Pub Date : 2025-12-03DOI: 10.1016/j.tox.2025.154364
Katharina S. Nitsche , Paul L. Carmichael , Wouter Bakker , Hans Bouwmeester , Iris Müller
Liver microphysiological systems (MPS) have gained increasing attention as human-relevant models for chemical safety assessments, particularly for studies with defined endpoints, such as cholestatic injury. In this study, we built upon a previously established HepaRG-based liver MPS model using the OrganoPlate® 3-lane system. Our aim in this proof-of-concept study was to characterise the synthetic capacity and metabolic function, focusing on the bile acid secretion, under both basal and chemically treated conditions at three independent time points. Undifferentiated HepaRG cells were seeded into the perfusion channels coated with Matrigel and cultured under flow condition without the addition of dimethyl sulfoxide (DMSO). We monitored cell self-organisation, health, and maturation using microscopy, viability assays, albumin and individual bile acid secretion profiling, and gene expression analysis. To assess the metabolic competence and treatment responses regarding the bile acid secretion, the cells were exposed to rifampicin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 48 h. Despite the absence of DMSO supplementation, HepaRG cells self-organised into maturing aggregates and demonstrated inducible CYP1A2 and CYP3A4 activity by day 3. Although the synthetic capacity was generally low, the model secreted all primary (conjugated) bile acids and exhibited clear time-dependent changes in the bile acid composition under treatment. These proof-of-concept findings highlight the potential of flow conditions to enable in situ HepaRG maturation and represent a promising step toward defining a potential context of use as a tool for cholestatic injury.
{"title":"Characterising a HepaRG liver microphysiological system for individual bile acid secretion and chemical induced disruptions","authors":"Katharina S. Nitsche , Paul L. Carmichael , Wouter Bakker , Hans Bouwmeester , Iris Müller","doi":"10.1016/j.tox.2025.154364","DOIUrl":"10.1016/j.tox.2025.154364","url":null,"abstract":"<div><div>Liver microphysiological systems (MPS) have gained increasing attention as human-relevant models for chemical safety assessments, particularly for studies with defined endpoints, such as cholestatic injury. In this study, we built upon a previously established HepaRG-based liver MPS model using the OrganoPlate® 3-lane system. Our aim in this proof-of-concept study was to characterise the synthetic capacity and metabolic function, focusing on the bile acid secretion, under both basal and chemically treated conditions at three independent time points. Undifferentiated HepaRG cells were seeded into the perfusion channels coated with Matrigel and cultured under flow condition without the addition of dimethyl sulfoxide (DMSO). We monitored cell self-organisation, health, and maturation using microscopy, viability assays, albumin and individual bile acid secretion profiling, and gene expression analysis. To assess the metabolic competence and treatment responses regarding the bile acid secretion, the cells were exposed to rifampicin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 48 h. Despite the absence of DMSO supplementation, HepaRG cells self-organised into maturing aggregates and demonstrated inducible CYP1A2 and CYP3A4 activity by day 3. Although the synthetic capacity was generally low, the model secreted all primary (conjugated) bile acids and exhibited clear time-dependent changes in the bile acid composition under treatment. These proof-of-concept findings highlight the potential of flow conditions to enable <em>in situ</em> HepaRG maturation and represent a promising step toward defining a potential context of use as a tool for cholestatic injury.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154364"},"PeriodicalIF":4.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688192","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 : 2025-12-02DOI: 10.1016/j.tox.2025.154363
Kang Wang , Huixian Chen , Pinyi Chen , Lei Wu , Yan Jiang , Tao Chen
Perfluorooctane sulfonamide (PFOSA), an immediate precursor of perfluorooctane sulfonate (PFOS), is widely detected in the environment. Recent studies have indicated that the aryl hydrocarbon receptor (AhR) mediates PFOSA-induced cardiac defects; however, the precise mechanisms remain unclear. Given that genes involved in endoplasmic reticulum stress (ERS) are enriched in zebrafish larvae following PFOSA exposure, we hypothesized that AhR mediates PFOSA-induced cardiac defects through ERS. In this study, we observed a dose-dependent increase in the ERS markers Grp78 and Chop in the hearts of zebrafish larvae exposed to PFOSA. Furthermore, PFOSA-induced ERS activated the PERK branch of the unfolded protein response (UPR), while inhibition of either AhR or reactive oxygen species (ROS) significantly attenuated PFOSA-triggered ERS and PERK branch activation. The results further demonstrated that PFOSA-induced ERS and PERK activation led to 1) mitochondrial calcium overload through the Ip3r/Grp75/Vdac1 complex, and 2) downregulation of PGC-1α resulting from CHOP overexpression. Collectively, these events resulted in apoptosis in the zebrafish embryonic heart. AhR/ROS-dependent ERS, PERK branch activation, and mitochondrial damage were also observed in rat embryonic cardiomyocytes exposed to PFOSA. In conclusion, our findings indicate that PFOSA induces ERS and activates the PERK branch through the AhR/ROS axis, leading to mitochondrial damage via calcium overload and PGC-1α suppression, ultimately resulting in apoptosis and cardiac defects. Overall, these results highlight the fundamental role of ERS in the cardiac developmental toxicity of PFOSA.
{"title":"AhR/ROS-mediated endoplasmic reticulum stress contributes to PFOSA-induced cardiac defects","authors":"Kang Wang , Huixian Chen , Pinyi Chen , Lei Wu , Yan Jiang , Tao Chen","doi":"10.1016/j.tox.2025.154363","DOIUrl":"10.1016/j.tox.2025.154363","url":null,"abstract":"<div><div>Perfluorooctane sulfonamide (PFOSA), an immediate precursor of perfluorooctane sulfonate (PFOS), is widely detected in the environment. Recent studies have indicated that the aryl hydrocarbon receptor (AhR) mediates PFOSA-induced cardiac defects; however, the precise mechanisms remain unclear. Given that genes involved in endoplasmic reticulum stress (ERS) are enriched in zebrafish larvae following PFOSA exposure, we hypothesized that AhR mediates PFOSA-induced cardiac defects through ERS. In this study, we observed a dose-dependent increase in the ERS markers Grp78 and Chop in the hearts of zebrafish larvae exposed to PFOSA. Furthermore, PFOSA-induced ERS activated the PERK branch of the unfolded protein response (UPR), while inhibition of either AhR or reactive oxygen species (ROS) significantly attenuated PFOSA-triggered ERS and PERK branch activation. The results further demonstrated that PFOSA-induced ERS and PERK activation led to 1) mitochondrial calcium overload through the Ip3r/Grp75/Vdac1 complex, and 2) downregulation of PGC-1α resulting from CHOP overexpression. Collectively, these events resulted in apoptosis in the zebrafish embryonic heart. AhR/ROS-dependent ERS, PERK branch activation, and mitochondrial damage were also observed in rat embryonic cardiomyocytes exposed to PFOSA. In conclusion, our findings indicate that PFOSA induces ERS and activates the PERK branch through the AhR/ROS axis, leading to mitochondrial damage via calcium overload and PGC-1α suppression, ultimately resulting in apoptosis and cardiac defects. Overall, these results highlight the fundamental role of ERS in the cardiac developmental toxicity of PFOSA.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154363"},"PeriodicalIF":4.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669377","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}
Zinc oxide nanoparticles (ZNPs) are extensively used in cosmetics and topical medications and are considered safe for normal skin. However, patients with inflammatory dermatoses, who have an impaired skin barrier, may be at increased risk of percutaneous exposure to ZNPs. Limited research currently exists on the percutaneous toxicity of ZNPs in such conditions. Therefore, this study aimed to evaluate the safety of ZNPs in inflammatory dermatoses. ZNP treatment increased inflammatory human immortalised keratinocyte (HaCaT) cell death and significantly elevated phosphorylated mixed lineage kinase domain-like protein (p-MLKL) protein expression in a concentration-dependent manner, showing that ZNPs trigger necroptosis in HaCaT cells. Further exploration revealed that ZNPs induced mitochondrial swelling and rupture and abnormal opening of the mitochondrial permeability transition pore (mPTP) in inflammatory HaCaT cells as well as decreased the expression of spastic paraplegia 7 (SPG7), a critical protein of the mPTP. Furthermore, phosphatidylserine decarboxylase (PISD) expression in the inner mitochondrial membrane (IMM) was significantly reduced. SPG7 overexpression reversed mPTP opening and necroptosis, whereas PISD overexpression directly upregulated SPG7 expression, inhibited mPTP opening, and reversed necroptosis. Our results indicate that ZNPs contribute to mPTP opening and mitochondrial swelling and rupture via the PISD/SPG7 pathway, an important mechanism leading to necroptosis in inflammatory HaCaT cells. Overall, this study highlights the potential hazards of ZNP exposure in patients with inflammatory dermatoses, reveals the mechanism of injury by which ZNPs induce skin toxicity, and provides data for future dermatotoxicological studies on ZNPs.
{"title":"Mechanism of PISD/SPG7-mediated mPTP opening in necroptosis of inflammatory HaCaT cells induced by nano-zinc oxide.","authors":"Menglei Wang, Qianwen Yang, Wantong Xiao, Yawen Luo, Jiawen Chen, Ziyi Tang, Yu Wei, Haiqing Li, Wanchun You, Yue Zheng, Li Li","doi":"10.1016/j.tox.2025.154258","DOIUrl":"10.1016/j.tox.2025.154258","url":null,"abstract":"<p><p>Zinc oxide nanoparticles (ZNPs) are extensively used in cosmetics and topical medications and are considered safe for normal skin. However, patients with inflammatory dermatoses, who have an impaired skin barrier, may be at increased risk of percutaneous exposure to ZNPs. Limited research currently exists on the percutaneous toxicity of ZNPs in such conditions. Therefore, this study aimed to evaluate the safety of ZNPs in inflammatory dermatoses. ZNP treatment increased inflammatory human immortalised keratinocyte (HaCaT) cell death and significantly elevated phosphorylated mixed lineage kinase domain-like protein (p-MLKL) protein expression in a concentration-dependent manner, showing that ZNPs trigger necroptosis in HaCaT cells. Further exploration revealed that ZNPs induced mitochondrial swelling and rupture and abnormal opening of the mitochondrial permeability transition pore (mPTP) in inflammatory HaCaT cells as well as decreased the expression of spastic paraplegia 7 (SPG7), a critical protein of the mPTP. Furthermore, phosphatidylserine decarboxylase (PISD) expression in the inner mitochondrial membrane (IMM) was significantly reduced. SPG7 overexpression reversed mPTP opening and necroptosis, whereas PISD overexpression directly upregulated SPG7 expression, inhibited mPTP opening, and reversed necroptosis. Our results indicate that ZNPs contribute to mPTP opening and mitochondrial swelling and rupture via the PISD/SPG7 pathway, an important mechanism leading to necroptosis in inflammatory HaCaT cells. Overall, this study highlights the potential hazards of ZNP exposure in patients with inflammatory dermatoses, reveals the mechanism of injury by which ZNPs induce skin toxicity, and provides data for future dermatotoxicological studies on ZNPs.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154258"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804916","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 : 2025-12-01Epub Date: 2025-08-07DOI: 10.1016/j.tox.2025.154259
José R Palacios-Valladares, Christian D Ortiz-Robles, Lea A Cupul-Uicab, Omar B Rivera-Maya, Luisa C Hernández-Kelly, Rosa M García-Hernández, Rocio Gómez, Mariano E Cebrián, Emma S Calderon-Aranda
Evidence from cellular and animal model studies has shown that p,p-dichloro-diphenyl-trichloroethane (p,p'-DDT) and p,p-dichloro-diphenyl-dichloroethylene (p,p'-DDE) negatively affect the macrophage's inflammatory response and resistance to pathogen infections. Still, no evidence is available on the p,p'-DDE effects on human macrophages, even though there is a translational value to human public health. This study aimed to determine p,p'-DDE serum concentrations in human volunteers with non-occupational exposure and to investigate the effect of ex vivo exposure to p,p'-DDE on the polarization of human monocyte-derived macrophages (hMDM) toward the M1 phenotype. p,p'-DDE from thirty healthy male volunteers was quantified by gas chromatography with a micro-electron capture detector. The hMDM were differentiated using GM-CSF. hMDM were exposed to 25-2500 ng/ml p,p'-DDE for 48 h, and after 24 h of exposure, they were activated with LPS+IFN-γ to the M1 phenotype for 24 h. p,p ´ -DDT was detected in 4/30 individuals (mean= 0.54 ± 0.35 ng/ml), and 30/30 had p,p ´ -DDE (mean=0.57 ± 0.34 ng/ml). Ex vivo, p,p ´ -DDE did not affect cell viability but decreased the expression of M1-polarization markers (HLA-DR and CD68). Bivariate and multivariate analyses revealed that in the M1 macrophage phenotype, 25-2500 ng/ml p,p'-DDE, in a concentration-dependent manner, decreased NO•- -production, IL-1β, TNF-α, and IL-12 secretion, while increasing ROS. Our study showed that humans are still exposed to p,p'-DDE. Experimental results suggest that p,p'-DDE negatively interferes with the polarization of hMDMs toward the M1 phenotype at environmentally relevant concentrations, influencing key inflammatory mediators critical to innate immunity against pathogens and inducing oxidative stress. This study is the first to evaluate the effect of the p,p'-DDE on polarization of hMDMs to the M1-phenotype. It may contribute to addressing studies to determine whether the incidence of pathologies associated with inflammatory macrophage dysfunction is higher in human populations exposed to DDT and its metabolites. These data will be valuable for implementing policy and health intervention strategies in individuals still exposed to this pesticide.
{"title":"Ex vivo exposure to p,p'-DDE decreases human macrophage polarization to the M1 phenotype.","authors":"José R Palacios-Valladares, Christian D Ortiz-Robles, Lea A Cupul-Uicab, Omar B Rivera-Maya, Luisa C Hernández-Kelly, Rosa M García-Hernández, Rocio Gómez, Mariano E Cebrián, Emma S Calderon-Aranda","doi":"10.1016/j.tox.2025.154259","DOIUrl":"10.1016/j.tox.2025.154259","url":null,"abstract":"<p><p>Evidence from cellular and animal model studies has shown that p,p-dichloro-diphenyl-trichloroethane (p,p'-DDT) and p,p-dichloro-diphenyl-dichloroethylene (p,p'-DDE) negatively affect the macrophage's inflammatory response and resistance to pathogen infections. Still, no evidence is available on the p,p'-DDE effects on human macrophages, even though there is a translational value to human public health. This study aimed to determine p,p'-DDE serum concentrations in human volunteers with non-occupational exposure and to investigate the effect of ex vivo exposure to p,p'-DDE on the polarization of human monocyte-derived macrophages (hMDM) toward the M1 phenotype. p,p'-DDE from thirty healthy male volunteers was quantified by gas chromatography with a micro-electron capture detector. The hMDM were differentiated using GM-CSF. hMDM were exposed to 25-2500 ng/ml p,p'-DDE for 48 h, and after 24 h of exposure, they were activated with LPS+IFN-γ to the M1 phenotype for 24 h. p,p ´ -DDT was detected in 4/30 individuals (mean= 0.54 ± 0.35 ng/ml), and 30/30 had p,p ´ -DDE (mean=0.57 ± 0.34 ng/ml). Ex vivo, p,p ´ -DDE did not affect cell viability but decreased the expression of M1-polarization markers (HLA-DR and CD68). Bivariate and multivariate analyses revealed that in the M1 macrophage phenotype, 25-2500 ng/ml p,p'-DDE, in a concentration-dependent manner, decreased NO<sup>•-</sup> -production, IL-1β, TNF-α, and IL-12 secretion, while increasing ROS. Our study showed that humans are still exposed to p,p'-DDE. Experimental results suggest that p,p'-DDE negatively interferes with the polarization of hMDMs toward the M1 phenotype at environmentally relevant concentrations, influencing key inflammatory mediators critical to innate immunity against pathogens and inducing oxidative stress. This study is the first to evaluate the effect of the p,p'-DDE on polarization of hMDMs to the M1-phenotype. It may contribute to addressing studies to determine whether the incidence of pathologies associated with inflammatory macrophage dysfunction is higher in human populations exposed to DDT and its metabolites. These data will be valuable for implementing policy and health intervention strategies in individuals still exposed to this pesticide.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154259"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812436","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}
Imidacloprid (IMI), a major neonicotinoid insecticide, raises concerns about neurodevelopmental abnormalities, particularly attention deficit hyperactivity disorder. However, the involvement of cerebellar development in IMI-induced developmental neurotoxicity has not been studied. Here, this study investigated the maternal exposure effects of IMI on the developing cerebellum in rats. Pregnant Sprague-Dawley rats were fed diet containing IMI at 0 (control), 83, 250 or 750 ppm from gestational day 6 through gestation, and dams treated with the diet during lactation until day 21 postpartum. Male offspring were raised without IMI until postnatal day 77. IMI exposure caused progressive changes of impaired motor coordination (≥ 250 ppm IMI groups) and loss of Purkinje cells (≥ 83 ppm) and granule cells (≥ 250 ppm). IMI suppressed granule cell proliferation by inhibiting sonic hedgehog-mediated cell cycle activation by downregulating Pcna, Cdk2, Shh, and Gli and promoted granule cell apoptosis by upregulating Casp3 during IMI exposure. Neuroinflammation and oxidative stress were key contributors to IMI-induced apoptosis in cerebellar neurons by downregulating Sod2 and upregulating Tnf. The obtained results suggest that exposure to even a lowest dose of IMI (83 ppm; 5.5-14.1 mg/kg/day) can lead to cerebellar defects in rat offspring.
{"title":"Progressive motor dysfunction and loss of cerebellar Purkinje and granule cells in rat offspring after maternal exposure to imidacloprid.","authors":"Xinyu Zou, Yuri Ebizuka, Yuri Sakamaki, Momoka Shobudani, Qian Tang, Mengyuan Luo, Mio Kobayashi, Tetsuhito Kigata, Makoto Shibutani","doi":"10.1016/j.tox.2025.154246","DOIUrl":"10.1016/j.tox.2025.154246","url":null,"abstract":"<p><p>Imidacloprid (IMI), a major neonicotinoid insecticide, raises concerns about neurodevelopmental abnormalities, particularly attention deficit hyperactivity disorder. However, the involvement of cerebellar development in IMI-induced developmental neurotoxicity has not been studied. Here, this study investigated the maternal exposure effects of IMI on the developing cerebellum in rats. Pregnant Sprague-Dawley rats were fed diet containing IMI at 0 (control), 83, 250 or 750 ppm from gestational day 6 through gestation, and dams treated with the diet during lactation until day 21 postpartum. Male offspring were raised without IMI until postnatal day 77. IMI exposure caused progressive changes of impaired motor coordination (≥ 250 ppm IMI groups) and loss of Purkinje cells (≥ 83 ppm) and granule cells (≥ 250 ppm). IMI suppressed granule cell proliferation by inhibiting sonic hedgehog-mediated cell cycle activation by downregulating Pcna, Cdk2, Shh, and Gli and promoted granule cell apoptosis by upregulating Casp3 during IMI exposure. Neuroinflammation and oxidative stress were key contributors to IMI-induced apoptosis in cerebellar neurons by downregulating Sod2 and upregulating Tnf. The obtained results suggest that exposure to even a lowest dose of IMI (83 ppm; 5.5-14.1 mg/kg/day) can lead to cerebellar defects in rat offspring.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154246"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765577","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 : 2025-12-01Epub Date: 2025-07-26DOI: 10.1016/j.tox.2025.154243
Simin Zhan, Chun Li, Kaiyi Zeng, Yanhao Ran, Chenyu Liu, Yunshuo Zhang, Zekai Zeng, Chuntian Wang, Ziqing Yang
Phthalates are typical environmental pollutants that, as plasticizers, are released into the environment through waste, accumulate in organisms, and have reproductive toxicity and potential carcinogenic risks. However, the specific regulatory mechanisms by which phthalates induce liver cancer are still unclear. This study investigates the role of CYP2C9 in liver cancer (LIHC) and its interaction with plasticizers such as BBP and DBP. Toxicological analyses reveal that CYP2C9 is significantly downregulated in LIHC, correlating with poorer patient survival rates. Differential expression analysis using TCGA and GTEx databases confirms high CYP2C9 expression in liver cells, negatively associated with immune cell infiltration. Methylation and mutation analyses indicate a significant relationship between CYP2C9 expression and methylation levels. Additionally, molecular dynamics simulations demonstrate strong binding stability between CYP2C9 and BBP. These findings underscore the critical role of CYP2C9 in liver cancer progression and support its potential as a therapeutic target.
{"title":"Phthalate exposure and hepatocellular carcinoma: Unraveling mechanisms through network toxicology.","authors":"Simin Zhan, Chun Li, Kaiyi Zeng, Yanhao Ran, Chenyu Liu, Yunshuo Zhang, Zekai Zeng, Chuntian Wang, Ziqing Yang","doi":"10.1016/j.tox.2025.154243","DOIUrl":"10.1016/j.tox.2025.154243","url":null,"abstract":"<p><p>Phthalates are typical environmental pollutants that, as plasticizers, are released into the environment through waste, accumulate in organisms, and have reproductive toxicity and potential carcinogenic risks. However, the specific regulatory mechanisms by which phthalates induce liver cancer are still unclear. This study investigates the role of CYP2C9 in liver cancer (LIHC) and its interaction with plasticizers such as BBP and DBP. Toxicological analyses reveal that CYP2C9 is significantly downregulated in LIHC, correlating with poorer patient survival rates. Differential expression analysis using TCGA and GTEx databases confirms high CYP2C9 expression in liver cells, negatively associated with immune cell infiltration. Methylation and mutation analyses indicate a significant relationship between CYP2C9 expression and methylation levels. Additionally, molecular dynamics simulations demonstrate strong binding stability between CYP2C9 and BBP. These findings underscore the critical role of CYP2C9 in liver cancer progression and support its potential as a therapeutic target.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154243"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733432","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 : 2025-11-29DOI: 10.1016/j.tox.2025.154362
Junpyo Gong , In Guk Park , Seokyoung Hwang , Jayhyun Cho, Min Ju Lee, Minkyu Kim, Junseo Kang, Seungchan An, Minsoo Noh
Obesogens are chemicals, often encountered as environmental contaminants, that disrupt metabolic regulation and promote obesity. Here, we present a cheminformatics framework that integrates interaction-profile docking simulations with cluster-level enrichment analysis to enhance read-across and prioritize candidate environmental metabolic disruptors. Protein-ligand contact features from docking to obesity-related nuclear receptors were summarized at the pose level and combined into a 327-dimensional interaction-profile descriptor. Dimensionality-reduced descriptors from 6022 Tox21 compounds were clustered, and enrichment analysis against Tox21 assay results identified clusters associated with specific nuclear receptor activities. One cluster was selectively enriched for peroxisome proliferator-activated receptor γ (PPARγ) agonists. Although benzophenone-4 (BP-4, sulisobenzone), a sunscreen UV filter in this cluster, is labeled as inactive in Tox21, experimental validation confirmed selective PPARγ binding and recruitment of SRC-2 and PGC-1α coactivators. In human bone marrow-derived mesenchymal stem cells, BP-4 promoted adipogenic differentiation, lipid accumulation, and adiponectin production, establishing its potential as an environmental obesogen. This study demonstrates the power of combining interaction-profile read-across with functional assays to predict environmental metabolic disruptors and provides a mechanistic template for systematic chemical safety evaluation.
{"title":"Interaction-profile cheminformatic read-across identifies the UV filter benzophenone-4 as a PPARγ agonist and potential obesogen","authors":"Junpyo Gong , In Guk Park , Seokyoung Hwang , Jayhyun Cho, Min Ju Lee, Minkyu Kim, Junseo Kang, Seungchan An, Minsoo Noh","doi":"10.1016/j.tox.2025.154362","DOIUrl":"10.1016/j.tox.2025.154362","url":null,"abstract":"<div><div>Obesogens are chemicals, often encountered as environmental contaminants, that disrupt metabolic regulation and promote obesity. Here, we present a cheminformatics framework that integrates interaction-profile docking simulations with cluster-level enrichment analysis to enhance read-across and prioritize candidate environmental metabolic disruptors. Protein-ligand contact features from docking to obesity-related nuclear receptors were summarized at the pose level and combined into a 327-dimensional interaction-profile descriptor. Dimensionality-reduced descriptors from 6022 Tox21 compounds were clustered, and enrichment analysis against Tox21 assay results identified clusters associated with specific nuclear receptor activities. One cluster was selectively enriched for peroxisome proliferator-activated receptor γ (PPARγ) agonists. Although benzophenone-4 (BP-4, sulisobenzone), a sunscreen UV filter in this cluster, is labeled as inactive in Tox21, experimental validation confirmed selective PPARγ binding and recruitment of SRC-2 and PGC-1α coactivators. In human bone marrow-derived mesenchymal stem cells, BP-4 promoted adipogenic differentiation, lipid accumulation, and adiponectin production, establishing its potential as an environmental obesogen. This study demonstrates the power of combining interaction-profile read-across with functional assays to predict environmental metabolic disruptors and provides a mechanistic template for systematic chemical safety evaluation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154362"},"PeriodicalIF":4.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655654","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 : 2025-11-28DOI: 10.1016/j.tox.2025.154358
Nouf M. Alyami , Rasha Alonaizan , Hussah Alobaid , Saleh Maodaa , Norah S. Alothman , Noura M. Alshiban , Zainab A. Alnakhli , Meshari M. Alyami , Rafa Almeer
This study investigated the effects of lanthanum oxide nanoparticles (La₂O₃ NPs) on cognitive and motor functions in female mice. We used behavioral tests, biochemical analysis, and tissue examination. Our findings indicate that neurotoxicity is dose-dependent, with distinct mechanisms at play. Low doses (60 mg/kg) caused severe oxidative stress, increasing a key damage marker (MDA) by 40–80 times and depleting antioxidants (glutathione) in the blood. These doses also led to the accumulation of pro-oxidant metals (Fe, Mn, Cu, Ti) and a reduction in brain calcium levels, as determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). At moderate doses, mice exhibited hyperactive movement but normal muscle strength, indicating a brain-specific effect. In contrast, high doses (300 mg/kg) triggered a different pattern of damage. This included a harmful calcium-potassium imbalance, disruption of key brain health signals (BDNF pathway), and widespread neuronal death. These changes are associated with significant cognitive deficits in avoidance learning and a complete lack of response to warning stimuli. Histopathological analysis revealed that neurotoxicity primarily affected motor coordination pathways, with degeneration observed in the cerebellum and medulla. We propose that La₂O₃ NPs release La³ ⁺ ions, which disrupt cellular calcium balance and produce harmful reactive oxygen species (ROS). This leads to two toxicity phases: at low doses, metal ions drive ROS generation, while at high doses, nanoparticle aggregation causes a catastrophic failure of ion regulation in neurons. These findings have important implications for understanding nanomaterial-induced neurodegeneration and creating protective strategies against La₂O₃ exposure.
{"title":"Dose-inverted neurotoxicity: La₂O₃ nanoparticles cause redox dysregulation at low concentrations but excitotoxic catastrophe at high doses","authors":"Nouf M. Alyami , Rasha Alonaizan , Hussah Alobaid , Saleh Maodaa , Norah S. Alothman , Noura M. Alshiban , Zainab A. Alnakhli , Meshari M. Alyami , Rafa Almeer","doi":"10.1016/j.tox.2025.154358","DOIUrl":"10.1016/j.tox.2025.154358","url":null,"abstract":"<div><div>This study investigated the effects of lanthanum oxide nanoparticles (La₂O₃ NPs) on cognitive and motor functions in female mice. We used behavioral tests, biochemical analysis, and tissue examination. Our findings indicate that neurotoxicity is dose-dependent, with distinct mechanisms at play. Low doses (60 mg/kg) caused severe oxidative stress, increasing a key damage marker (MDA) by 40–80 times and depleting antioxidants (glutathione) in the blood. These doses also led to the accumulation of pro-oxidant metals (Fe, Mn, Cu, Ti) and a reduction in brain calcium levels, as determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). At moderate doses, mice exhibited hyperactive movement but normal muscle strength, indicating a brain-specific effect. In contrast, high doses (300 mg/kg) triggered a different pattern of damage. This included a harmful calcium-potassium imbalance, disruption of key brain health signals (BDNF pathway), and widespread neuronal death. These changes are associated with significant cognitive deficits in avoidance learning and a complete lack of response to warning stimuli. Histopathological analysis revealed that neurotoxicity primarily affected motor coordination pathways, with degeneration observed in the cerebellum and medulla. We propose that La₂O₃ NPs release La³ ⁺ ions, which disrupt cellular calcium balance and produce harmful reactive oxygen species (ROS). This leads to two toxicity phases: at low doses, metal ions drive ROS generation, while at high doses, nanoparticle aggregation causes a catastrophic failure of ion regulation in neurons. These findings have important implications for understanding nanomaterial-induced neurodegeneration and creating protective strategies against La₂O₃ exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154358"},"PeriodicalIF":4.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649339","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 : 2025-11-28DOI: 10.1016/j.tox.2025.154361
Tingting Miao , Shubiao Zou , Binwu Xu , Zisu Deng , Mengjiao Di , Houqun Ying
Objective
2,4,6-Triiodophenol (TIP) is a highly toxic iodinated disinfection byproduct that is generated during water disinfection, and TIP is widely detected in drinking water. This study aimed to investigate the nephrotoxicity of TIP and its potential mechanisms.
Materials and Methods
An in vitro exposure model was constructed by using mouse glomerular mesangial cells (MES-13 cell line). The cytotoxicity of TIP was evaluated via the CCK-8 assay and microscopic morphological observation. The expression of inflammatory cytokines was detected by qRT-PCR and ELISA. Oxidative stress markers, including malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), were detected using ELISA, and cell apoptosis was analyzed by flow cytometry.
Results
TIP exhibited obvious dose-dependent cytotoxicity in MES-13 cells. Low concentrations of exposure showed no significant cytotoxicity, whereas high concentrations of exposure markedly inhibited cell viability. Moreover, TIP can promote the gene and protein expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). However, while the gene expression of the anti-inflammatory cytokine IL-10 was increased, its protein expression level showed no significant change, suggesting a post-transcriptional regulation or a protein translation delay effect. Further studies revealed that TIP not only overactivates oxidative stress but also induces aberrant apoptotic regulation. This finding indicates that MES-13 cells may respond to TIP-induced damage by regulating oxidative stress and cell apoptosis.
Conclusions
This study firstly demonstrated that TIP can induce glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis. Our findings not only provide experimental evidence to elucidate the nephrotoxic mechanisms of TIP but also contribute to establishing relevant strategies for health risk prevention and control.
{"title":"2,4,6-triiodophenol induces glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis","authors":"Tingting Miao , Shubiao Zou , Binwu Xu , Zisu Deng , Mengjiao Di , Houqun Ying","doi":"10.1016/j.tox.2025.154361","DOIUrl":"10.1016/j.tox.2025.154361","url":null,"abstract":"<div><h3>Objective</h3><div>2,4,6-Triiodophenol (TIP) is a highly toxic iodinated disinfection byproduct that is generated during water disinfection, and TIP is widely detected in drinking water. This study aimed to investigate the nephrotoxicity of TIP and its potential mechanisms.</div></div><div><h3>Materials and Methods</h3><div>An <em>in vitro</em> exposure model was constructed by using mouse glomerular mesangial cells (MES-13 cell line). The cytotoxicity of TIP was evaluated via the CCK-8 assay and microscopic morphological observation. The expression of inflammatory cytokines was detected by qRT-PCR and ELISA. Oxidative stress markers, including malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), were detected using ELISA, and cell apoptosis was analyzed by flow cytometry.</div></div><div><h3>Results</h3><div>TIP exhibited obvious dose-dependent cytotoxicity in MES-13 cells. Low concentrations of exposure showed no significant cytotoxicity, whereas high concentrations of exposure markedly inhibited cell viability. Moreover, TIP can promote the gene and protein expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). However, while the gene expression of the anti-inflammatory cytokine IL-10 was increased, its protein expression level showed no significant change, suggesting a post-transcriptional regulation or a protein translation delay effect. Further studies revealed that TIP not only overactivates oxidative stress but also induces aberrant apoptotic regulation. This finding indicates that MES-13 cells may respond to TIP-induced damage by regulating oxidative stress and cell apoptosis.</div></div><div><h3>Conclusions</h3><div>This study firstly demonstrated that TIP can induce glomerular mesangial cell damage through inflammatory imbalance, oxidative stress overactivation, and aberrant apoptosis. Our findings not only provide experimental evidence to elucidate the nephrotoxic mechanisms of TIP but also contribute to establishing relevant strategies for health risk prevention and control.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154361"},"PeriodicalIF":4.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649379","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 : 2025-11-27DOI: 10.1016/j.tox.2025.154360
Kai Kang, Ying Huang
In recent years, the increasing prevalence of environmental pollutants has raised concerns about their potential role in intestinal-related diseases. Previous studies have shown that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect intestinal health, but the specific mechanisms remain unclear. Herein, we aimed to elucidate the potential molecular mechanisms underlying ATBC-induced intestinal toxicity. We systematically screened professional databases, including ChEMBL, STITCH, and GSE16879, and identified 29 potential targets associated with ATBC-related intestinal toxicity. Through rigorous filtering using the STRING platform and Cytoscape software, 15 hub genes were ultimately selected, and four core targets—ATM, FYN, IDH2, and TOP1—were identified using two machine-learning methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these core targets were primarily enriched in NF-κb pathways. Molecular docking simulations using the AutoDock software further confirmed strong binding interactions between ATBC and the core targets, and IDH2 was selected for the following analyses. In vitro experiments demonstrated that ATBC treatment decreases IDH2 expression in NCM460 and HCT116 cells and activates the NF-κB pathway. Given the pivotal role of the IDH2 gene in cellular energy metabolism, we systematically evaluated reactive oxygen species (ROS) levels and performed JC-1 staining assays. Our findings demonstrate that ATBC significantly promotes intracellular ROS accumulation, induces mitochondrial membrane-potential depolarization, and concurrently triggers cellular lipid peroxidation damage. Overall, our findings confirm that ATBC induces intestinal damage by regulating the IDH2/NF-κB pathway and lipid peroxidation, and lay the foundation for the development of preventive and therapeutic strategies against intestinal damage caused by exposure to ATBC-containing plastics.
{"title":"Acetyl tributyl citrate induces intestinal toxicity by regulating the IDH2/NF-κB pathway and lipid peroxidation","authors":"Kai Kang, Ying Huang","doi":"10.1016/j.tox.2025.154360","DOIUrl":"10.1016/j.tox.2025.154360","url":null,"abstract":"<div><div>In recent years, the increasing prevalence of environmental pollutants has raised concerns about their potential role in intestinal-related diseases. Previous studies have shown that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect intestinal health, but the specific mechanisms remain unclear. Herein, we aimed to elucidate the potential molecular mechanisms underlying ATBC-induced intestinal toxicity. We systematically screened professional databases, including ChEMBL, STITCH, and GSE16879, and identified 29 potential targets associated with ATBC-related intestinal toxicity. Through rigorous filtering using the STRING platform and Cytoscape software, 15 hub genes were ultimately selected, and four core targets—ATM, FYN, IDH2, and TOP1—were identified using two machine-learning methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these core targets were primarily enriched in NF-κb pathways. Molecular docking simulations using the AutoDock software further confirmed strong binding interactions between ATBC and the core targets, and IDH2 was selected for the following analyses. <em>In vitro</em> experiments demonstrated that ATBC treatment decreases IDH2 expression in NCM460 and HCT116 cells and activates the NF-κB pathway. Given the pivotal role of the IDH2 gene in cellular energy metabolism, we systematically evaluated reactive oxygen species (ROS) levels and performed JC-1 staining assays. Our findings demonstrate that ATBC significantly promotes intracellular ROS accumulation, induces mitochondrial membrane-potential depolarization, and concurrently triggers cellular lipid peroxidation damage. Overall, our findings confirm that ATBC induces intestinal damage by regulating the IDH2/NF-κB pathway and lipid peroxidation, and lay the foundation for the development of preventive and therapeutic strategies against intestinal damage caused by exposure to ATBC-containing plastics.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154360"},"PeriodicalIF":4.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145640217","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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