Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100231
Giovanni Tossetta , Sonia Fantone , Antonio Domenico Procopio , Armanda Pugnaloni , Alessandro Francesco Gualtieri , Daniela Marzioni
It is known that mineral fibres can be found in placental tissues, but their effect is not known on these tissues. BeWo in vitro model of syncytiotrophoblast, the outer layer of maternal-foetal barrier, is necessary to understand if mineral fibres can alter placental cell turnover and consequently to influence the outcome of pregnancy. We performed in vitro experiments using chrysotile UICC (UICC), chrysotile Valmalenco (VM) and erionite (ERI) to investigate the potential cytotoxic effects of these mineral fibres on BeWo cells. We demonstrated that all fibres are toxic while only UICC fibres caused a DNA damage that the cells were not able to repair through RAD51 activity. In addition, we demonstrated that DNA replication is not altered while cyclin D1 showed a significant decrease in VM and UICC suggesting that the cell cycle is altered in G1 phase. Moreover, UICC increased active form of caspase 3 demonstrating that apoptosis can be induced in BeWo cells. We suggest that although morphological changes are not visible in BeWo cells treated with these mineral fibres, DNA damage can lead to altered placenta physiology that can be seen late when the damage at the foetal tissues has already occurred.
{"title":"Effects of mineral fibres in an in vitro placental syncytiotrophoblast model","authors":"Giovanni Tossetta , Sonia Fantone , Antonio Domenico Procopio , Armanda Pugnaloni , Alessandro Francesco Gualtieri , Daniela Marzioni","doi":"10.1016/j.crtox.2025.100231","DOIUrl":"10.1016/j.crtox.2025.100231","url":null,"abstract":"<div><div>It is known that mineral fibres can be found in placental tissues, but their effect is not known on these tissues. BeWo in vitro model of syncytiotrophoblast, the outer layer of maternal-foetal barrier, is necessary to understand if mineral fibres can alter placental cell turnover and consequently to influence the outcome of pregnancy. We performed in vitro experiments using chrysotile UICC (UICC), chrysotile Valmalenco (VM) and erionite (ERI) to investigate the potential cytotoxic effects of these mineral fibres on BeWo cells. We demonstrated that all fibres are toxic while only UICC fibres caused a DNA damage that the cells were not able to repair through RAD51 activity. In addition, we demonstrated that DNA replication is not altered while cyclin D1 showed a significant decrease in VM and UICC suggesting that the cell cycle is altered in G1 phase. Moreover, UICC increased active form of caspase 3 demonstrating that apoptosis can be induced in BeWo cells. We suggest that although morphological changes are not visible in BeWo cells treated with these mineral fibres, DNA damage can lead to altered placenta physiology that can be seen late when the damage at the foetal tissues has already occurred.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100231"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100230
Retno Murwanti , Ritmaleni , Navista Sri Octa Ujiantari , I Made Rhamandana Putra , Aliffian Farhan Wahyudi , Vigha Ilmanafi Arifka
Ovarian cancer ranks as Indonesia’s third-leading cause of cancer-related death, emphasising the need for innovative treatments. This study combined bioinformatics, molecular docking, and experimental assays to tackle this challenge. We identified 166 ovarian cancer-related genes, with MYC standing out as a key target. Analysis of MYC mutations revealed prevalent alterations, though no significant survival differences were observed in patients with or without the mutations. Molecular docking pinpointed compound B155 as a promising MYC inhibitor. A preliminary cytotoxicity assay revealed compound B155′s notable activity, with an 87.19 % inhibition of cell viability at 50 μM. Most of the other curcumin analogues only caused more than 50 % inhibition at the same concentration. This result suggests alternative mechanisms of action, possibly antioxidant effects, warranting further exploration. In summary, this study unveiled MYC as a prime target for ovarian cancer treatment, with curcumin analogues like B155 showing potential. Nonetheless, the complex factors affecting cytotoxicity underscore the need for deeper investigation into these compounds’ mechanisms in ovarian cancer cells.
{"title":"Bioinformatics study and cytotoxicity of several curcumin analogues in ovarian cancer","authors":"Retno Murwanti , Ritmaleni , Navista Sri Octa Ujiantari , I Made Rhamandana Putra , Aliffian Farhan Wahyudi , Vigha Ilmanafi Arifka","doi":"10.1016/j.crtox.2025.100230","DOIUrl":"10.1016/j.crtox.2025.100230","url":null,"abstract":"<div><div>Ovarian cancer ranks as Indonesia’s third-leading cause of cancer-related death, emphasising the need for innovative treatments. This study combined bioinformatics, molecular docking, and experimental assays to tackle this challenge. We identified 166 ovarian cancer-related genes, with MYC standing out as a key target. Analysis of MYC mutations revealed prevalent alterations, though no significant survival differences were observed in patients with or without the mutations. Molecular docking pinpointed compound B155 as a promising MYC inhibitor. A preliminary cytotoxicity assay revealed compound B155′s notable activity, with an 87.19 % inhibition of cell viability at 50 μM. Most of the other curcumin analogues only caused more than 50 % inhibition at the same concentration. This result suggests alternative mechanisms of action, possibly antioxidant effects, warranting further exploration. In summary, this study unveiled MYC as a prime target for ovarian cancer treatment, with curcumin analogues like B155 showing potential. Nonetheless, the complex factors affecting cytotoxicity underscore the need for deeper investigation into these compounds’ mechanisms in ovarian cancer cells.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100230"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100243
Shari Price , Krista G. Zindel , Joshua K. Overcash , Elizabeth Glaze , Sandy Eldridge
Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer therapy and is showing promise for other non-cancer disease indications. CAR T cells are directed to a target antigen that is overexpressed by tumor cells. On-target toxicity can arise if the targeted protein is also expressed in normal cell populations. Additionally, off-target toxicity may occur if the CAR T cell recognizes or cross-reacts with a non-target protein thereby activating the T cells leading to subsequent adverse sequela. Given the nature of this biological class as a human cellular product, standard safety assessments in animals are largely not appropriate as the drug product is derived from human cells and the associated CAR often lacks reactivity with the animal homolog of the target protein. Undesired targeting of healthy/normal tissue that express the intended target antigen (on-target/off-tumor), as well as unintended targeting of other antigens expressed on healthy/normal tissue is a safety concern that may be explored using human induced pluripotent stem cell (hiPSC)-derived test systems as surrogates for various normal cell types. The panel of hiPSC-derived cells is intended to broadly represent different human cell types from vital organs that can be targets for severe adverse events. Herein the development of an orthogonal approach to an in vitro co-culture assay used to assess unintended CAR T cell cytotoxicity in normal cells is described. Experimental considerations including assay and cell model qualification are presented, and an orthogonal workflow described. Finally, an illustrative case of experimental CD33 CAR T cells co-cultured with a select panel of hiPSC-derived normal cells serves as a springboard for other CAR T cell developers to consider in their nonclinical safety programs.
{"title":"Development of a workflow for in vitro on– and off-target cytotoxicity assessment of CAR T cell therapies to support first-in-human clinical trials: An orthogonal approach using human induced pluripotent stem cell-derived cells as a surrogate for normal vital organ systems","authors":"Shari Price , Krista G. Zindel , Joshua K. Overcash , Elizabeth Glaze , Sandy Eldridge","doi":"10.1016/j.crtox.2025.100243","DOIUrl":"10.1016/j.crtox.2025.100243","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer therapy and is showing promise for other non-cancer disease indications. CAR T cells are directed to a target antigen that is overexpressed by tumor cells. On-target toxicity can arise if the targeted protein is also expressed in normal cell populations. Additionally, off-target toxicity may occur if the CAR T cell recognizes or cross-reacts with a non-target protein thereby activating the T cells leading to subsequent adverse sequela. Given the nature of this biological class as a human cellular product, standard safety assessments in animals are largely not appropriate as the drug product is derived from human cells and the associated CAR often lacks reactivity with the animal homolog of the target protein. Undesired targeting of healthy/normal tissue that express the intended target antigen (on-target/off-tumor), as well as unintended targeting of other antigens expressed on healthy/normal tissue is a safety concern that may be explored using human induced pluripotent stem cell (hiPSC)-derived test systems as surrogates for various normal cell types. The panel of hiPSC-derived cells is intended to broadly represent different human cell types from vital organs that can be targets for severe adverse events. Herein the development of an orthogonal approach to an in vitro co-culture assay used to assess unintended CAR T cell cytotoxicity in normal cells is described. Experimental considerations including assay and cell model qualification are presented, and an orthogonal workflow described. Finally, an illustrative case of experimental CD33 CAR T cells co-cultured with a select panel of hiPSC-derived normal cells serves as a springboard for other CAR T cell developers to consider in their nonclinical safety programs.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100243"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100255
Boyu Pan , Xiwen Feng , Fujian Jiang , Rui Li , Han Zhu , Kunpeng Wang
The indoor air environment has become an essential environmental factor affecting children’s health and safety, among which nicotine and PM2.5, two common combined factors, have become pathogenic factors in indoor area that induce lung cancer in children. In order to reveal the specific mechanism of that, we developed the model of Systematic Environmental Information Medicine Engineering (SEIME), which combines environmental engineering, bioinformatics, and computational biology multidisciplinary approaches. We initially developed a comprehensive computational fluid dynamics (CFD) model, which was subsequently integrated with data from the GEO database, TCGA database, single-cell online databases, and molecular docking analyses to enhance our research framework. CFD results revealed that indoor concentrations of PM2.5 and nicotine were significantly higher than the recommended values of 15 µg/m3 and 1 µg/m3 in the WHO Global Air Quality Guidelines. Meanwhile, bioinformatics results indicated that MAPK and PI3K-Akt were important signaling pathways for inducing non-small cell lung cancer (NSCLC) in children. In addition, GADD45A and NPAS2, as key targets affecting children’s NSCLC, were identified. Subsequently, drug repositioning and molecular docking assays were conducted, and more importantly, related small molecule targeted drugs were screened. Therefore, this study has set up a new interdisciplinary analysis model-SEIME, using environmental information medicine engineering to solve environmental disease models under the influence of multiple factors, and providing theoretical basis for molecular target screening and disease treatment.
{"title":"Indoor airborne carcinogen synergy in children: systematic interdisciplinary approach to PM2.5-nicotine driven lung tumorigenesis and targeted intervention","authors":"Boyu Pan , Xiwen Feng , Fujian Jiang , Rui Li , Han Zhu , Kunpeng Wang","doi":"10.1016/j.crtox.2025.100255","DOIUrl":"10.1016/j.crtox.2025.100255","url":null,"abstract":"<div><div>The indoor air environment has become an essential environmental factor affecting children’s health and safety, among which nicotine and PM2.5, two common combined factors, have become pathogenic factors in indoor area that induce lung cancer in children. In order to reveal the specific mechanism of that, we developed the model of Systematic Environmental Information Medicine Engineering (SEIME), which combines environmental engineering, bioinformatics, and computational biology multidisciplinary approaches. We initially developed a comprehensive computational fluid dynamics (CFD) model, which was subsequently integrated with data from the GEO database, TCGA database, single-cell online databases, and molecular docking analyses to enhance our research framework. CFD results revealed that indoor concentrations of PM2.5 and nicotine were significantly higher than the recommended values of 15 µg/m<sup>3</sup> and 1 µg/m<sup>3</sup> in the WHO Global Air Quality Guidelines. Meanwhile, bioinformatics results indicated that MAPK and PI3K-Akt were important signaling pathways for inducing non-small cell lung cancer (NSCLC) in children. In addition, GADD45A and NPAS2, as key targets affecting children’s NSCLC, were identified. Subsequently, drug repositioning and molecular docking assays were conducted, and more importantly, related small molecule targeted drugs were screened. Therefore, this study has set up a new interdisciplinary analysis model-SEIME, using environmental information medicine engineering to solve environmental disease models under the influence of multiple factors, and providing theoretical basis for molecular target screening and disease treatment.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100255"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ototoxicity is a major dose-limiting side effect of cisplatin, a highly effective anti-cancer drug used to treat many solid tumors. Oxidative stress plays a central role in mediating cisplatin-induced ototoxicity. However, broad-spectrum antioxidants that prevent ototoxicity compromise the anti-cancer activity of cisplatin. Therefore, there is a need to identify novel interventional targets/compounds for otoprotection. Recent reports indicated that cisplatin-induced nitration of cochlear proteins is a critical factor in causing ototoxicity, and inhibition of cochlear nitrative stress mitigated cisplatin-induced ototoxicity. The use of peroxynitrite decomposition catalysts that selectively target nitrative stress appears to be an attractive strategy for mitigating the ototoxic effects of cisplatin because they do not scavenge free radicals. We hypothesized that cotreatment with selective inhibitors of nitrative stress prevents cisplatin-induced ototoxicity without compromising the anti-cancer effects. Here, we test this hypothesis by investigating the effect of MnTBAP cotreatment on cell viability, nitrative stress, DNA damage, and cell migration in cisplatin-treated organ of Corti as well as cancer cells. Our results indicate that cisplatin treatment decreases cell viability in both auditory and cancer cells, while cotreatment with MnTBAP mitigates cisplatin-induced cytotoxicity in the auditory cells but not in the cancer cells. Collectively, the findings of this study suggest that selective targeting of cisplatin-induced nitrative stress is a promising strategy for mitigating the ototoxic effects of cisplatin because it does not compromise the anti-cancer effects.
{"title":"Differential effect of targeting cisplatin-induced nitrative stress using MnTBAP in auditory and cancer cells","authors":"Shomaila Mehmood, Pankaj Bhatia, Nicole Doyon-Reale, Samson Jamesdaniel","doi":"10.1016/j.crtox.2025.100241","DOIUrl":"10.1016/j.crtox.2025.100241","url":null,"abstract":"<div><div>Ototoxicity is a major dose-limiting side effect of cisplatin, a highly effective anti-cancer drug used to treat many solid tumors. Oxidative stress plays a central role in mediating cisplatin-induced ototoxicity. However, broad-spectrum antioxidants that prevent ototoxicity compromise the anti-cancer activity of cisplatin. Therefore, there is a need to identify novel interventional targets/compounds for otoprotection. Recent reports indicated that cisplatin-induced nitration of cochlear proteins is a critical factor in causing ototoxicity, and inhibition of cochlear nitrative stress mitigated cisplatin-induced ototoxicity. The use of peroxynitrite decomposition catalysts that selectively target nitrative stress appears to be an attractive strategy for mitigating the ototoxic effects of cisplatin because they do not scavenge free radicals. We hypothesized that cotreatment with selective inhibitors of nitrative stress prevents cisplatin-induced ototoxicity without compromising the anti-cancer effects. Here, we test this hypothesis by investigating the effect of MnTBAP cotreatment on cell viability, nitrative stress, DNA damage, and cell migration in cisplatin-treated organ of Corti as well as cancer cells. Our results indicate that cisplatin treatment decreases cell viability in both auditory and cancer cells, while cotreatment with MnTBAP mitigates cisplatin-induced cytotoxicity in the auditory cells but not in the cancer cells. Collectively, the findings of this study suggest that selective targeting of cisplatin-induced nitrative stress is a promising strategy for mitigating the ototoxic effects of cisplatin because it does not compromise the anti-cancer effects.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100241"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144106152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100268
Gudisa Bereda
Food contaminants—including chemical, biological, physical, allergenic, and radiological agents—pose major global food safety challenges. This review synthesizes evidence from 2014 to 2025 on Food contaminants sources, cellular and molecular mechanisms, monitoring strategies, and mitigation approaches. Major food contaminants include heavy metals (lead, mercury, cadmium, and arsenic), mycotoxins (aflatoxins, and ochratoxin A), pesticide residues, allergens, microplastics, per- and polyfluoroalkyl substances (PFAS), radioactive isotopes (cesium-137, and iodine-131), and microbial agents such as Bacillus, Salmonella, Listeria, and Escherichia species. At the molecular level, heavy metals trigger oxidative stress, mitochondrial dysfunction, and DNA damage; aflatoxins form DNA adducts, driving carcinogenesis; organophosphate residues inhibit cholinesterase; allergens activate IgE-mediated hypersensitivity; and radiological agents generate reactive oxygen species, causing lipid peroxidation and genomic instability. Regulatory agencies, including WHO, FDA, EFSA, and the European Commission, classify metals as priority hazardous substances and set maximum residue limits (MRLs), tolerable daily intakes (TDIs), and action levels for vulnerable populations, such as children. For example, cadmium in wheat is limited to 100 ppb in the EU, lead in candy to 0.1 ppm, and arsenic in apple juice to 10 ppb. Advanced detection technologies, such as liquid chromatography–mass spectrometry (LC-MS) and inductively coupled plasma mass spectrometry (ICP-MS), enable precise monitoring of contaminants at trace levels. Mitigation strategies emphasize improved agricultural practices, safe processing, allergen control, environmental monitoring, and policy enforcement. Ongoing research on emerging contaminants, particularly PFAS and nanoplastics, is crucial to strengthening food safety systems and protecting public health.
{"title":"Toxicological impacts and mitigation strategies of food contaminants: a global perspective and comprehensive narrative review","authors":"Gudisa Bereda","doi":"10.1016/j.crtox.2025.100268","DOIUrl":"10.1016/j.crtox.2025.100268","url":null,"abstract":"<div><div>Food contaminants—including chemical, biological, physical, allergenic, and radiological agents—pose major global food safety challenges. This review synthesizes evidence from 2014 to 2025 on Food contaminants sources, cellular and molecular mechanisms, monitoring strategies, and mitigation approaches. Major food contaminants include heavy metals (lead, mercury, cadmium, and arsenic), mycotoxins (aflatoxins, and ochratoxin A), pesticide residues, allergens, microplastics, per- and polyfluoroalkyl substances (PFAS), radioactive isotopes (cesium-137, and iodine-131), and microbial agents such as Bacillus, Salmonella, Listeria, and Escherichia species. At the molecular level, heavy metals trigger oxidative stress, mitochondrial dysfunction, and DNA damage; aflatoxins form DNA adducts, driving carcinogenesis; organophosphate residues inhibit cholinesterase; allergens activate IgE-mediated hypersensitivity; and radiological agents generate reactive oxygen species, causing lipid peroxidation and genomic instability. Regulatory agencies, including WHO, FDA, EFSA, and the European Commission, classify metals as priority hazardous substances and set maximum residue limits (MRLs), tolerable daily intakes (TDIs), and action levels for vulnerable populations, such as children. For example, cadmium in wheat is limited to 100 ppb in the EU, lead in candy to 0.1 ppm, and arsenic in apple juice to 10 ppb. Advanced detection technologies, such as liquid chromatography–mass spectrometry (LC-MS) and inductively coupled plasma mass spectrometry (ICP-MS), enable precise monitoring of contaminants at trace levels. Mitigation strategies emphasize improved agricultural practices, safe processing, allergen control, environmental monitoring, and policy enforcement. Ongoing research on emerging contaminants, particularly PFAS and nanoplastics, is crucial to strengthening food safety systems and protecting public health.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100268"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100216
Yue Ge , Maliha S. Nash , Aimen K. Farraj
Air pollution exposure, especially particulate matter (PM) and ozone (O3), poses significant health risks, but the systemic metabolic consequences of combined exposures to PM and O3, remain poorly understood. This study investigated systemic metabolic changes in male spontaneously hypertensive (SH) rats following inhalation exposure to concentrated ambient particles (CAPs) (PM2.5, 150 μg/m3), ozone (O3) (0.2 ppm), and their combination. Rats were exposed for 4 h, and serum samples were collected 1-hour post-exposure. Using targeted metabolomics, we identified significant alterations in metabolites involved in lipid metabolism (phosphatidylcholines), energy metabolism (acylcarnitine C3), and oxidative stress (glutamine). Notably, the combination exposure induced distinct metabolic changes, including increased acylcarnitine C3 levels, suggesting heightened mitochondrial dysfunction. Principal component analysis revealed overlapping profiles between CAPs and controls, indicating a subtler impact of CAPs compared to ozone or combined exposure. These systemic metabolic alterations are aligned with our previously published proteomics findings in cardiac tissues from the same rats, which showed elevated inflammatory markers (e.g., IL-6, TNF-α) and mitochondrial dysfunction. In conclusion, this study provides new insights into the systemic metabolic effects of air pollutant exposure, identifies novel metabolic targets of pollutant-induced toxicity, highlights the complex interactions resulting from combined exposure to multiple pollutants, and underscores the importance of assessing the combined effects of multiple pollutants in air pollution risk assessments.
{"title":"Metabolomic profiling reveals systemic metabolic disruptions induced by combined exposure to particulate matter and ozone","authors":"Yue Ge , Maliha S. Nash , Aimen K. Farraj","doi":"10.1016/j.crtox.2025.100216","DOIUrl":"10.1016/j.crtox.2025.100216","url":null,"abstract":"<div><div>Air pollution exposure, especially particulate matter (PM) and ozone (O<sub>3</sub>), poses significant health risks, but the systemic metabolic consequences of combined exposures to PM and O<sub>3</sub>, remain poorly understood. This study investigated systemic metabolic changes in male spontaneously hypertensive (SH) rats following inhalation exposure to concentrated ambient particles (CAPs) (PM2.5, 150 μg/m<sup>3</sup>), ozone (O<sub>3</sub>) (0.2 ppm), and their combination. Rats were exposed for 4 h, and serum samples were collected 1-hour post-exposure. Using targeted metabolomics, we identified significant alterations in metabolites involved in lipid metabolism (phosphatidylcholines), energy metabolism (acylcarnitine C3), and oxidative stress (glutamine). Notably, the combination exposure induced distinct metabolic changes, including increased acylcarnitine C3 levels, suggesting heightened mitochondrial dysfunction. Principal component analysis revealed overlapping profiles between CAPs and controls, indicating a subtler impact of CAPs compared to ozone or combined exposure. These systemic metabolic alterations are aligned with our previously published proteomics findings in cardiac tissues from the same rats, which showed elevated inflammatory markers (e.g., IL-6, TNF-α) and mitochondrial dysfunction. In conclusion, this study provides new insights into the systemic metabolic effects of air pollutant exposure, identifies novel metabolic targets of pollutant-induced toxicity, highlights the complex interactions resulting from combined exposure to multiple pollutants, and underscores the importance of assessing the combined effects of multiple pollutants in air pollution risk assessments.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100216"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100217
Minkyoung Sung , Yeon-Ji Lee , Soo-Eun Sung , Kyung-Ku Kang , Jae Woo Park , Yujeong Lee , Dongmin Kim , Sunjong Lee , Joo-Hee Choi , Sijoon Lee
Microplastics are pollutants that occur in various environments and habitats. Inflammatory bowel disease (IBD) is a chronic inflammatory disease accompanied with diarrhea, and the number of patients has increased worldwide. In this study, manufactured fragmented polyethylene-microplastics in the size range of 10–30 ㎛, were oxidized by exposure to ultraviolet light, and then administered to a dextran sodium sulfate-induced colitis mouse model to observe the effects of polyethylene-microplastics on IBD. In the microplastics-treated groups, an increase in disease activity index score, histopathological score, and a decrease in the areas of goblet cells were observed. In addition, the tight junction proteins, ZO-1 and Occludin, were significantly decreased, whereas MPO was significantly increased. Interestingly, E-cadherin, which is an adheren junction, was also decreased, presumably because of the physical effects of microplastics. The results suggest that polyethylene-microplastics worsen IBD and microplastics can affect not only tight junctions, but also adheren junctions.
{"title":"Exacerbation of polyethylene microplastics in animal models of DSS-induced colitis through damage to intestinal epithelial cell conjunctions","authors":"Minkyoung Sung , Yeon-Ji Lee , Soo-Eun Sung , Kyung-Ku Kang , Jae Woo Park , Yujeong Lee , Dongmin Kim , Sunjong Lee , Joo-Hee Choi , Sijoon Lee","doi":"10.1016/j.crtox.2025.100217","DOIUrl":"10.1016/j.crtox.2025.100217","url":null,"abstract":"<div><div>Microplastics are pollutants that occur in various environments and habitats. Inflammatory bowel disease (IBD) is a chronic inflammatory disease accompanied with diarrhea, and the number of patients has increased worldwide. In this study, manufactured fragmented polyethylene-microplastics in the size range of 10–30 ㎛, were oxidized by exposure to ultraviolet light, and then administered to a dextran sodium sulfate-induced colitis mouse model to observe the effects of polyethylene-microplastics on IBD. In the microplastics-treated groups, an increase in disease activity index score, histopathological score, and a decrease in the areas of goblet cells were observed. In addition, the tight junction proteins, ZO-1 and Occludin, were significantly decreased, whereas MPO was significantly increased. Interestingly, E-cadherin, which is an adheren junction, was also decreased, presumably because of the physical effects of microplastics. The results suggest that polyethylene-microplastics worsen IBD and microplastics can affect not only tight junctions, but also adheren junctions.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100217"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This review examines various classes of drugs, focusing on their therapeutic and adverse effects, particularly in relation to immunostimulation. We emphasize the potential of new approach methodologies (NAMs) to study both expected and unexpected immunostimulatory effects. By evaluating the modes of action of different immunostimulatory drugs, we aim to provide insights into effectively assessing unwanted immunostimulatory responses. The review begins by exploring drugs that stimulate the immune system—including immunostimulants, monoclonal antibodies, chemotherapeutics, and nucleic acid-based drugs—to outline NAMs that could be employed to evaluate immunostimulation.
{"title":"New approach methodologies to assess wanted and unwanted drugs-induced immunostimulation","authors":"Valeria Bettinsoli , Gloria Melzi , Irene Marchese , Sofia Pantaleoni , Francesca Carlotta Passoni , Emanuela Corsini","doi":"10.1016/j.crtox.2025.100222","DOIUrl":"10.1016/j.crtox.2025.100222","url":null,"abstract":"<div><div>This review examines various classes of drugs, focusing on their therapeutic and adverse effects, particularly in relation to immunostimulation. We emphasize the potential of new approach methodologies (NAMs) to study both expected and unexpected immunostimulatory effects. By evaluating the modes of action of different immunostimulatory drugs, we aim to provide insights into effectively assessing unwanted immunostimulatory responses. The review begins by exploring drugs that stimulate the immune system—including immunostimulants, monoclonal antibodies, chemotherapeutics, and nucleic acid-based drugs—to outline NAMs that could be employed to evaluate immunostimulation.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100222"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2024.100208
Benedikt Bauer, Helena Rossi, Henning Hintzsche
The anthraquinone dye Alizarin Red S (ARS) is used for marking live animals, specifically as a tool for monitoring the stock of the endangered European eel by marking caught fish with ARS before releasing the eels back into the wild. As ARS can be found in recaptured eels even years later, knowledge of potential health hazards of ARS is essential for assessing the food safety of eels marked with ARS. As the compound class of anthraquinones is known for their genotoxic and carcinogenic properties, concerns were raised regarding the food safety of marked eels. Up to now, no data for characterizing the hazard potential of ARS is available. In this study, we aimed at closing this data gap. We tested ARS in liver (HepG2), cervix (HeLa) and lymphoblast (TK-6) cells and identified HepG2 cells as the cell line most sensitive to ARS-induced cytotoxicity. We then investigated oxidative stress, DNA strand breaks, and micronucleus formation in these cells and did not observe effects at sub-cytotoxic concentrations.
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