Archives of Toxicology最新文献

{"title":"Predictive biomarkers for embryotoxicity: a machine learning approach to mitigating multicollinearity in RNA-Seq","authors":"Yixian Quah,&nbsp;Soontag Jung,&nbsp;Jireh Yi-Le Chan,&nbsp;Onju Ham,&nbsp;Ji-Seong Jeong,&nbsp;Sangyun Kim,&nbsp;Woojin Kim,&nbsp;Seung-Chun Park,&nbsp;Seung-Jin Lee,&nbsp;Wook-Joon Yu","doi":"10.1007/s00204-024-03852-w","DOIUrl":"10.1007/s00204-024-03852-w","url":null,"abstract":"<div><p>Multicollinearity, characterized by significant co-expression patterns among genes, often occurs in high-throughput expression data, potentially impacting the predictive model’s reliability. This study examined multicollinearity among closely related genes, particularly in RNA-Seq data obtained from embryoid bodies (EB) exposed to 5-fluorouracil perturbation to identify genes associated with embryotoxicity. Six genes—<i>Dppa5a</i>, <i>Gdf3</i>, <i>Zfp42</i>, <i>Meis1</i>, <i>Hoxa2</i>, and <i>Hoxb1</i>—emerged as candidates based on domain knowledge and were validated using qPCR in EBs perturbed by 39 test substances. We conducted correlation studies and utilized the variance inflation factor (VIF) to examine the existence of multicollinearity among the genes. Recursive feature elimination with cross-validation (RFECV) ranked <i>Zfp42</i> and <i>Hoxb1</i> as the top two among the seven features considered, identifying them as potential early embryotoxicity assessment biomarkers. As a result, a <i>t</i> test assessing the statistical significance of this two-feature prediction model yielded a <i>p</i> value of 0.0044, confirming the successful reduction of redundancies and multicollinearity through RFECV. Our study presents a systematic methodology for using machine learning techniques in transcriptomics data analysis, enhancing the discovery of potential reporter gene candidates for embryotoxicity screening research, and improving the predictive model's predictive accuracy and feasibility while reducing financial and time constraints.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 12","pages":"4093 - 4105"},"PeriodicalIF":4.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid quantitative high-throughput mouse embryoid body model for embryotoxicity assessment","authors":"Yixian Quah,&nbsp;Soontag Jung,&nbsp;Onju Ham,&nbsp;Ji-Seong Jeong,&nbsp;Sangyun Kim,&nbsp;Woojin Kim,&nbsp;Jireh Yi-Le Chan,&nbsp;Seung-Chun Park,&nbsp;Seung-Jin Lee,&nbsp;Wook-Joon Yu","doi":"10.1007/s00204-024-03845-9","DOIUrl":"10.1007/s00204-024-03845-9","url":null,"abstract":"<div><p>Individuals are exposed to a wide arrays of hazardous chemicals on a daily basis through various routes, many of which have not undergone comprehensive toxicity assessments. While traditional developmental toxicity tests involving pregnant animals are known for their reliability, they are also associated with high costs and time requirements. Consequently, there is an urgent demand for alternative, cost-efficient, and rapid in vitro testing methods. This study aims to address the challenges related to automating and streamlining the screening of early developmental toxicity of chemicals by introducing a mouse embryoid body test (EBT) model in a 384-ultra low attachment well format. Embryoid bodies (EBs) generated in this format were characterized by a spontaneous differentiation trajectory into cardiac mesoderm by as analyzed by RNA-seq. Assessing prediction accuracy using reference compounds suggested in the ICH S5(R3) guideline and prior studies resulted in the establishment of the acceptance criteria and applicability domain of the EBT model. The results indicated an 84.38% accuracy in predicting the developmental toxicity of 23 positive and 9 negative reference compounds, with an optimized cutoff threshold of 750 µM. Overall, the developed EBT model presents a promising approach for more rapid, high-throughput chemical screening, thereby facilitating well-informed decision-making in environmental management and safety assessments.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3897 - 3908"},"PeriodicalIF":4.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of the scientific literature on experimental toxicity studies of COVID-19 vaccines, with special attention to publications in toxicology journals","authors":"Jose L. Domingo","doi":"10.1007/s00204-024-03854-8","DOIUrl":"10.1007/s00204-024-03854-8","url":null,"abstract":"<div><p>Since the reports of the first cases of COVID-19, in less than 5 years, a huge number of documents regarding that disease and the coronavirus (SARS-CoV-2), responsible for the infection, have been published. The tremendous number of scientific documents covers many topics on different issues directly related to COVID-19/SARS-CoV-2. The number of articles—including reviews—reporting adverse/side effects of the approved COVID-19 vaccines is considerable. A wide range of adverse/side effects have been reported in humans after COVID-19 vaccination: thrombotic events/thrombocytopenia, myocarditis/pericarditis, cutaneous reactions, immune-mediated effects, psychiatric adverse events, systemic lupus erythematosus, reproductive toxicity, and other miscellaneous adverse effects. In contrast, information on nonclinical studies conducted to assess the potential toxicity/adverse effects of the COVID-19 vaccines in laboratory animals, is comparatively very scarce. The present review was aimed at revising the scientific literature regarding the studies in laboratory animals on the toxic/adverse effects of COVID-19 vaccines. In addition, the investigations reported in those specific toxicology journals with the highest impact factors have been examined one by one. The results of the present review indicate that most nonclinical/experimental studies on the adverse/toxic effects of the COVID-19 vaccines and/or potential candidates showed—in general terms—a good safety profile. Only in some animal studies were certain adverse effects found. However, a rather surprising result has been the limited number of available (in the databases PubMed and Scopus) nonclinical studies performed by the companies that have been the largest manufacturers of mRNA vaccines in the world. It is assumed that these studies have been conducted. However, they have not been published in scientific journals, which does not allow the judgment of the international scientific community, including toxicologists.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3603 - 3617"},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03854-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated blood-ethanol concentration promotes reduction of aliphatic ketones (acetone and ethyl methyl ketone) to secondary alcohols along with slower oxidation to aliphatic diols","authors":"A. W. Jones","doi":"10.1007/s00204-024-03860-w","DOIUrl":"10.1007/s00204-024-03860-w","url":null,"abstract":"<div><p>Many people convicted for drunken driving suffer from an alcohol use disorder and some traffic offenders consume denatured alcohol for intoxication purposes. Venous blood samples from people arrested for driving under the influence of alcohol were analyzed in triplicate by headspace gas chromatography (HS-GC) using three different stationary phases. The gas chromatograms from this analysis sometimes showed peaks with retention times corresponding to acetone, ethyl methyl ketone (2-butanone), 2-propanol, and 2-butanol in addition to ethanol and the internal standard (1-propanol). Further investigations showed that these drink-driving suspects had consumed an industrial alcohol (T-Red) for intoxication purposes, which contained &gt; 90% w/v ethanol, acetone (~ 2% w/v), 2-butanone (~ 5% w/v) as well as Bitrex to impart a bitter taste. In <i>n</i> = 75 blood samples from drinkers of T-Red, median concentrations of ethanol, acetone, 2-butanone, 2-propanol and 2-butanol were 2050 mg/L (2.05 g/L), 97 mg/L, 48 mg/L, 26 mg/L and 20 mg/L, respectively. In a separate GC analysis, 2,3-butanediol (median concentration 87 mg/L) was identified in blood samples containing 2-butanone. When the redox state of the liver is shifted to a more reduced potential (excess NADH), which occurs during metabolism of ethanol, this favors the reduction of low molecular ketones into secondary alcohols via the alcohol dehydrogenase (ADH) pathway. Routine toxicological analysis of blood samples from apprehended drivers gave the opportunity to study metabolism of acetone and 2-butanone without having to administer these substances to human volunteers.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 12","pages":"4013 - 4019"},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unrevealing the mechanisms behind the cardioprotective effect of wheat polyphenolics","authors":"Pratik Chakraborty,&nbsp;Saikat Dewanjee","doi":"10.1007/s00204-024-03850-y","DOIUrl":"10.1007/s00204-024-03850-y","url":null,"abstract":"<div><p>Cardiovascular diseases pose a major threat to both life expectancy and quality of life worldwide, and a concerning level of disease burden has been attained, particularly in middle- and low-income nations. Several drugs presently in use lead to multiple adverse events. Thus, it is urgently needed to develop safe, affordable, and effective management of cardiovascular diseases. Emerging evidence reveals a positive association between polyphenol consumption and cardioprotection. Whole wheat grain and allied products are good sources of polyphenolic compounds bearing enormous cardioprotective potential. Polyphenolic extract of the entire wheat grain contains different phenolic compounds viz. ferulic acid, caffeic acid, chlorogenic acid, p-coumaric acid, sinapic acid, syringic acid, vanillic acid, apigenin, quercetin, luteolin, etc. which exert cardioprotection by reducing oxidative stress and interfering with different toxicological processes. The antioxidant capacity has been thought to exert the cardioprotective mechanism of wheat grain polyphenolics, which predominantly suppresses oxidative stress, inflammation and fibrosis by downregulating several pathogenic signaling events. However, the combined effect of polyphenolics appears to be more prominent than that of a single molecule, which might be attained due to the synergy resulting in multimodal cardioprotective benefits from multiple phenolics. The current article covers the bioaccessibility and possible effects of wheat-derived polyphenolics in protecting against several cardiovascular disorders. This review discusses the mechanistic pharmacology of individual wheat polyphenols on the cardiovascular system. It also highlights the comparative superiority of polyphenolic extracts over a single phenolic.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3543 - 3567"},"PeriodicalIF":4.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transport of perfluoroalkyl substances across human induced pluripotent stem cell-derived intestinal epithelial cells in comparison with primary human intestinal epithelial cells and Caco-2 cells","authors":"Aafke W. F. Janssen,&nbsp;Loes P. M. Duivenvoorde,&nbsp;Karsten Beekmann,&nbsp;Nicole Pinckaers,&nbsp;Bart van der Hee,&nbsp;Annelies Noorlander,&nbsp;Liz L. Leenders,&nbsp;Jochem Louisse,&nbsp;Meike van der Zande","doi":"10.1007/s00204-024-03851-x","DOIUrl":"10.1007/s00204-024-03851-x","url":null,"abstract":"<div><p>Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model. This model was extensively characterized and compared with the widely applied human colonic adenocarcinoma cell line Caco-2 and a human primary IEC-based model, described to most closely resemble in vivo tissue. The hiPSC-derived IEC layers demonstrated polarized monolayers with tight junctions and a mucus layer. The monolayers consisted of enterocytes, stem cells, goblet cells, enteroendocrine cells, and Paneth cells that are also present in native tissue. Transcriptomics analysis revealed distinct differences in gene expression profiles, where the hiPSC-derived IECs showed the highest expression of intestinal tissue-specific genes relative to the primary IEC-based model and the Caco-2 cells clustered closer to the primary IEC-based model than the hiPSC-derived IECs. The order of PFAS transport was largely similar between the models and the apparent permeability (<i>P</i>_app) values of PFAS in apical to basolateral direction in the hiPSC-derived IEC model were in the following order: PFHxS &gt; PFOA &gt; HFPO-DA &gt; PFNA &gt; PFOS. In conclusion, the hiPSC-derived IEC model highly resembles human intestinal physiology and is therefore a promising novel in vitro model to study transport of chemicals across the intestinal barrier for risk assessment of chemicals.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3777 - 3795"},"PeriodicalIF":4.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03851-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative case study on NAMs: towards enhancing specific target organ toxicity analysis","authors":"Kristina Jochum,&nbsp;Andrea Miccoli,&nbsp;Cornelia Sommersdorf,&nbsp;Oliver Poetz,&nbsp;Albert Braeuning,&nbsp;Tewes Tralau,&nbsp;Philip Marx-Stoelting","doi":"10.1007/s00204-024-03839-7","DOIUrl":"10.1007/s00204-024-03839-7","url":null,"abstract":"<div><p>Traditional risk assessment methodologies in toxicology have relied upon animal testing, despite concerns regarding interspecies consistency, reproducibility, costs, and ethics. New Approach Methodologies (NAMs), including cell culture and multi-level omics analyses, hold promise by providing mechanistic information rather than assessing organ pathology. However, NAMs face limitations, like lacking a whole organism and restricted toxicokinetic interactions. This is an inherent challenge when it comes to the use of omics data from in vitro studies for the prediction of organ toxicity in vivo. One solution in this context are comparative in vitro–in vivo studies as they allow for a more detailed assessment of the transferability of the respective NAM data. Hence, hepatotoxic and nephrotoxic pesticide active substances were tested in human cell lines and the results subsequently related to the biology underlying established effects in vivo. To this end, substances were tested in HepaRG and RPTEC/tERT1 cells at non-cytotoxic concentrations and analyzed for effects on the transcriptome and parts of the proteome using quantitative real-time PCR arrays and multiplexed microsphere-based sandwich immunoassays, respectively. Transcriptomics data were analyzed using three bioinformatics tools. Where possible, in vitro endpoints were connected to in vivo observations. Targeted protein analysis revealed various affected pathways, with generally fewer effects present in RPTEC/tERT1. The strongest transcriptional impact was observed for Chlorotoluron in HepaRG cells (increased <i>CYP1A1</i> and <i>CYP1A2</i> expression). A comprehensive comparison of early cellular responses with data from in vivo studies revealed that transcriptomics outperformed targeted protein analysis, correctly predicting up to 50% of in vivo effects.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3641 - 3658"},"PeriodicalIF":4.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03839-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicokinetics, in vivo metabolic profiling and tissue distribution of chlorfenapyr in mice","authors":"Shunjie Zhang,&nbsp;Xin wang,&nbsp;Xia yang,&nbsp;Ziyang Ma,&nbsp;Peng Liu,&nbsp;Shiyuan Tang,&nbsp;Min Zhao,&nbsp;Haijun Chen,&nbsp;Qiang Qiu,&nbsp;Minghai Tang,&nbsp;Aihua Peng,&nbsp;Yu Cao","doi":"10.1007/s00204-024-03846-8","DOIUrl":"10.1007/s00204-024-03846-8","url":null,"abstract":"<div><p>Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by <i>Streptomyces</i> spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (<i>t</i>_1/2), area under the curve (AUC) and peak concentration (<i>C</i>_max) values of tralopyril were significantly higher than those of chlorfenapyr (<i>P</i> &lt; 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood–brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC–MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3763 - 3775"},"PeriodicalIF":4.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) on function and homeostasis in human and rat pancreatic beta-cell lines","authors":"Nela Pavlíková,&nbsp;Jan Šrámek,&nbsp;Vlasta Němcová,&nbsp;Lola Bajard","doi":"10.1007/s00204-024-03841-z","DOIUrl":"10.1007/s00204-024-03841-z","url":null,"abstract":"<div><p>Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 11","pages":"3859 - 3874"},"PeriodicalIF":4.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03841-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP2E1 in 1,4-dioxane metabolism and liver toxicity: insights from CYP2E1 knockout mice study","authors":"Yewei Wang,&nbsp;Georgia Charkoftaki,&nbsp;David J. Orlicky,&nbsp;Emily Davidson,&nbsp;Reza Aalizadeh,&nbsp;Ning Sun,&nbsp;Gary Ginsberg,&nbsp;David C. Thompson,&nbsp;Vasilis Vasiliou,&nbsp;Ying Chen","doi":"10.1007/s00204-024-03811-5","DOIUrl":"10.1007/s00204-024-03811-5","url":null,"abstract":"<div><p>1,4-Dioxane (DX), an emerging water contaminant, is classified as a Group 2B liver carcinogen based on animal studies. Understanding of the mechanisms of action of DX liver carcinogenicity is important for the risk assessment and control of this environmental pollution. Previous studies demonstrate that high-dose DX exposure in mice through drinking water for up to 3 months caused liver mild cytotoxicity and oxidative DNA damage, a process correlating with hepatic CYP2E1 induction and elevated oxidative stress. To access the role of CYP2E1 in DX metabolism and liver toxicity, in the current study, male and female Cyp2e1-null mice were exposed to DX in drinking water (5000 ppm) for 1 week or 3 months. DX metabolism, redox and molecular investigations were subsequently performed on male Cyp2e1-null mice for cross-study comparisons to similarly treated male wildtype (WT) and glutathione (GSH)-deficient Gclm-null mice. Our results show that Cyp2e1-null mice of both genders were resistant to DX-induced hepatocellular cytotoxicity. In male Cyp2e1-null mice exposed to DX for 3 months, firstly, DX metabolism to β-hydroxyethoxyacetic acid was reduced to ~ 36% of WT levels; secondly, DX-induced hepatic redox dysregulation (lipid peroxidation, GSH oxidation, and activation of NRF2 antioxidant response) was substantially attenuated; thirdly, liver oxidative DNA damage was at a comparable level to DX-exposed WT mice, accompanied by suppression of DNA damage repair response; lastly, no aberrant proliferative or preneoplastic lesions were noted in DX-exposed livers. Overall, this study reveals, for the first time, that CYP2E1 is the main enzyme for DX metabolism at high dose and a primary contributor to DX-induced liver oxidative stress and associated cytotoxicity. High dose DX-induced genotoxicity may occur via CYP2E1-independent pathway(s), potentially involving impaired DNA damage repair.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 10","pages":"3241 - 3257"},"PeriodicalIF":4.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}