in neurons immunostained for Tau-1 or transfected with MAP2B-red fluorescent protein, respectively, using automated image analysis protocols. At environmentally relevant concentrations (0.0001, 0.1, and 100 nM) that did not affect cell viability, PCB 37 caused sex-, age-, and concentration-dependent increases in apoptosis, axonal, and dendritic growth. Pretreatment with the CREB inhibitor 666–15 (500 nM) blocked the effects of PCB 37 on apoptosis and dendritic morphology but not axonal growth. These findings suggest that the pro-apoptotic and dendrite-promoting effects of PCB 37 are mediated by CREB signaling, but that CREB-independent mechanisms underlie PCB 37 effects on axonal growth. Overall, these findings identify PCB 37 as a potential developmental neurotoxicant and further support increasing evidence identifying CREB as a convergent mechanism of developmental neurotoxicity.
{"title":"PCB 37 (3,4, 4’-trichlorobiphenyl) increased apoptosis and modulated neuronal morphogenesis in primary rat cortical neuron-glia cocultures in a concentration-, sex-, age-, and CREB-dependent manner","authors":"Jessie R. Badley , Peter M. Andrew , Hans-Joachim Lehmler , Pamela J. Lein","doi":"10.1016/j.neuro.2025.08.004","DOIUrl":"10.1016/j.neuro.2025.08.004","url":null,"abstract":"<div><div>Higher-chlorinated (HC) polychlorinated biphenyls (PCBs) are known developmental neurotoxicants. In contrast, there are limited data regarding the developmental neurotoxicity of lower-chlorinated (LC) PCBs despite the increasing environmental prevalence and detection of LC-PCBs in contemporary human tissues, including the perinatal brain. This study characterized the neurotoxic effects of the LC-PCB congener PCB 37 in primary male and female rat cortical neuron-glia co-cultures. Cultures were exposed to varying concentrations of PCB 37 for 48 h beginning on day <em>in vitro</em> 0 or 7. Cell viability was assessed by measuring lactate dehydrogenase release into the culture medium and the percentage of live cells identified using Calcein-AM and Hoechst staining. Apoptosis was measured using fluorometric assays of caspase 3/7 activity and Annexin V binding. Axonal and dendritic growth were quantified in neurons immunostained for Tau-1 or transfected with MAP2B-red fluorescent protein, respectively, using automated image analysis protocols. At environmentally relevant concentrations (0.0001, 0.1, and 100 nM) that did not affect cell viability, PCB 37 caused sex-, age-, and concentration-dependent increases in apoptosis, axonal, and dendritic growth. Pretreatment with the CREB inhibitor 666–15 (500 nM) blocked the effects of PCB 37 on apoptosis and dendritic morphology but not axonal growth. These findings suggest that the pro-apoptotic and dendrite-promoting effects of PCB 37 are mediated by CREB signaling, but that CREB-independent mechanisms underlie PCB 37 effects on axonal growth. Overall, these findings identify PCB 37 as a potential developmental neurotoxicant and further support increasing evidence identifying CREB as a convergent mechanism of developmental neurotoxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 168-180"},"PeriodicalIF":3.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-08DOI: 10.1016/j.neuro.2025.08.001
Dalisa R. Kendricks, Jariatu Stallone, DaNashia S. Thomas, Leslie R. Aksu, Kaylie I. Kirkwood-Donelson, Alan K. Jarmusch, Christopher A. McPherson, Jesse D. Cushman
Chlorpyrifos is an organophosphorus insecticide known to produce severe neurotoxicity following early developmental exposure. So far, little data describes the neurobehavioral and metabolic consequences of low-dose exposures, near the threshold to produce cholinesterase inhibition. The purpose of the current study was to characterize the impact of prenatal exposure to a low dose of chlorpyrifos, at 0.5 mg/kg/day, and compare observed neurobehavioral and metabolic changes to a well-defined daily dose of 5 mg/kg. Pregnant C57BL/6 J dams were exposed to either 0, 0.5, or 5 mg/kg/day chlorpyrifos from gestation day 6.5–17.5. A metabolic profile was determined in dams and pups at the end of exposure and behavior was analyzed in offspring during late adolescence and early adulthood. Exposure to 5 mg/kg chlorpyrifos disrupted metabolites associated with the oxidative stress response and with energy metabolism within the brain and produced long-term impairment in spontaneous behavior and learning in offspring. Exposure to the lower dose of 0.5 mg/kg/day reduced levels of metabolites downstream of ornithine, a process that was also disrupted with exposure to 5 mg/kg/day. Further, 0.5 mg/kg/day chlorpyrifos impaired spontaneous behavior in offspring during adulthood, though no significant effects on learning or reversal were seen. These findings support a conclusion that prenatal low dose chlorpyrifos exposure produces long-term metabolic and neurobehavioral impairment that resemble deficits seen with high dose exposure.
{"title":"Neurobehavioral and metabolic effects of prenatal low-dose chlorpyrifos in C57BL/6J mice","authors":"Dalisa R. Kendricks, Jariatu Stallone, DaNashia S. Thomas, Leslie R. Aksu, Kaylie I. Kirkwood-Donelson, Alan K. Jarmusch, Christopher A. McPherson, Jesse D. Cushman","doi":"10.1016/j.neuro.2025.08.001","DOIUrl":"10.1016/j.neuro.2025.08.001","url":null,"abstract":"<div><div>Chlorpyrifos is an organophosphorus insecticide known to produce severe neurotoxicity following early developmental exposure. So far, little data describes the neurobehavioral and metabolic consequences of low-dose exposures, near the threshold to produce cholinesterase inhibition. The purpose of the current study was to characterize the impact of prenatal exposure to a low dose of chlorpyrifos, at 0.5 mg/kg/day, and compare observed neurobehavioral and metabolic changes to a well-defined daily dose of 5 mg/kg. Pregnant C57BL/6 J dams were exposed to either 0, 0.5, or 5 mg/kg/day chlorpyrifos from gestation day 6.5–17.5. A metabolic profile was determined in dams and pups at the end of exposure and behavior was analyzed in offspring during late adolescence and early adulthood. Exposure to 5 mg/kg chlorpyrifos disrupted metabolites associated with the oxidative stress response and with energy metabolism within the brain and produced long-term impairment in spontaneous behavior and learning in offspring. Exposure to the lower dose of 0.5 mg/kg/day reduced levels of metabolites downstream of ornithine, a process that was also disrupted with exposure to 5 mg/kg/day. Further, 0.5 mg/kg/day chlorpyrifos impaired spontaneous behavior in offspring during adulthood, though no significant effects on learning or reversal were seen. These findings support a conclusion that prenatal low dose chlorpyrifos exposure produces long-term metabolic and neurobehavioral impairment that resemble deficits seen with high dose exposure.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 132-144"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diesel Exhaust Particles (DEPs) emitted by diesel engines represent a substantial contributor to ambient particulate matter. Extensive research has demonstrated that DEPs pose significant risks to human health. This study seeks to elucidate the molecular mechanisms underlying DEPs-induced dysfunction of the blood-brain barrier (BBB). The research team exposed bEND.3 cells to various concentrations of DEPs for 24 h and evaluated parameters including cell morphology, viability, inflammatory markers, oxidative stress, tight junction protein expression, and modulation of the RhoA/ROCK signaling pathway. The findings revealed that DEPs exposure resulted in morphological and ultrastructural alterations, elevated apoptosis rates, and reduced cell viability. Additionally, DEPs stimulated the release of pro-inflammatory cytokines, induced oxidative stress, disrupted tight junction protein expression, increased BBB permeability, and activated the RhoA/ROCK signaling pathway, thereby amplifying these deleterious effects. Collectively, our results demonstrate that DEPs impair BBB functionality through a cascade of cellular injury mechanisms. These findings highlight the profound impact of air pollution on the central nervous system and underscore the urgent need for stringent regulations on diesel emissions to protect brain health, particularly among populations in urban areas with high exposure to traffic-related emissions.
{"title":"Diesel exhaust particles induced blood-brain barrier dysfunction through inflammation, oxidative stress, and activation of the RhoA/ROCK signaling pathway","authors":"Yanming Lv, Yingying Chen, Zhijian Gao, Siqi Liu, Ya Zhang, Huimin Suo, Shuying Gao","doi":"10.1016/j.neuro.2025.08.002","DOIUrl":"10.1016/j.neuro.2025.08.002","url":null,"abstract":"<div><div>Diesel Exhaust Particles (DEPs) emitted by diesel engines represent a substantial contributor to ambient particulate matter. Extensive research has demonstrated that DEPs pose significant risks to human health. This study seeks to elucidate the molecular mechanisms underlying DEPs-induced dysfunction of the blood-brain barrier (BBB). The research team exposed bEND.3 cells to various concentrations of DEPs for 24 h and evaluated parameters including cell morphology, viability, inflammatory markers, oxidative stress, tight junction protein expression, and modulation of the RhoA/ROCK signaling pathway. The findings revealed that DEPs exposure resulted in morphological and ultrastructural alterations, elevated apoptosis rates, and reduced cell viability. Additionally, DEPs stimulated the release of pro-inflammatory cytokines, induced oxidative stress, disrupted tight junction protein expression, increased BBB permeability, and activated the RhoA/ROCK signaling pathway, thereby amplifying these deleterious effects. Collectively, our results demonstrate that DEPs impair BBB functionality through a cascade of cellular injury mechanisms. These findings highlight the profound impact of air pollution on the central nervous system and underscore the urgent need for stringent regulations on diesel emissions to protect brain health, particularly among populations in urban areas with high exposure to traffic-related emissions.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 122-131"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-08DOI: 10.1016/j.neuro.2025.08.003
Klistenes Alves de Lima , Alana Gomes de Souza , Adriano José Maia Chaves Filho , João Victor Souza Oliveira , Michele Albuquerque Jales de Carvalho , Melina Mottin , Camila Nayane de Carvalho Lima , Antonio Eufrásio Vieira-Neto , Iardja Stéfane Lopes Sales , Francisco Josimar Girão Júnior , Carolina Horta Andrade , Marta Maria de França Fonteles
Carbapenems are broad-spectrum β-lactam antibiotics widely used in critical and hospitalized patients. They are usually well tolerated; however, under certain conditions, these drugs are associated with central nervous system toxicity and proconvulsant activity. Here, we investigated the proconvulsant action of different generation carbapenems: imipenem (IMI), meropenem (MERO), and ertapenem (ERTA) in mice through behavioral analysis. We also propose possible molecular mechanisms for this side effect through an integrative experimental and computational approach. For this, male mice received carbapenems at doses of 250 and 500 mg/kg, or saline, subcutaneously, for 7 days. On the last day, the pilocarpine-induced seizure test was performed. On the last day, the pilocarpine-induced seizure test was performed, and latency to the first seizure and latency of death were recorded. Subsequently, oxidative stress markers were measured in brain areas. Additionally, using the three-dimensional structure of the drugs, we performed computational target prediction and molecular docking calculations. IMI and MERO, at both tested doses, reduced seizure latency and death latency compared to pilocarpine group. This effect occurred only with the higher dose of ERTA (500 mg/kg). Furthermore, IMI increased lipid peroxidation in all brain areas, MERO in the hippocampus and prefrontal cortex, and ERTA only in the hippocampus. The three carbapenems increased nitrite/nitrate levels in all brain areas, while only IMI at 500 mg/kg decreased GSH. Computational studies predicted that GABAA receptor, Glutathione S-transferase Pi, Glutathione S-transferase Mu 1, and Glutathione S-transferase A2 could be promising targets for the CNS toxicity of carbapenems, related to their proconvulsant effect. Therefore, our data contribute to the current understanding of CNS toxicity associated with carbapenems and propose the participation of oxidative stress and the interaction with GABA and GSH synthesis systems in the molecular mechanism of their proconvulsant effect.
{"title":"Integrative behavior analysis, oxidative stress markers determination and molecular docking to investigate proconvulsant action of betalactamic carbapenems","authors":"Klistenes Alves de Lima , Alana Gomes de Souza , Adriano José Maia Chaves Filho , João Victor Souza Oliveira , Michele Albuquerque Jales de Carvalho , Melina Mottin , Camila Nayane de Carvalho Lima , Antonio Eufrásio Vieira-Neto , Iardja Stéfane Lopes Sales , Francisco Josimar Girão Júnior , Carolina Horta Andrade , Marta Maria de França Fonteles","doi":"10.1016/j.neuro.2025.08.003","DOIUrl":"10.1016/j.neuro.2025.08.003","url":null,"abstract":"<div><div>Carbapenems are broad-spectrum β-lactam antibiotics widely used in critical and hospitalized patients. They are usually well tolerated; however, under certain conditions, these drugs are associated with central nervous system toxicity and proconvulsant activity. Here, we investigated the proconvulsant action of different generation carbapenems: imipenem (IMI), meropenem (MERO), and ertapenem (ERTA) in mice through behavioral analysis. We also propose possible molecular mechanisms for this side effect through an integrative experimental and computational approach. For this, male mice received carbapenems at doses of 250 and 500 mg/kg, or saline, subcutaneously, for 7 days. On the last day, the pilocarpine-induced seizure test was performed. On the last day, the pilocarpine-induced seizure test was performed, and latency to the first seizure and latency of death were recorded. Subsequently, oxidative stress markers were measured in brain areas. Additionally, using the three-dimensional structure of the drugs, we performed computational target prediction and molecular docking calculations. IMI and MERO, at both tested doses, reduced seizure latency and death latency compared to pilocarpine group. This effect occurred only with the higher dose of ERTA (500 mg/kg). Furthermore, IMI increased lipid peroxidation in all brain areas, MERO in the hippocampus and prefrontal cortex, and ERTA only in the hippocampus. The three carbapenems increased nitrite/nitrate levels in all brain areas, while only IMI at 500 mg/kg decreased GSH. Computational studies predicted that GABA<sub>A</sub> receptor, Glutathione S-transferase Pi, Glutathione S-transferase Mu 1, and Glutathione S-transferase A2 could be promising targets for the CNS toxicity of carbapenems, related to their proconvulsant effect. Therefore, our data contribute to the current understanding of CNS toxicity associated with carbapenems and propose the participation of oxidative stress and the interaction with GABA and GSH synthesis systems in the molecular mechanism of their proconvulsant effect.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 155-167"},"PeriodicalIF":3.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1016/j.neuro.2025.07.010
Benjamin Hing , Robert Taylor , Samuel Eliasen , Hanna E. Stevens
Pyrethroid insecticides are widely used in agriculture and households, and their exposure can affect neurodevelopment. Few studies have evaluated how preconception parental exposure could also affect this process. To address this knowledge gap, adult C57Bl6/J mice were gavaged daily with α-cypermethrin at a human relevant low (0.3 mg/kg) or high (10 mg/kg) dose in corn oil for four weeks prior to conception. Offspring embryonic day 16 dorsal forebrain was extracted for transcriptomic analysis. In offspring forebrains of exposed compared to unexposed parents, there was increasing number of differentially expressed genes (DEGs) from paternal (least) to maternal to both parent exposure (most). A dose dependent effect was observed in offspring forebrain for paternal and maternal preconceptual exposures. Maternal and both parent exposures led to upregulated genes in offspring brain for biological processes involved in translation with predicted activation of EIF4E, a gene associated with autism. In contrast, paternal exposure upregulated cell cycle related DNA damage signaling processes. After any parent exposure, there was upregulation of biological processes involved in mitochondria function and oxidative stress and a downregulation of neuronal and synaptic processes with predicted inhibition of BDNF signaling. Weighted gene correlation network analysis identified modules associated with different parent exposures that were over-represented with DEGs and had similar functional signatures as DEG-related pathways. Importantly, DEGs in offspring forebrain after any parent exposure were over-represented with genes related to autism spectrum disorder (ASD) and stress vulnerability. The study highlights the potential contribution of preconception parental pyrethroid exposure to aberrant brain functioning.
{"title":"Parental preconceptual α-cypermethrin exposure alters embryonic brain transcriptomics in mice: Implications for autism spectrum disorder and stress vulnerability","authors":"Benjamin Hing , Robert Taylor , Samuel Eliasen , Hanna E. Stevens","doi":"10.1016/j.neuro.2025.07.010","DOIUrl":"10.1016/j.neuro.2025.07.010","url":null,"abstract":"<div><div>Pyrethroid insecticides are widely used in agriculture and households, and their exposure can affect neurodevelopment. Few studies have evaluated how preconception parental exposure could also affect this process. To address this knowledge gap, adult C57Bl6/J mice were gavaged daily with α-cypermethrin at a human relevant low (0.3 mg/kg) or high (10 mg/kg) dose in corn oil for four weeks prior to conception. Offspring embryonic day 16 dorsal forebrain was extracted for transcriptomic analysis. In offspring forebrains of exposed compared to unexposed parents, there was increasing number of differentially expressed genes (DEGs) from paternal (least) to maternal to both parent exposure (most). A dose dependent effect was observed in offspring forebrain for paternal and maternal preconceptual exposures. Maternal and both parent exposures led to upregulated genes in offspring brain for biological processes involved in translation with predicted activation of <em>EIF4E</em>, a gene associated with autism. In contrast, paternal exposure upregulated cell cycle related DNA damage signaling processes. After any parent exposure, there was upregulation of biological processes involved in mitochondria function and oxidative stress and a downregulation of neuronal and synaptic processes with predicted inhibition of <em>BDNF</em> signaling. Weighted gene correlation network analysis identified modules associated with different parent exposures that were over-represented with DEGs and had similar functional signatures as DEG-related pathways. Importantly, DEGs in offspring forebrain after any parent exposure were over-represented with genes related to autism spectrum disorder (ASD) and stress vulnerability. The study highlights the potential contribution of preconception parental pyrethroid exposure to aberrant brain functioning.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 181-196"},"PeriodicalIF":3.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-26DOI: 10.1016/j.neuro.2025.07.009
Daniel José Barbosa , Inês C. Santos , Tatiana Moyisyeyenko , Cristina Mendes , Ana Filipa Sobral
The small nematode Caenorhabditis elegans (C. elegans) has emerged as a valuable tool in neurotoxicology due to its well-characterized nervous system, genetic tractability, and high conservation of molecular pathways with humans. These characteristics allow to study cellular and molecular mechanisms triggered by neurotoxic substances. In C. elegans, behavioral, molecular, neurophysiological, and neuronal morphology assays, together with genetic models targeting dopaminergic, glutamatergic, GABAergic, and cholinergic neurons, as well as models for mitochondrial dysfunction and oxidative stress, are valuable for elucidating mechanisms of neurotoxicity. Additionally, C. elegans is widely used for high-throughput neurotoxicity screenings, with automated systems enhancing scalability and accuracy. Despite its advantages, C. elegans has some limitations for translating data to humans, including the absence of a blood-brain barrier and complex brain regions, as well as differences in metabolism. However, it remains a strong model for neurotoxic screening and mechanistic studies. This review offers a broader, updated perspective by addressing not only classical neurotoxicants (e.g., heavy metals, pesticides) but also increasingly relevant substances like microplastics and industrial chemicals, psychotropic medications, and drugs of abuse. It also provides a detailed overview of diverse C. elegans behavioral, molecular, and neurophysiological neurotoxicity assays, and genetic models for neurotransmitter signaling, mitochondrial dysfunction, and oxidative stress. Importantly, it also discusses the relevance of C. elegans within regulatory frameworks such as adverse outcome pathways (AOPs), a connection largely overlooked in prior reviews. These features address gaps in the current literature and distinguish this work from existing reviews on the topic.
{"title":"C. elegans as a powerful model for neurotoxicity assessment","authors":"Daniel José Barbosa , Inês C. Santos , Tatiana Moyisyeyenko , Cristina Mendes , Ana Filipa Sobral","doi":"10.1016/j.neuro.2025.07.009","DOIUrl":"10.1016/j.neuro.2025.07.009","url":null,"abstract":"<div><div>The small nematode <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) has emerged as a valuable tool in neurotoxicology due to its well-characterized nervous system, genetic tractability, and high conservation of molecular pathways with humans. These characteristics allow to study cellular and molecular mechanisms triggered by neurotoxic substances. In <em>C. elegans,</em> behavioral, molecular, neurophysiological, and neuronal morphology assays, together with genetic models targeting dopaminergic, glutamatergic, GABAergic, and cholinergic neurons, as well as models for mitochondrial dysfunction and oxidative stress, are valuable for elucidating mechanisms of neurotoxicity. Additionally, <em>C. elegans</em> is widely used for high-throughput neurotoxicity screenings, with automated systems enhancing scalability and accuracy. Despite its advantages, <em>C. elegans</em> has some limitations for translating data to humans, including the absence of a blood-brain barrier and complex brain regions, as well as differences in metabolism. However, it remains a strong model for neurotoxic screening and mechanistic studies. This review offers a broader, updated perspective by addressing not only classical neurotoxicants (<em>e.g.,</em> heavy metals, pesticides) but also increasingly relevant substances like microplastics and industrial chemicals, psychotropic medications, and drugs of abuse. It also provides a detailed overview of diverse <em>C. elegans</em> behavioral, molecular, and neurophysiological neurotoxicity assays, and genetic models for neurotransmitter signaling, mitochondrial dysfunction, and oxidative stress. Importantly, it also discusses the relevance of <em>C. elegans</em> within regulatory frameworks such as adverse outcome pathways (AOPs), a connection largely overlooked in prior reviews. These features address gaps in the current literature and distinguish this work from existing reviews on the topic.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 85-110"},"PeriodicalIF":3.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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