Chemical Research in Toxicology最新文献

{"title":"","authors":"Medjda Bellamri, Scott J. Walmsley, Lihua Yao, Thomas A. Rosenquist, Christopher J. Weight, Peter W. Villalta and Robert J. Turesky*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modelling <i>In vitro</i> Mutagenicity Using Multi-Task Deep Learning and REACH Data.","authors":"Panagiotis G Karamertzanis, Mike Rasenberg, Imran Shah, Grace Patlewicz","doi":"10.1021/acs.chemrestox.5c00152","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00152","url":null,"abstract":"<p><p>Under REACH, mutagenicity assessment relies on <i>in vitro</i> testing (gene mutation test in bacteria and/or mammalian cells, as well as chromosomal aberration or micronucleus assays in mammalian cells) followed by <i>in vivo</i> testing if necessary. This study explored the possibility of using the inherent correlation between these <i>in vitro</i> assays to create multi-task deep learning models and examine if they outperform single-task models. An extensive genotoxicity dataset with over 12,000 substances was compiled, including algorithmically curated REACH data and information from several public sources. Genotoxicity information was also retrieved from ToxValDB and literature sources to construct external (hold-out) test sets for a stringent assessment of the models' generalized performance. A range of single-task and multi-task models were investigated from classical machine learning techniques and chemical fingerprints to deep learning methods using graphs for molecular structure representation. The best deep learning single-task model achieved a cross-validation balanced accuracy of 73-84% for the four <i>in vitro</i> assays and exceeded classical machine learning by 2-8%. Gene mutation detection for specific bacterial strains and metabolic activation modes exhibited balanced accuracy 82-85%, with improvements ranging from 7% to 12%. Multi-task deep learning models for specific bacterial strains and metabolic activation modes had on average 8% higher cross-validation test balanced accuracy than single-task models but were comparable when assay outcomes were aggregated. The best deep learning models for specific bacterial strains and metabolic activation modes showed external balanced accuracy of 72-78 % when there were at least 200 positives and 200 negatives. The dimensionality-reduced molecular embeddings from graph neural network models were able to distinguish positives from negatives and cluster structures that trigger known genotoxicity structural alerts. The models were also used to identify structural moieties linked to predicted negative genotoxicity in bacteria and positive genotoxicity in mammalian cells.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663839","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}

{"title":"Circular RNAs: A Potential Regulator in Environmental Chemical Carcinogenesis.","authors":"Huijun Huang, Yiqi Zhou, Yiyan Huang, Jiaxin Wang, Shiyi Ouyang, Meiqi Lan, Lieyang Fan, Yun Zhou","doi":"10.1021/acs.chemrestox.5c00146","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00146","url":null,"abstract":"<p><p>Circular RNA (circRNA), a class of evolutionarily conserved, structurally stable, and tissue-specifically expressed noncoding RNA, is increasingly recognized as a key regulator of diverse biological processes and disease pathogenesis, including cancer. While the roles of circRNAs in tumorigenesis are well-documented, their involvement in the tumorigenesis induced by environmental chemical carcinogens (ECCs) remains relatively unexplored. Recent studies have identified aberrant expressions of specific circRNAs during ECC exposure-related carcinogenesis, suggesting their critical regulatory functions. Given their unique structure and broad regulatory roles, circRNAs exhibit great potential as diagnostic, therapeutic, and prognostic biomarkers for ECC exposure-associated cancers. This review summarizes the characteristics and functions of circRNAs, as well as the potential regulatory mechanisms in ECC exposure-induced cancer and the dysregulations of circRNAs caused by ECCs. We highlight the complexity and heterogeneity of circRNA regulatory networks, emphasizing the need for integrated and dynamic investigations to fully elucidate the underlying mechanisms. Future research efforts should prioritize biomarker studies to facilitate the prevention, early detection, and effective treatment of ECC exposure-associated cancers.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657853","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}

{"title":"Phthalate Exposure: Prevalence, Health Effects, Regulatory Frameworks, and Remediation.","authors":"Abdulkhalik Mansuri, Charvi Trivedi, Shaivee Chokshi, Keya Jantrania, Ashutosh Kumar","doi":"10.1021/acs.chemrestox.4c00338","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00338","url":null,"abstract":"<p><p>Phthalates, a ubiquitous class of plasticizers, are widely used to enhance the flexibility and durability of plastics. However, their noncovalent association with polymer matrices allows them to leach readily into the environment, raising significant global concerns. This review provides a comprehensive analysis of phthalates, including their chemical structures, properties, and applications, alongside their environmental prevalence and potential health risks. Particular emphasis is placed on the mechanisms of phthalate toxicity, including endocrine disruption, oxidative stress, and epigenetic modifications, with a critical discussion on how these mechanisms contribute to observed health outcomes. The bioaccumulation of phthalates in diverse environments is discussed, highlighting their presence in soil, water, and air. Advanced analytical techniques for phthalate detection are reviewed, with a focus on their strengths and limitations, and the need for more sensitive and accurate methods to monitor environmental contamination is underscored. Epidemiological and laboratory studies are critically examined to provide a detailed understanding of the developmental, reproductive, and systemic health effects associated with phthalate exposure. This review goes beyond summarizing existing knowledge by integrating discussions on regulatory frameworks, current challenges, and future directions for reducing environmental and health risks posed by phthalates. By addressing gaps in recent literature and consolidating diverse findings, this work aims to serve as a valuable resource for researchers and policymakers engaged in mitigating the impacts of phthalates on living organisms and ecosystems.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574455","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}

{"title":"Conformation-Dependent Lesion Bypass and Mutagenicity of Bulky 2-Acetylaminofluorene-Guanine DNA Adduct in Epigenetically Relevant Sequence Contexts.","authors":"Yi-Tzai Chen, Rui Qi, Ang Cai, Bongsup P Cho, Deyu Li","doi":"10.1021/acs.chemrestox.5c00055","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00055","url":null,"abstract":"<p><p>DNA base cytosine can be modified epigenetically by adding a methyl group to form 5-methylcytosine (5mC). 5mC in DNA CpG islands plays a crucial role in mammalian cell development and epigenetic regulation. While 5mC does not block DNA replication and is not mutagenic, the biological consequences of 5mC affecting the flanking guanine with a bulky modification during DNA replication are not well understood. This paper examined the lesion bypass and mutagenicity of the 2-acetylaminofluorene-modified guanine DNA adduct (dG-AAF) in epigenetically relevant sequence contexts in <i>Escherichia coli</i>. The C/5mC context exhibited significantly different bypass and mutagenicity profiles for dG-AAF. The biological outcomes also varied depending on the nature of the 3' flanking base and the lesion bulkiness. In addition, we extensively observed a unique type of -1 G deletion when the lesion was flanked by 3' purines, possibly due to the formation of a stacked slipped mutagenic intermediate. However, there was no such deletion with 3' pyrimidines. Our findings provide a new perspective on the role of epigenetic markers in DNA replication and could help to develop methods to identify mutation patterns associated with specific mutational signatures or spectra in cancer.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558425","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}

{"title":"AI-Driven Integration of Transcriptomics, Quantum Mechanics, and Physiology for Predicting Drug-Induced Liver Injury in Data-Limited Scenarios.","authors":"Roshan Bhave, Babatunde Bello, Divesh Bhatt, Joseph Machulcz, Jacqueline A R Shea, Maksim Khotimchenko, Weida Tong, Szczepan W Baran, Jyotika Varshney","doi":"10.1021/acs.chemrestox.4c00542","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00542","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is a significant concern with prescription medications and supplements. Accordingly, it is crucial to develop tools and approaches that can predict DILI likelihood of existing medications and supplements, as well as potential drug candidates under development. The complexity of liver injury mechanisms and the limited availability of DILI data hamper the development of robust predictive models. In order to overcome these challenges, this study investigated enriching machine learning/artificial intelligence (ML/AI) models that predict the risk of DILI using drug structural parameters along with rat liver transcriptomics data, quantum mechanics-derived features of the drug molecules, and metrics for interspecies variability of drug exposure. The enrichment of ML/AI models with such features dramatically improved ML/AI models' DILI predictive ability, even in a severely data-limited scenario. The approach used in the study, especially the incorporation of knowledge-based features to enrich AI models, holds tremendous promise for not only assessing safety and toxicity assessments of drug candidates but also in other aspects such as target engagement and efficacy of these candidates, early in the development phase.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537401","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}

{"title":"","authors":"Brett Hagan,&nbsp;Louis Groff,&nbsp;Grace Patlewicz and Imran Shah*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalytic-Dependent Role of DNA Polymerase κ in Nucleotide Excision Repair.","authors":"Abbey Rebok, Mariela C Torres, Julia R Ambrose, Thomas E Spratt","doi":"10.1021/acs.chemrestox.5c00085","DOIUrl":"10.1021/acs.chemrestox.5c00085","url":null,"abstract":"<p><p>DNA polymerase kappa (pol κ) is an error-prone Y-family polymerase primarily associated with translesion DNA synthesis (TLS), a DNA damage tolerance mechanism that prevents replication fork stalling. Pol κ has been implicated in other DNA repair and tolerance pathways such as nucleotide excision repair (NER). However, the role of error-prone pol κ in the NER pathway remains unclear. We sought to investigate if pol κ had a catalytic role in NER by using the pol κ selective nucleoside analogue, <i>N</i>²-(4-ethynylbenzyl)-2'-deoxyguanosine (EBndG). Here, we identified robust, cell cycle-independent catalytic activity of pol κ in cells not treated with DNA-damaging agents. We identified approximately 40% of pol κ catalytic activity was reduced with loss of either XPC or XPA, but not CSB, indicating pol κ has a role in global genome-NER. We monitored pol κ catalytic activity after treatment with benzo(<i>a</i>)pyrene diol epoxide and UVB radiation, and we observed that pol κ catalytic activity increased in an NER-dependent manner. Our study highlights that pol κ is consistently active in cells and possesses a key catalytic role in NER.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1103-1112"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140870","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}

{"title":"","authors":"Abbey Rebok,&nbsp;Mariela C. Torres,&nbsp;Julia R. Ambrose and Thomas E. Spratt*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Per- and Polyfluoroalkyl Substances Suppress Macrophage Alternative Activation to Disrupt Hepatic Lipid Metabolism.","authors":"Lijuan You, Xiaohong Wang, Yuan Zhi, Huiling Wang, Zhisen Zhuang, Jing Yang, Qiannan Zhang, Hailin Shang, Yongning Li, Yi Wan, Xudong Jia, Hui Yang","doi":"10.1021/acs.chemrestox.5c00066","DOIUrl":"10.1021/acs.chemrestox.5c00066","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants with diverse toxic effects (e.g., hepatotoxicity and metabolism disorder). Macrophages played a key role in metabolic response; however, the effect of macrophage on PFAS-induced toxicity and the underlying mechanisms remain poorly understood. In this study, we constructed a high-content cell model by utilizing the activation and differentiation of human THP-1 monocytes into alternative activation of macrophages, enabling rapid quantitative screening of numerous PFAS. We applied the cell model to screen 10 PFASs and identified that PFOA and PFUnDA significantly suppressed alternative activation of macrophages by disrupting the PPAR signaling pathway. Oral exposure to PFOA and PFUnDA in WT mice also significantly impaired alternative activation of macrophages in the liver and induced hepatocyte hypertrophy, liver dysfunction, and systemic lipid metabolism disorders. Moreover, macrophage-specific knockout of PPARγ exacerbated PFOA and PFUnDA-induced suppression of macrophage alternative activation and subsequent hepatotoxicity. Activation balance between PPARα and PPARγ may be a critical factor by PFOA and PFUnDA to affect the alternative activation of macrophage. These findings highlight the immunometabolism regulatory role of macrophage activation in PFAS-induced hepatotoxicity in humans.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1091-1102"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172199","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}