Breast cancer is a major public health problem, and distant metastases are the main cause of morbidity and mortality. Chlorpyrifos is an organophosphate that promotes Epithelial-Mesenchymal Transition-like phenotype in breast cancer cell lines and modulates the Breast Cancer Stem Cells activating two key processes related to the metastatic cascade. Here, we investigated whether Chlorpyrifos may induce distant metastases in an in vivo triple negative tumor model. Also, we studied the expression of Breast Cancer Stem Cell and Epithelial-Mesenchymal Transition activation-markers in Triple Negative Breast Cancer mice tumors and human cells. We demonstrate that Chlorpyrifos modulates stem cell plasticity as a function of growth conditions in monolayer or three-dimensional culture. Furthermore, Chlorpyrifos decreased the doubling period, increased tumor volume, stimulated the infiltration of adjacent muscle fibers and induced lung and lymphatic node metastases in mice. Finally, Chlorpyrifos modulated the expression of Epithelial-Mesenchymal Transition and Breast Cancer Stem Cell markers in mice exposed to the pesticide. All our findings confirm that Chlorpyrifos promotes breast cancer progression, enhances stemness and Epithelial-Mesenchymal Transition marker expression and generates lung metastases in an in vivo model induced in mice.
{"title":"Chlorpyrifos induces lung metastases and modulation of cancer stem cell markers in triple negative breast cancer model","authors":"Marianela Lasagna , Mariana Mardirosian , Daniel Zappia , Lucia Enriquez , Noelia Miret , Lara Dahir , Elsa Zotta , Andrea Randi , Mariel Núñez , Claudia Cocca","doi":"10.1016/j.tox.2025.154059","DOIUrl":"10.1016/j.tox.2025.154059","url":null,"abstract":"<div><div>Breast cancer is a major public health problem, and distant metastases are the main cause of morbidity and mortality. Chlorpyrifos is an organophosphate that promotes Epithelial-Mesenchymal Transition-like phenotype in breast cancer cell lines and modulates the Breast Cancer Stem Cells activating two key processes related to the metastatic cascade. Here, we investigated whether Chlorpyrifos may induce distant metastases in an <em>in vivo</em> triple negative tumor model. Also, we studied the expression of Breast Cancer Stem Cell and Epithelial-Mesenchymal Transition activation-markers in Triple Negative Breast Cancer mice tumors and human cells. We demonstrate that Chlorpyrifos modulates stem cell plasticity as a function of growth conditions in monolayer or three-dimensional culture. Furthermore, Chlorpyrifos decreased the doubling period, increased tumor volume, stimulated the infiltration of adjacent muscle fibers and induced lung and lymphatic node metastases in mice. Finally, Chlorpyrifos modulated the expression of Epithelial-Mesenchymal Transition and Breast Cancer Stem Cell markers in mice exposed to the pesticide. All our findings confirm that Chlorpyrifos promotes breast cancer progression, enhances stemness and Epithelial-Mesenchymal Transition marker expression and generates lung metastases in an <em>in vivo</em> model induced in mice.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154059"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011299","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154057
Yaqi Xing , Wusheng Zhong , Xuejun Wu , Zhengzhong Ni , Wenya Lv , Ying Fan , Ling Chen , Haorui Lin , Yangmin Xie , Jianwei Lin , Yongdong Niu
Aflatoxin B1 (AFB1) has been reported to synergize with hepatitis B virus (HBV) to induce development of hepatocellular carcinoma (HCC). Precise daily exposure to AFB1 and its contribution to liver injury have not been quantified and have even been disregarded due to lack of convenient detection, and the strong species specificity of HBV infection has restricted research on their synergistic harm. Hence, our objective was to investigate the molecular mechanisms by which AFB1 exacerbates HBV-related injury. We constructed tree shrew models with 400 μg HBV plasmid and 4 mg/kg AFB1 co-exposure for 4–6 days. Injury and molecule expression resulting from HBV and AFB1 toxicity were observed in vivo and in vitro. Expression datasets of tree shrew livers, human HCC, and pregnane X receptor (PXR) activation were employed to screen vital pathways and target genes. The oncogenic hepatitis B virus x (HBx) protein, HBV-related histopathological damage, metabolic dysregulation, and several cancer-related signaling pathways were enriched in injured tree shrew livers, and PXR signaling was inhibited after co-exposure to HBV and AFB1. Furthermore, in human HCC and HBV-integrated Hep3B and HepG2.215 cells, FTCD Antisense RNA 1 (FTCD-AS1), PXR and mannose-binding lectin-associated serine protease 1 (MASP1) exhibited strong correlation. Overexpression of FTCD-AS1 and PXR alleviated cell damage in exposure to 5 μM AFB1 for 48 h. In summary, inactivation of the FTCD-AS1-PXR-MASP1 axis was pinpointed as the key event in AFB1-enhanced HBV infection, metabolic dysregulation and carcinogenic injury.
{"title":"AFB1 consolidates HBV harm to induce liver injury and carcinogenic risk by inactivating FTCD-AS1-PXR-MASP1 axis","authors":"Yaqi Xing , Wusheng Zhong , Xuejun Wu , Zhengzhong Ni , Wenya Lv , Ying Fan , Ling Chen , Haorui Lin , Yangmin Xie , Jianwei Lin , Yongdong Niu","doi":"10.1016/j.tox.2025.154057","DOIUrl":"10.1016/j.tox.2025.154057","url":null,"abstract":"<div><div>Aflatoxin B1 (AFB1) has been reported to synergize with hepatitis B virus (HBV) to induce development of hepatocellular carcinoma (HCC). Precise daily exposure to AFB1 and its contribution to liver injury have not been quantified and have even been disregarded due to lack of convenient detection, and the strong species specificity of HBV infection has restricted research on their synergistic harm. Hence, our objective was to investigate the molecular mechanisms by which AFB1 exacerbates HBV-related injury. We constructed tree shrew models with 400 μg HBV plasmid and 4 mg/kg AFB1 co-exposure for 4–6 days. Injury and molecule expression resulting from HBV and AFB1 toxicity were observed <em>in vivo</em> and <em>in vitro</em>. Expression datasets of tree shrew livers, human HCC, and pregnane X receptor (PXR) activation were employed to screen vital pathways and target genes. The oncogenic hepatitis B virus x (HBx) protein, HBV-related histopathological damage, metabolic dysregulation, and several cancer-related signaling pathways were enriched in injured tree shrew livers, and PXR signaling was inhibited after co-exposure to HBV and AFB1. Furthermore, in human HCC and HBV-integrated Hep3B and HepG2.215 cells, FTCD Antisense RNA 1 (FTCD-AS1), PXR and mannose-binding lectin-associated serine protease 1 (MASP1) exhibited strong correlation. Overexpression of FTCD-AS1 and PXR alleviated cell damage in exposure to 5 μM AFB1 for 48 h. In summary, inactivation of the FTCD-AS1-PXR-MASP1 axis was pinpointed as the key event in AFB1-enhanced HBV infection, metabolic dysregulation and carcinogenic injury.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154057"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012202","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154065
Gokul Sudhakaran , R. Karthikeyan , S. Madesh , V.N. Dhaareshwar , Raman Pachaiappan , Rajakrishnan Rajagopal , Ilavenil Soundharrajan , S. Karthick Raja Namasivayam , Jesu Arockiaraj
Aniline Blue is a synthetic dye extensively used in various industries, including textiles, plastics, and biological research due to its effective staining properties. However, its environmental and health impacts, particularly its neurotoxic effects, are poorly understood. While the dye has been associated with carcinogenicity and organ toxicity, the neurobehavioral consequences of Aniline Blue exposure remain underexplored. This study aims to address this research gap by evaluating the neurotoxic effects of Aniline Blue using adult zebrafish as a model organism. We conducted a series of experiments to assess the dose-dependent toxicity of Aniline Blue, examining survival rates, cognitive function, anxiety-related behaviors, locomotor activity, oxidative stress markers, histopathological changes, and gene expression profiles. Zebrafish were exposed to varying concentrations of Aniline Blue over a specified period, followed by behavioral assays, biochemical analyses, and gene expression studies. The results revealed an apparent dose-dependent decline in survival rates, with higher concentrations of Aniline Blue significantly impairing cognitive function and increasing anxiety-like behaviors. Biochemical assays showed a reduction in antioxidant enzyme activities (SOD and CAT) and an increase in LDH activity, indicating oxidative stress. Histopathological analysis confirmed severe neuronal damage, including neuroinflammation and cell death. Gene expression analysis further highlighted the modulation of critical genes associated with neuroinflammation, neurotrophic support, and synaptic function, with potential implications for neurodegenerative diseases such as Alzheimer’s. In conclusion, the study provides critical insights into the neurotoxic effects of Aniline Blue, emphasizing the need for caution in its use across industries.
{"title":"Neurotoxic effects and cognitive decline induced by Aniline Blue dye in an in-vivo zebrafish model","authors":"Gokul Sudhakaran , R. Karthikeyan , S. Madesh , V.N. Dhaareshwar , Raman Pachaiappan , Rajakrishnan Rajagopal , Ilavenil Soundharrajan , S. Karthick Raja Namasivayam , Jesu Arockiaraj","doi":"10.1016/j.tox.2025.154065","DOIUrl":"10.1016/j.tox.2025.154065","url":null,"abstract":"<div><div>Aniline Blue is a synthetic dye extensively used in various industries, including textiles, plastics, and biological research due to its effective staining properties. However, its environmental and health impacts, particularly its neurotoxic effects, are poorly understood. While the dye has been associated with carcinogenicity and organ toxicity, the neurobehavioral consequences of Aniline Blue exposure remain underexplored. This study aims to address this research gap by evaluating the neurotoxic effects of Aniline Blue using adult zebrafish as a model organism. We conducted a series of experiments to assess the dose-dependent toxicity of Aniline Blue, examining survival rates, cognitive function, anxiety-related behaviors, locomotor activity, oxidative stress markers, histopathological changes, and gene expression profiles. Zebrafish were exposed to varying concentrations of Aniline Blue over a specified period, followed by behavioral assays, biochemical analyses, and gene expression studies. The results revealed an apparent dose-dependent decline in survival rates, with higher concentrations of Aniline Blue significantly impairing cognitive function and increasing anxiety-like behaviors. Biochemical assays showed a reduction in antioxidant enzyme activities (SOD and CAT) and an increase in LDH activity, indicating oxidative stress. Histopathological analysis confirmed severe neuronal damage, including neuroinflammation and cell death. Gene expression analysis further highlighted the modulation of critical genes associated with neuroinflammation, neurotrophic support, and synaptic function, with potential implications for neurodegenerative diseases such as Alzheimer’s. In conclusion, the study provides critical insights into the neurotoxic effects of Aniline Blue, emphasizing the need for caution in its use across industries.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154065"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068203","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154069
Xue-Ke Zhang , Xuan Li , Xing-Xing Han , Dong-Ying Sun , Yu-Qin Wang , Zi-Zhuo Cao , Lu Liu , Zi-Han Meng , Guo-Jing Li , Yu-Jie Dong , Dan-Yang Li , Xiao-Qing Peng , Hui-Juan Zou , Dong Zhang , Xiao-Feng Xu
Cadmium (Cd) is a toxic heavy metal with a high propensity to accumulate within the body, and Cd accumulation has been shown to cause organ damage. However, it is unclear whether Cd accumulation is a cause of impaired decidualization, which induces to spontaneous abortion (SA). In this study, we found that the decidual Cd concentration was increased in patients with SA and positively correlated with the occurrence of SA. The levels of two decidualization markers (prolactin, PRL and insulin-like growth factor binding protein 1, IGFBP1) were reduced in the decidua of all-cause SA patients. Using 8-week ICR female mice, we further established a uterus-specific Cd accumulation mouse model and verified that Cd-accumulating mice had increased numbers of absorbed fetuses and defective decidualization. Finally, using in vitro-cultured human ENdometrial stromal cells (hEnSCs), we found that Cd accumulation significantly inhibited decidualization; and moreover, Cd treatment downregulated the regulatory genes upstream of PRL and IGFBP1 such as PGR, ESR1, ESR2 and FOXO1. This study suggests that Cd accumulation could produce impaired decidualization by downregulating the upstream regulators of PRL and IGFBP1, thereby increasing the risk of SA. Our study offered new possibilities for the prevention and treatment of spontaneous abortion.
{"title":"Cadmium induces spontaneous abortion by impairing endometrial stromal cell decidualization","authors":"Xue-Ke Zhang , Xuan Li , Xing-Xing Han , Dong-Ying Sun , Yu-Qin Wang , Zi-Zhuo Cao , Lu Liu , Zi-Han Meng , Guo-Jing Li , Yu-Jie Dong , Dan-Yang Li , Xiao-Qing Peng , Hui-Juan Zou , Dong Zhang , Xiao-Feng Xu","doi":"10.1016/j.tox.2025.154069","DOIUrl":"10.1016/j.tox.2025.154069","url":null,"abstract":"<div><div>Cadmium (Cd) is a toxic heavy metal with a high propensity to accumulate within the body, and Cd accumulation has been shown to cause organ damage. However, it is unclear whether Cd accumulation is a cause of impaired decidualization, which induces to spontaneous abortion (SA). In this study, we found that the decidual Cd concentration was increased in patients with SA and positively correlated with the occurrence of SA. The levels of two decidualization markers (prolactin, PRL and insulin-like growth factor binding protein 1, IGFBP1) were reduced in the decidua of all-cause SA patients. Using 8-week ICR female mice, we further established a uterus-specific Cd accumulation mouse model and verified that Cd-accumulating mice had increased numbers of absorbed fetuses and defective decidualization. Finally, using in <em>vitro</em>-cultured human ENdometrial stromal cells (hEnSCs), we found that Cd accumulation significantly inhibited decidualization; and moreover, Cd treatment downregulated the regulatory genes upstream of PRL and IGFBP1 such as PGR, ESR1, ESR2 and FOXO1. This study suggests that Cd accumulation could produce impaired decidualization by downregulating the upstream regulators of PRL and IGFBP1, thereby increasing the risk of SA. Our study offered new possibilities for the prevention and treatment of spontaneous abortion.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154069"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075586","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154054
Xu Hong , Sheng Wang , Qing Zhang , Lanlan Li , Hang Liu , Hongxu Yang , Danyang Wu , Xingcun Liu , Tong Shen
Bisphenol A (BPA) is a typical environmental endocrine disruptor which have been broadly confirmed to be associated with malignant tumors, including colorectal cancer (CRC). Lipid metabolism reprogramming performed important biological effects in cancer progression. While the role of lipid metabolism in CRC progression upon BPA exposure remain elusive. Here, we found that BPA exposure enhanced de novo ceramide synthesis in vitro, along with upregulated ceramide synthase in high-BPA tumor tissue of CRC patients. Simultaneously, we demonstrated that BPA exposure exacerbated tumor biological behavior and epithelial mesenchymal transition (EMT), concurrent with elevated EMT expression of CRC tissue in high BPA group. Subsequently, the inhibition of ceramide synthase and pharmacological stimulation experiments revealed that ceramide accumulation activated EMT and exacerbated CRC progression, including Cer (d18:1/16:0) and Cer (d18:1/24:1). Collectively our findings elucidated the pathogenesis of ceramide accumulation escalating tumor progression under environmental BPA exposure, providing a strong basis for further investigation of dysregulated ceramide metabolism to boost tumor development and avoid metastatic relapse.
{"title":"Bisphenol A exacerbates colorectal cancer progression through enhancing ceramide synthesis","authors":"Xu Hong , Sheng Wang , Qing Zhang , Lanlan Li , Hang Liu , Hongxu Yang , Danyang Wu , Xingcun Liu , Tong Shen","doi":"10.1016/j.tox.2025.154054","DOIUrl":"10.1016/j.tox.2025.154054","url":null,"abstract":"<div><div>Bisphenol A (BPA) is a typical environmental endocrine disruptor which have been broadly confirmed to be associated with malignant tumors, including colorectal cancer (CRC). Lipid metabolism reprogramming performed important biological effects in cancer progression. While the role of lipid metabolism in CRC progression upon BPA exposure remain elusive. Here, we found that BPA exposure enhanced <em>de novo</em> ceramide synthesis <em>in vitro</em>, along with upregulated ceramide synthase in high-BPA tumor tissue of CRC patients. Simultaneously, we demonstrated that BPA exposure exacerbated tumor biological behavior and epithelial mesenchymal transition (EMT), concurrent with elevated EMT expression of CRC tissue in high BPA group. Subsequently, the inhibition of ceramide synthase and pharmacological stimulation experiments revealed that ceramide accumulation activated EMT and exacerbated CRC progression, including Cer (d18:1/16:0) and Cer (d18:1/24:1). Collectively our findings elucidated the pathogenesis of ceramide accumulation escalating tumor progression under environmental BPA exposure, providing a strong basis for further investigation of dysregulated ceramide metabolism to boost tumor development and avoid metastatic relapse.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154054"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984818","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 : 2025-02-01DOI: 10.1016/j.tox.2024.154032
Serena Mirata , Vanessa Almonti , Mario Passalacqua , Stefania Vernazza , Anna Maria Bassi , Dario Di Giuseppe , Alessandro F. Gualtieri , Sonia Scarfì
Asbestos minerals have been widely exploited due to their physical-chemical properties, and chrysotile asbestos has accounted for about 95% of all asbestos commercially employed worldwide. The exposure to chrysotile, classified like other five amphibole asbestos species as carcinogenic to humans, represents a serious occupational and environmental hazard. Nevertheless, this mineral is still largely employed in about 65% of the countries worldwide, which still allow its “safe use”. The complex mechanisms through which the mineral fibres induce toxicity are not yet completely understood. In this regard, the morphometric parameters of asbestos fibres (e.g., length, width, aspect ratio) are known for their fundamental role in determining the degree of pathogenicity. In this context, the potential toxicity of short chrysotile fibres remains widely debated due to the contradictory results from countless studies. Thus, the present study investigated the different toxicity mechanisms of two representative batches of short (length ≤5 µm) and long (length >5 µm) chrysotile fibres obtained by cryogenic milling. The fibre doses were based upon equal mass and size, since due to chrysotile ability to form bundles, it was not possible to calculate the number of fibers applied per cell. The cytotoxic, genotoxic, and pro-inflammatory potential of the two size-separated chrysotile fractions was investigated on human THP-1-derived macrophages and HECV endothelial cells, both separately and in a co-culture setup, mimicking the alveolar pro-inflammatory microenvironment, in time course experiments up to 1 week. Both chrysotile fractions displayed cytotoxic, genotoxic, and pro-inflammatory effects, with results comparable to the well-known damaging effects of crocidolite asbestos, or higher, as in the case of the longer chrysotile fraction. Furthermore, in presence of HECV, fibre-treated macrophages showed prolonged inflammation, indicating an interesting crosstalk between these cells able to sustain a low-grade chronic inflammation in the lung. In conclusion, these results help to shed light on some important open questions on the mechanisms of toxicity of chrysotile asbestos fibres.
{"title":"Toxicity of size separated chrysotile fibres: The relevance of the macrophage-endothelial axis crosstalk","authors":"Serena Mirata , Vanessa Almonti , Mario Passalacqua , Stefania Vernazza , Anna Maria Bassi , Dario Di Giuseppe , Alessandro F. Gualtieri , Sonia Scarfì","doi":"10.1016/j.tox.2024.154032","DOIUrl":"10.1016/j.tox.2024.154032","url":null,"abstract":"<div><div>Asbestos minerals have been widely exploited due to their physical-chemical properties, and chrysotile asbestos has accounted for about 95% of all asbestos commercially employed worldwide. The exposure to chrysotile, classified like other five amphibole asbestos species as carcinogenic to humans, represents a serious occupational and environmental hazard. Nevertheless, this mineral is still largely employed in about 65% of the countries worldwide, which still allow its “safe use”. The complex mechanisms through which the mineral fibres induce toxicity are not yet completely understood. In this regard, the morphometric parameters of asbestos fibres (<em>e.g.</em>, length, width, aspect ratio) are known for their fundamental role in determining the degree of pathogenicity. In this context, the potential toxicity of short chrysotile fibres remains widely debated due to the contradictory results from countless studies. Thus, the present study investigated the different toxicity mechanisms of two representative batches of short (length ≤5 µm) and long (length >5 µm) chrysotile fibres obtained by cryogenic milling. The fibre doses were based upon equal mass and size, since due to chrysotile ability to form bundles, it was not possible to calculate the number of fibers applied per cell. The cytotoxic, genotoxic, and pro-inflammatory potential of the two size-separated chrysotile fractions was investigated on human THP-1-derived macrophages and HECV endothelial cells, both separately and in a co-culture setup, mimicking the alveolar pro-inflammatory microenvironment, in time course experiments up to 1 week. Both chrysotile fractions displayed cytotoxic, genotoxic, and pro-inflammatory effects, with results comparable to the well-known damaging effects of crocidolite asbestos, or higher, as in the case of the longer chrysotile fraction. Furthermore, in presence of HECV, fibre-treated macrophages showed prolonged inflammation, indicating an interesting crosstalk between these cells able to sustain a low-grade chronic inflammation in the lung. In conclusion, these results help to shed light on some important open questions on the mechanisms of toxicity of chrysotile asbestos fibres.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154032"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824501","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 : 2025-02-01DOI: 10.1016/j.tox.2024.154042
Manyu Zhao , Qing Chen , Xuxi Chen , Shuyu Gong , Mengzhu Wang , Shanshan Zhao , Sihan Wang , Wen Du , Yunyi Xu , Lijun Peng , Yuqin Yao
Apoptosis of alveolar macrophages (AMs) induced by silica is one of the crucial driving factors of silicosis inflammation and fibrosis. However, the mechanism of silica-induced AMs apoptosis remains unclear. In this study, transcriptome sequencing identified 11 differentially expressed (DE)-mRNAs enriched in the regulation of apoptotic signaling pathways in AMs treated with 250 μg/mL silica for 24 h, of which tripartite motif-containing 32 (Trim32) was the most significant and down-regulated. The decreased Trim32 promoted AMs apoptosis, while Trim32 overexpression inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h. MiR-6236-p5 was then identified by MiRNA sequencing as the most significant DE-miRNA potentially regulating Trim32 expression, and the interaction between miR-6236-p5 and Trim32 3′-UTR was confirmed by dual luciferase reporter gene assay. Treated with 100 nM miR-6236-p5 inhibitor increased the expression of Trim32 and inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h, while miR-6236-p5 mimic promoted the apoptosis of silica-induced AMs. In conclusion, this study identified Trim32 regulated by miR-6236-p5 played an important role in silica-induced AMs apoptosis based on RNA sequencing, which provided a novel clue for exploring the mechanism of silica-induced AMs apoptosis.
{"title":"Tripartite motif-containing 32 regulated by miR-6236-p5 inhibited silica-induced apoptosis of alveolar macrophages","authors":"Manyu Zhao , Qing Chen , Xuxi Chen , Shuyu Gong , Mengzhu Wang , Shanshan Zhao , Sihan Wang , Wen Du , Yunyi Xu , Lijun Peng , Yuqin Yao","doi":"10.1016/j.tox.2024.154042","DOIUrl":"10.1016/j.tox.2024.154042","url":null,"abstract":"<div><div>Apoptosis of alveolar macrophages (AMs) induced by silica is one of the crucial driving factors of silicosis inflammation and fibrosis. However, the mechanism of silica-induced AMs apoptosis remains unclear. In this study, transcriptome sequencing identified 11 differentially expressed (DE)-mRNAs enriched in the regulation of apoptotic signaling pathways in AMs treated with 250 μg/mL silica for 24 h, of which tripartite motif-containing 32 (Trim32) was the most significant and down-regulated. The decreased Trim32 promoted AMs apoptosis, while Trim32 overexpression inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h. MiR-6236-p5 was then identified by MiRNA sequencing as the most significant DE-miRNA potentially regulating Trim32 expression, and the interaction between miR-6236-p5 and Trim32 3′-UTR was confirmed by dual luciferase reporter gene assay. Treated with 100 nM miR-6236-p5 inhibitor increased the expression of Trim32 and inhibited the apoptosis of AMs induced by silica at 250 μg/mL for 24 h, while miR-6236-p5 mimic promoted the apoptosis of silica-induced AMs. In conclusion, this study identified Trim32 regulated by miR-6236-p5 played an important role in silica-induced AMs apoptosis based on RNA sequencing, which provided a novel clue for exploring the mechanism of silica-induced AMs apoptosis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154042"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915590","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154053
Guofen Liu , Jie Yang , Rongxian Li , Wenhong Li , De Liu , Nan Zhang , Yuan Zhao , Zuoshun He , Shiyan Gu
N6-methyladenosine (m6A) modification and LncRNAs play crucial regulatory roles in various pathophysiological processes, yet roles of m6A modification and the relationship between m6A modification and LncRNAs in cadmium-induced oxidative damage of pancreatic β-cells have not been fully elucidated. In this study, m6A agonist entacapone and inhibitor 3-deazadenosine were used to identify the effects of m6A on cadmium-induced oxidative damage as well as LncRNA changes. Our results indicate that elevated levels of m6A modification by entacapone can rescue the cell viability and attenuate the cell apoptosis, while the inhibition levels of m6A modification can exacerbate the cell death. Furthermore, the elevation of m6A modification can recover cadmium-induced oxidative damage to pancreatic β-cells, which characterized as inhibition the ROS accumulation, MDA contents, protein expressions of Nrf2 and Ho-1, while elevation the expressions of Sod1 and Gclc. On the contrary, the reduction levels of m6A modification can exacerbate the cadmium-induced oxidative damage. More importantly, six significantly differentially expressed LncRNAs were selected according to our preliminary sequencing data (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253072) and there is a clear correlation between the levels of these LncRNAs and m6A modification after cadmium treatment. Interestingly, the intervention of m6A modification levels can significantly affect the levels of these LncRNAs. In detail, the stimulation of m6A modification reversed the changes of cadmium-induced LncRNAs, while the m6A modification inhibition can significantly exacerbate the changes of cadmium-induced LncRNAs. In conclusion, our data revealed critical roles of m6A modification in cadmium-induced LncRNAs and oxidative damage. Our findings point to a new direction for future studies on the molecular mechanisms of pancreatic β-cell damage induced by cadmium.
{"title":"Roles of N6-methyladenosine in LncRNA changes and oxidative damage in cadmium-induced pancreatic β-cells","authors":"Guofen Liu , Jie Yang , Rongxian Li , Wenhong Li , De Liu , Nan Zhang , Yuan Zhao , Zuoshun He , Shiyan Gu","doi":"10.1016/j.tox.2025.154053","DOIUrl":"10.1016/j.tox.2025.154053","url":null,"abstract":"<div><div>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification and LncRNAs play crucial regulatory roles in various pathophysiological processes, yet roles of m<sup>6</sup>A modification and the relationship between m<sup>6</sup>A modification and LncRNAs in cadmium-induced oxidative damage of pancreatic β-cells have not been fully elucidated. In this study, m<sup>6</sup>A agonist entacapone and inhibitor 3-deazadenosine were used to identify the effects of m<sup>6</sup>A on cadmium-induced oxidative damage as well as LncRNA changes. Our results indicate that elevated levels of m<sup>6</sup>A modification by entacapone can rescue the cell viability and attenuate the cell apoptosis, while the inhibition levels of m<sup>6</sup>A modification can exacerbate the cell death. Furthermore, the elevation of m<sup>6</sup>A modification can recover cadmium-induced oxidative damage to pancreatic β-cells, which characterized as inhibition the ROS accumulation, MDA contents, protein expressions of Nrf2 and Ho-1, while elevation the expressions of Sod1 and Gclc. On the contrary, the reduction levels of m<sup>6</sup>A modification can exacerbate the cadmium-induced oxidative damage. More importantly, six significantly differentially expressed LncRNAs were selected according to our preliminary sequencing data (<span><span>https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253072</span><svg><path></path></svg></span>) and there is a clear correlation between the levels of these LncRNAs and m<sup>6</sup>A modification after cadmium treatment. Interestingly, the intervention of m<sup>6</sup>A modification levels can significantly affect the levels of these LncRNAs. In detail, the stimulation of m<sup>6</sup>A modification reversed the changes of cadmium-induced LncRNAs, while the m<sup>6</sup>A modification inhibition can significantly exacerbate the changes of cadmium-induced LncRNAs. In conclusion, our data revealed critical roles of m<sup>6</sup>A modification in cadmium-induced LncRNAs and oxidative damage. Our findings point to a new direction for future studies on the molecular mechanisms of pancreatic β-cell damage induced by cadmium.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154053"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972203","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154067
Yujie Shi , Runyang Hong , Zhencheng Fan , Ran Huan , Yajie Gao , Min Ma , Tingting Liu , Chun Pan
Microplastics (MPs), as the crucial environmental pollutants, can be easily transported into the human body and accumulate in the liver. However, current studies mainly focus on acute exposure to MPs, investigations on long-term interactions with MPs alone remain limited. Thereby, we examined noxious properties of MPs and selected the most common polystyrene (PS) MPs as the research object, including unmodified PS MPs (PS-MPs) and positive-charged PS MPs (PS-NH2) at 10 mg/L employing oral drinking water methods in mice for six consecutive months in vivo. In vitro, we treated the human hepatocyte cells with MPs at 25 μg/mL to explore involved mechanisms. The results revealed that six-month MPs exposure led to nonalcoholic fatty liver disease (NAFLD) including impaired liver functions, extensive lipid depositions accompanied by abnormal levels of metabolic genes and PS-NH2 MPs exerted a stronger effect than PS-MPs. Concurrently, mice treated with MPs revealed the accumulation of senescent hepatocytes, leading to increased secretions of senescent phenotypes in the liver. We also discovered that MPs initiated the HO-1/Nrf2 axis consequently inducing ferroptosis in vivo and in vitro, as shown by massive iron deposition, extensive lipid peroxidation along with significant protein expressions in ferroptosis-related markers. Additionally, targeting the HO-1/Nrf2 pathway to further alleviate ferroptosis with corresponding inhibitors could efficiently alleviate cell senescence. Therefore, our study reveals new evidence of the relationship between chronic exposure to MPs and NAFLD and furthers the understanding of how plastic pollution affects human health.
{"title":"Chronic environmental exposure to polystyrene microplastics increases the risk of nonalcoholic fatty liver disease","authors":"Yujie Shi , Runyang Hong , Zhencheng Fan , Ran Huan , Yajie Gao , Min Ma , Tingting Liu , Chun Pan","doi":"10.1016/j.tox.2025.154067","DOIUrl":"10.1016/j.tox.2025.154067","url":null,"abstract":"<div><div>Microplastics (MPs), as the crucial environmental pollutants, can be easily transported into the human body and accumulate in the liver. However, current studies mainly focus on acute exposure to MPs, investigations on long-term interactions with MPs alone remain limited. Thereby, we examined noxious properties of MPs and selected the most common polystyrene (PS) MPs as the research object, including unmodified PS MPs (PS-MPs) and positive-charged PS MPs (PS-NH<sub>2</sub>) at 10 mg/L employing oral drinking water methods in mice for six consecutive months <em>in vivo</em>. <em>In vitro</em>, we treated the human hepatocyte cells with MPs at 25 μg/mL to explore involved mechanisms. The results revealed that six-month MPs exposure led to nonalcoholic fatty liver disease (NAFLD) including impaired liver functions, extensive lipid depositions accompanied by abnormal levels of metabolic genes and PS-NH<sub>2</sub> MPs exerted a stronger effect than PS-MPs. Concurrently, mice treated with MPs revealed the accumulation of senescent hepatocytes, leading to increased secretions of senescent phenotypes in the liver. We also discovered that MPs initiated the HO-1/Nrf2 axis consequently inducing ferroptosis <em>in vivo</em> and <em>in vitro</em>, as shown by massive iron deposition, extensive lipid peroxidation along with significant protein expressions in ferroptosis-related markers. Additionally, targeting the HO-1/Nrf2 pathway to further alleviate ferroptosis with corresponding inhibitors could efficiently alleviate cell senescence. Therefore, our study reveals new evidence of the relationship between chronic exposure to MPs and NAFLD and furthers the understanding of how plastic pollution affects human health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154067"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047975","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 : 2025-02-01DOI: 10.1016/j.tox.2025.154064
Lina Huang, Peineng Liu, Xiaojie Huang
Drug-induced autoimmunity (DIA) is a non-IgE immune-related adverse drug reaction that poses substantial challenges in predictive toxicology due to its idiosyncratic nature, complex pathogenesis, and diverse clinical manifestations. To address these challenges, we developed InterDIA, an interpretable machine learning framework for predicting DIA toxicity based on molecular physicochemical properties. Multi-strategy feature selection and advanced ensemble resampling approaches were integrated to enhance prediction accuracy and overcome data imbalance. The optimized Easy Ensemble Classifier achieved robust performance in both 10-fold cross-validation (AUC value of 0.8836 and accuracy of 82.81 %) and external validation (AUC value of 0.8930 and accuracy of 85.00 %). Paired case studies of hydralazine/phthalazine and procainamide/N-acetylprocainamide demonstrated the model’s capacity to discriminate between structurally similar compounds with distinct immunogenic potentials. Mechanistic interpretation through SHAP (SHapley Additive exPlanations) analysis revealed critical physicochemical determinants of DIA, including molecular lipophilicity, partial charge distribution, electronic states, polarizability, and topological features. These molecular signatures were mechanistically linked to key processes in DIA pathogenesis, such as membrane permeability and tissue distribution, metabolic bioactivation susceptibility, immune protein recognition and binding specificity. SHAP dependence plots analysis identified specific threshold values for key molecular features, providing novel insights into structure-toxicity relationships in DIA. To facilitate practical application, we developed an open-access web platform enabling batch prediction with real-time visualization of molecular feature contributions through SHAP waterfall plots. This integrated framework not only advances our mechanistic understanding of DIA pathogenesis from a molecular perspective but also provides a valuable tool for early assessment of autoimmune toxicity risk during drug development.
{"title":"InterDIA: Interpretable prediction of drug-induced autoimmunity through ensemble machine learning approaches","authors":"Lina Huang, Peineng Liu, Xiaojie Huang","doi":"10.1016/j.tox.2025.154064","DOIUrl":"10.1016/j.tox.2025.154064","url":null,"abstract":"<div><div>Drug-induced autoimmunity (DIA) is a non-IgE immune-related adverse drug reaction that poses substantial challenges in predictive toxicology due to its idiosyncratic nature, complex pathogenesis, and diverse clinical manifestations. To address these challenges, we developed InterDIA, an interpretable machine learning framework for predicting DIA toxicity based on molecular physicochemical properties. Multi-strategy feature selection and advanced ensemble resampling approaches were integrated to enhance prediction accuracy and overcome data imbalance. The optimized Easy Ensemble Classifier achieved robust performance in both 10-fold cross-validation (AUC value of 0.8836 and accuracy of 82.81 %) and external validation (AUC value of 0.8930 and accuracy of 85.00 %). Paired case studies of hydralazine/phthalazine and procainamide/N-acetylprocainamide demonstrated the model’s capacity to discriminate between structurally similar compounds with distinct immunogenic potentials. Mechanistic interpretation through SHAP (SHapley Additive exPlanations) analysis revealed critical physicochemical determinants of DIA, including molecular lipophilicity, partial charge distribution, electronic states, polarizability, and topological features. These molecular signatures were mechanistically linked to key processes in DIA pathogenesis, such as membrane permeability and tissue distribution, metabolic bioactivation susceptibility, immune protein recognition and binding specificity. SHAP dependence plots analysis identified specific threshold values for key molecular features, providing novel insights into structure-toxicity relationships in DIA. To facilitate practical application, we developed an open-access web platform enabling batch prediction with real-time visualization of molecular feature contributions through SHAP waterfall plots. This integrated framework not only advances our mechanistic understanding of DIA pathogenesis from a molecular perspective but also provides a valuable tool for early assessment of autoimmune toxicity risk during drug development.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154064"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053770","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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