Chem. Res. Toxicol. [JOURNAL]
Sun
200 papers
Aetokthonotoxin, the Causative Agent of Vacuolar Myelinopathy, Uncouples Oxidative Phosphorylation due to Protonophore Activity.
Rebhahn VIC, Saoud M, Winterhalter M … +10 more , Schanbacher F, Jobst M, Ruiz R, Sonntag A, Kollatz J, Sprengel R, Donovan SF, Del Favero G, Rennert R, Niedermeyer THJ
Chem Res Toxicol · 2025 Sep · PMID 40712083 · Full text
Aetokthonotoxin (AETX) is an emerging environmental toxin produced by the freshwater cyanobacterium . Accumulating in the food chain, it causes vacuolar myelinopathy, a neurological disease affecting a wide range of wild...
Aetokthonotoxin (AETX) is an emerging environmental toxin produced by the freshwater cyanobacterium . Accumulating in the food chain, it causes vacuolar myelinopathy, a neurological disease affecting a wide range of wildlife characterized by the development of large intramyelinic vacuoles in the white matter of the brain. So far, the mode of action of AETX is unknown. After discovering that AETX is cytostatic and arrests cancer cell lines in the G phase, metabolomic profiling of AETX-treated cells as well as an assessment of the physicochemical properties of the compound suggested that AETX is a weakly acidic uncoupler of mitochondrial respiration. We confirmed this hypothesis by assays on mammalian cells, finding that AETX has the expected effects on mitochondrial network morphology, mitochondrial membrane potential, and oxygen consumption rate, resulting in affected ATP generation. We confirmed that AETX is capable of transporting protons across lipid bilayers. In summary, we demonstrate that AETX is a protonophore that uncouples oxidative phosphorylation in mitochondria, which is the primary event of AETX intoxication.
Mechanistic Insights into CYP2A6 Inactivation by Visnagin and Its Impact on Pharmacokinetic Properties of Tegafur.
Yang D, Zhang Q, Ye T … +7 more , Cheng Z, Tang H, Dai J, Cheng X, Peng Y, Li W, Zheng J
Chem Res Toxicol · 2025 Aug · PMID 40696501 · Publisher ↗
Visnagin (VNG), a furanochromone, is a major active component of the plant (L.) Lam often used for the preparation of tea products. This study aims to comprehensively investigate the mechanism of VNG-mediated CYP2A6 enz...
Visnagin (VNG), a furanochromone, is a major active component of the plant (L.) Lam often used for the preparation of tea products. This study aims to comprehensively investigate the mechanism of VNG-mediated CYP2A6 enzyme inactivation and the effects of VNG on the pharmacokinetics of the antitumor drug tegafur. The results demonstrate that VNG irreversibly inhibits CYP2A6 in a time-, concentration-, and NADPH-dependent manner. This time-dependent inhibition was attenuated by coincubation with letrozole, a competitive inhibitor of CYP2A6. Glutathione and hydrogen peroxide/superoxide dismutase failed to reverse the VNG-induced inactivation of CYP2A6. GSH trapping experiments provided strong evidence for the formation of epoxide and/or γ-ketoaldehyde intermediates resulting from the metabolic activation of VNG. Furthermore, pretreatment with VNG extract significantly increased the plasma and area under the curve of tegafur in rats.
Applying New Approach Methods for Toxicokinetics for Chemical Risk Assessment.
Wambaugh JF, Paul Friedman K, Beal MA … +14 more , Moffat I, Hughes MF, Nong A, Dorne JCM, Ashraf MW, Barton-Maclaren TS, DeVito M, Ferguson SS, Judson RS, Long AS, Paini A, Sampani S, Thomas RS, Wetmore BA
Chem Res Toxicol · 2025 Aug · PMID 40694534 · Publisher ↗
Toxicokinetic (TK) modeling provides critical information linking chemical exposures to tissue concentrations, predicting persistence in the body and determining the route(s) of elimination. Unfortunately, TK data are no...
Toxicokinetic (TK) modeling provides critical information linking chemical exposures to tissue concentrations, predicting persistence in the body and determining the route(s) of elimination. Unfortunately, TK data are not available for most chemicals in commerce and the environment. To better understand and address these important information gaps, researchers and regulatory scientists from the international consortium of Accelerating the Pace of Chemical Risk Assessment herein present a flexible framework for characterizing the suitability of TK new approach methods (NAMs) to address chemical risk questions. High throughput toxicokinetics (HTTK) combines chemical-specific in vitro measures of TK with reproducible transparent and open-source TK models. HTTK supports the interpretation of data from in vitro bioactivity NAMs in a public health risk context and enhances the interpretation of biomonitoring data. A tiered framework has been developed focusing on two key aspects: (1) the regulatory decision context and (2) chemical properties and data. Differing levels of certainty are needed for relative risk prioritization, prospective risk assessment, and for protecting susceptible populations. Here HTTK is described with respect to measurement and modeling applications, relevant decision contexts, applicable chemistry, value of information, and certainty of predictions. In some cases, quantitative structure-property relationship (QSPR) models exist as alternatives to measurement and are discussed when they are appropriate. A series of examples applying the decision trees in specific public health scenarios are provided to illustrate that writing short responses, prompted by the decision trees and supported by the discussion and references collected here, may provide defensible written justification for or against the use of HTTK. The framework is intended to serve as a guide to chemical regulators and risk assessors who are interested to know when and where HTTK might be used for public health safety or risk decision making and when further expert guidance is needed.
Modelling Mutagenicity Using Multi-Task Deep Learning and REACH Data.
Karamertzanis PG, Rasenberg M, Shah I … +1 more , Patlewicz G
Chem Res Toxicol · 2025 Aug · PMID 40680271 · Publisher ↗
Under REACH, mutagenicity assessment relies on testing (gene mutation test in bacteria and/or mammalian cells, as well as chromosomal aberration or micronucleus assays in mammalian cells) followed by testing if necessa...
Under REACH, mutagenicity assessment relies on testing (gene mutation test in bacteria and/or mammalian cells, as well as chromosomal aberration or micronucleus assays in mammalian cells) followed by testing if necessary. This study explored the possibility of using the inherent correlation between these 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 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.
Circular RNAs: A Potential Regulator in Environmental Chemical Carcinogenesis.
Huang H, Zhou Y, Huang Y … +5 more , Wang J, Ouyang S, Lan M, Fan L, Zhou Y
Chem Res Toxicol · 2025 Aug · PMID 40674562 · Publisher ↗
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...
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.
ROS-Dependent Endoplasmic Reticulum Stress Is Involved in Silica-Induced Pulmonary Fibrosis through the GRP78/CHOP/TXNIP/NLRP3 Signaling Pathway in Rats.
Han GZ, Li S, Cui YY … +4 more , Shao B, Song Y, Jiang SL, Zhang ZQ
Chem Res Toxicol · 2025 Jul · PMID 40637414 · Publisher ↗
Several studies have suggested that silica-induced reactive oxygen species (ROS) stimulate the endoplasmic reticulum to undergo endoplasmic reticulum stress (ERS), which eventually leads to pulmonary fibrosis. However, t...
Several studies have suggested that silica-induced reactive oxygen species (ROS) stimulate the endoplasmic reticulum to undergo endoplasmic reticulum stress (ERS), which eventually leads to pulmonary fibrosis. However, the mechanisms by which ROS-dependent ERS leads to silicosis and fibrosis remain unclear. In this study, male rats were intratracheally instilled with a single dose of crystalline silica (SiO2) suspension (100 mg/mL, 1 mL) to establish silicosis and then were injected intravenously with 1 mL of N-Acetylcysteine (NAC) (at the dose of 20, 40, or 80 mg/kg, respectively) daily to inhibit ROS-dependent ERS. Rats given a single intratracheal dose of SiO suspension and subsequently receiving daily intravenous injections of phosphate buffer solution (PBS) served as models, while those given a single intratracheal dose of PBS and subsequently receiving daily intravenous injections of PBS served as controls. After 40 days, lung samples were taken for pathological observation, and the levels of glucose-regulated protein 78(GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), thioredoxin-interacting protein (TXNIP), and nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) were assessed. The results showed that compared with the control group, the lung tissues of the model rats exhibited obvious fibrosis and ERS, accompanied by the elevated levels of GRP78, CHOP, TXNIP, and NLRP3 inflammasome. After ROS were inhibited with NAC, the degree of lung fibrosis and ERS was significantly alleviated, and the levels of the aforementioned cytokines were also reduced. Moreover, the higher the dose of NAC intervention, the more pronounced the effects. The results demonstrated that ROS-dependent ERS is deeply involved in silica-induced pulmonary fibrosis through the GRP78/CHOP/TXNIP/NLRP3 signaling pathway in rats.
Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1,8-Dinitropyrene and Its Metabolite 1-Amino-8-nitropyrene via Nitroreduction in Human Lung Cells.
Su AL, Marques CF, Krzeminski J … +2 more , El-Bayoumy K, Penning TM
Chem Res Toxicol · 2025 Jul · PMID 40633532 · Full text
1,8-Dinitropyrene (1,8-DNP) is a diesel exhaust constituent classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. Its mutagenic properties can be attributed in part thro...
1,8-Dinitropyrene (1,8-DNP) is a diesel exhaust constituent classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. Its mutagenic properties can be attributed in part through the formation of covalent DNA adducts that result from mononitroreduction (e.g., -(deoxyguanosin-8-yl)-1-amino-8-nitropyrene). Recombinant aldo-keto reductases (AKRs) 1C1-1C3 catalyze the nitroreduction of 1,8-DNP, 1-nitropyrene, and 3-nitrobenzanthrone. Although are induced by nuclear factor erythroid 2-related factor 2 (NRF2), the contribution of NRF2 toward the nitroreduction of 1,8-DNP in human lung cells is currently unknown. We used highly sensitive and specific in-cell fluorescence assays to examine the ability of human lung A549 and HBEC3-KT cells to metabolize 1,8-DNP to yield 1-amino-8-nitropyrene (1,8-ANP) and 1,8-DNP to yield 1,8-diaminopyrene (1,8-DAP) via mono- and bis-nitroreduction, respectively. A549 cells generated both 1,8-ANP and 1,8-DAP from 1,8-DNP. By contrast, HBEC3-KT cells formed 1,8-ANP, but essentially no 1,8-DAP, from 1,8-DNP. We used genetic and pharmacological approaches to investigate the dependence of 1,8-DNP nitroreduction on AKR1C1-1C3 and NRF2. A549 cells with homozygous /NRF2 knockout did not exhibit decreased 1,8-ANP formation but showed decreased 1,8-DAP formation, indicating that the second but not the first nitroreduction step was NRF2-dependent. Treatment of HBEC3-KT cells with NRF2 activators (-sulforaphane (SFN) or 1-(2-cyano-3,12,28-trioxooleana-1,9(11)-dien-28-yl)-1-imidazole (CDDO-Im) did not increase the mononitroreduction of 1,8-DNP to 1,8-ANP but increased the conversion of 1,8-ANP to 1,8-DAP consistent with the second step requiring inducible NRF2. AKR1C isoform specific inhibitors showed that these enzymes accounted for the majority of 1,8-ANP and 1,8-DAP formation in both cell lines. The ability of A549 NRF2 knockout cells to still form 1,8-ANP coupled with their lack of AKR1C isoform expression indicated that a new nitroreductase was expressed as an adaptive response to NRF2 loss. We find that this nitroreductase is not NQO1, thioredoxin reductase, xanthine oxidase, or NADPH-P450 oxidoreductase.
Prediction of Internal Exposures after Virtual Oral Doses of Disparate Chemicals in Rats and Humans Using Simplified Physiologically Based Pharmacokinetic Models with Generated Input Parameters.
Yamazaki H, Shimizu M
Chem Res Toxicol · 2025 Jul · PMID 40628652 · Publisher ↗
Toxicological evaluation of industrial chemicals with a broad range of chemical structures, for example, bioactive food components, toxic food-derived compounds, and drugs, usually involves the estimation of human cleara...
Toxicological evaluation of industrial chemicals with a broad range of chemical structures, for example, bioactive food components, toxic food-derived compounds, and drugs, usually involves the estimation of human clearance by allometric extrapolation of traditionally determined rat profiles. Three general methods are used to utilize and expand observed time-dependent plasma concentration data after single oral doses of chemicals: empirical standard noncompartmental analysis, compartmental modeling, and physiologically based pharmacokinetic (PBPK) modeling. Application of the PBPK model for forward dosimetry (from external to internal concentrations) following oral administrations has recently been simplified by using -generated input parameters to evaluate internal exposures in humans without reference to any experimental data. Human PBPK model input parameters for a diverse range of compounds have been successfully estimated by using -generated chemical descriptors and machine learning tools. Key values for the fraction absorbed × intestinal availability, the absorption constant, the volume of systemic circulation, and the hepatic intrinsic clearance can be generated using mathematical equations to estimate values for sets of approximately 30 physicochemical properties or descriptors. After virtual oral dosing of more than 350 compounds, the plasma and liver concentrations generated by PBPK models (1) using traditionally determined input parameters and (2) using input parameters estimated were correlated in rat models and human models. This approach to pharmacokinetic modeling could potentially be applied in the clinical setting and during computational toxicological assessment of the potential risks of a wide range of general chemicals.
Phthalate Exposure: Prevalence, Health Effects, Regulatory Frameworks, and Remediation.
Mansuri A, Trivedi C, Chokshi S … +2 more , Jantrania K, Kumar A
Chem Res Toxicol · 2025 Aug · PMID 40622126 · Publisher ↗
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 en...
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.
Addressing Pitfalls of Metabolomics for Toxicology: A Call for Standardization, Reproducibility and Data Sharing.
Nian M, Chen X, Fang M
Chem Res Toxicol · 2025 Jul · PMID 40619682 · Publisher ↗
Metabolomics has emerged as a pivotal tool in toxicology, providing unique insights into biochemical and molecular disruptions upon toxicant exposure. However, its application faces challenges such as metabolite misannot...
Metabolomics has emerged as a pivotal tool in toxicology, providing unique insights into biochemical and molecular disruptions upon toxicant exposure. However, its application faces challenges such as metabolite misannotation, insufficient quality assurance and quality control (QA/QC), and limitations in dose-response and time-response studies. Pathway enrichment analysis is often hindered by incomplete databases and irrelevant background metabolites, leading to false positives or missed key pathways, while the lack of robust validation mechanisms can blur distinctions between general stress responses and toxicant-specific mechanisms. Addressing these pitfalls requires standardized protocols for sample preparation, analytical workflows, and data processing to ensure reproducibility. Rigorous QA/QC practices are essential to minimize batch effects, while cross-validation with transcriptomics and proteomics strengthens mechanistic insights. Comprehensive data sharing through public repositories enhances transparency and supports secondary analysis for novel discoveries. By adopting these strategies, metabolomics can achieve greater reliability and advance toxicological research by identifying early biomarkers, elucidating toxicant mechanisms, and improving environmental health assessments.
Conformation-Dependent Lesion Bypass and Mutagenicity of Bulky 2-Acetylaminofluorene-Guanine DNA Adduct in Epigenetically Relevant Sequence Contexts.
Chen YT, Qi R, Cai A … +2 more , Cho BP, Li D
Chem Res Toxicol · 2025 Aug · PMID 40613893 · Full text
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 doe...
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 . 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.
Isothiazole Disinfectants Inhibit Neurosteroid Production by Targeting Human and Rat 5α-Reductase Type 1.
Qi S, Cai L, Lu X … +7 more , Wang S, Shao S, Hector NJ, Mao B, Wang Y, Ge RS, Shangguan W
Chem Res Toxicol · 2025 Jul · PMID 40601901 · Publisher ↗
Isothiazole disinfectants are widely used antimicrobial preservatives found in various consumer products, raising concerns about their potential effects on human health. This study investigated the inhibitory effects of...
Isothiazole disinfectants are widely used antimicrobial preservatives found in various consumer products, raising concerns about their potential effects on human health. This study investigated the inhibitory effects of seven isothiazole disinfectants on human and rat steroid 5α-reductase type 1 (SRD5A1), a key enzyme in neurosteroid biosynthesis. Among the tested compounds, dichlorooctylisothiazole exhibited the strongest suppression on human SRD5A1 with an IC value of 3.23 μM, followed by octylisothiazole (5.10 μM), butylbenzo[]isothiazol-3(2H)-one (16.51 μM), benzisothiazole (31.64 μM), and methylchloroisothiazole (42.65 μM). Enzyme kinetics and molecular docking analyses revealed that these compounds acted through mixed/noncompetitive inhibition by binding to the NADPH-binding pocket via van der Waals and hydrogen bonds. Cell-based studies in human SF126 glioblastoma cells confirmed that these compounds penetrated cell membranes and reduced dihydrotestosterone production. Structure-activity relationship analysis showed that compounds with higher LogP, molecular weight, volume, heavy atom number, and apolar desolvation exhibited stronger inhibitory activity. 3D quantitative structure-activity relationship analysis incorporated hydrogen bond acceptor and hydrophobicity domain features. Additionally, dichlorooctylisothiazole showed significant inhibition of rat SRD5A1 with an IC of 21.47 μM. In conclusion, these findings reveal some isothiazole disinfectants as potential endocrine disruptors targeting neurosteroid biosynthesis via SRD5A1 and highlight clear structure-activity relationship and species-dependent variance.
Acetic Acid Inhalation-Induced Lung Injury: A Common Chemical with Underestimated Risks.
Rasin P, Prabhakaran P
Chem Res Toxicol · 2025 Jul · PMID 40601525 · Publisher ↗
Acetic acid is widely used; however, its inhalation can cause significant respiratory harm. This paper examines its toxicological mechanisms, overlooked health risks, and the need for targeted safety measures to prevent...
Acetic acid is widely used; however, its inhalation can cause significant respiratory harm. This paper examines its toxicological mechanisms, overlooked health risks, and the need for targeted safety measures to prevent lung injury in both domestic and occupational places.
AI-Driven Integration of Transcriptomics, Quantum Mechanics, and Physiology for Predicting Drug-Induced Liver Injury in Data-Limited Scenarios.
Bhave R, Bello B, Bhatt D … +6 more , Machulcz J, Shea JAR, Khotimchenko M, Tong W, Baran SW, Varshney J
Chem Res Toxicol · 2025 Aug · PMID 40598914 · Publisher ↗
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...
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.
Machine Learning Models Based on Enlarged Chemical Spaces for Screening Carcinogenic Chemicals.
Wu C, Chen J, Zhang Y … +4 more , Wang Z, Xiao Z, Liu W, Wang H
Chem Res Toxicol · 2025 Jul · PMID 40579351 · Publisher ↗
Machine learning (ML) models for screening carcinogenic chemicals are critical for the sound management of chemicals. Previous models were built on small-scale datasets and lacked applicability domain (AD) characterizati...
Machine learning (ML) models for screening carcinogenic chemicals are critical for the sound management of chemicals. Previous models were built on small-scale datasets and lacked applicability domain (AD) characterization that is necessary for regulatory applications of the models. In the current study, an enlarged dataset containing 1697 compounds (940 carcinogens and 757 non-carcinogens) was curated and employed to construct screening models based on 12 types of molecular fingerprints, four ML algorithms, and two graph neural networks. The AD of the optimal model was defined by a state-of-the-art characterization methodology (AD) based on the analysis of structure-activity landscapes (SALs). Results showed that an optimal model based on the random forest algorithm with the PubChem fingerprints outperformed previous ones, with an area under the receiver operating characteristic curve of 86.2% on the validation set imposed with the AD. The optimal model, coupled with the AD, was employed to screen carcinogenic chemicals in the Inventory of Existing Chemical Substances of China (IECSC) and plastic additives datasets, identifying 1282 chemicals from the IECSC and 841 plastic additives as carcinogenic chemicals. The screening model coupled with AD may serve as a promising tool for prioritizing chemicals of carcinogenic concern, facilitating the sound management of chemicals.
AmesFormer: State-of-the-Art Mutagenicity Prediction with Graph Transformers.
Thompson LA, Evans JG, Matthews ST
Chem Res Toxicol · 2025 Jul · PMID 40571292 · Publisher ↗
The Ames mutagenicity test is a gold standard assay for the safety assessment of new chemicals. However, many in silico models rely on challenging-to-interpret ensemble strategies and molecular fingerprint data, which ne...
The Ames mutagenicity test is a gold standard assay for the safety assessment of new chemicals. However, many in silico models rely on challenging-to-interpret ensemble strategies and molecular fingerprint data, which neglects gestalt molecular structure. To improve upon these models, we propose AmesFormer, a graph transformer neural network that shows state-of-the-art performance when paired with our new Ames data set. We briefly review the current state of Ames modeling with a focus on graph neural networks. We then benchmark AmesFormer on a standardized test data set against 22 other Ames models, achieving state of the art (SOTA) performance. We uniquely report the calibration performance of our model and attempt to improve it using temperature scaling. We support our findings with reference to other models from the literature and with developments in machine learning (ML) and graph theory. Overall, we present a high-performance, accessible, and open-source computational model for Ames mutagenicity, with significant potential for regulatory and drug development applications.
Untargeted DNA Adductomics Identifies Aristolochic Acid III as a Potent DNA-Damaging Agent among 11 Substituted Aromatic Genotoxicants in the Rat Urinary System.
Bellamri M, Walmsley SJ, Yao L … +4 more , Rosenquist TA, Weight CJ, Villalta PW, Turesky RJ
Chem Res Toxicol · 2025 Jul · PMID 40521810 · Full text
An untargeted, data-independent acquisition high-resolution accurate tandem mass spectrometry method using an Orbitrap mass spectrometer was employed to screen for DNA adducts formed from 11 environmental and dietary aro...
An untargeted, data-independent acquisition high-resolution accurate tandem mass spectrometry method using an Orbitrap mass spectrometer was employed to screen for DNA adducts formed from 11 environmental and dietary aromatic or substituted aromatic carcinogens in the kidney, urinary bladder, prostate, pancreas, liver, and the lung of male rats 24 h after treatment. Among the carcinogens investigated, DNA adducts of the structurally related nitrophenanthrenes 3-nitrobenzanthrone (3-NBA), an atmospheric pollutant, and 8-methoxy-6-nitrophenanthro[3,4-]-1,3-dioxole-5-carboxylic acid (AA-I), a naturally occurring genotoxicant from Aristolochiaceae plants, were the most abundant across most organs, forming both 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) adducts. In contrast, significantly lower DNA adduct levels were formed with the aromatic amine 4-aminobiphenyl and 2-nitrofluorene, an oxidized derivative of 2-aminofluorene; the heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-]quinoxaline, 2-amino-1-methyl-6-phenylimidazo[4,5-]pyridine, 2-amino-α-carboline, and 2-amino-3-methyl-α-carboline; and the polycyclic aromatic hydrocarbon benzo[]pyrene. DNA adducts of -toluidine and 2-naphthylamine were not detected. Most notably, 10-methoxy-6-nitrophenanthro[3,4-]-1,3-dioxole-5-carboxylic acid (AA-III), an isomer of AA-I, which was later identified as a minor contaminant (5.3%) in the purified herbal extract assayed, exhibited strong organotropism for DNA damage within the urinary system. Dose-adjusted levels of dA and dG adducts of AA-III were 30 to 80 times higher than those of AA-I in the kidney and urinary bladder. This strikingly high organ-specific DNA adduct formation in the urinary system was unique to AA-III and was not observed for the structurally related 3-NBA and AA-I, or the other carcinogens tested. Given that AA-III frequently occurs with AA-I in herbs, these findings underscore the need for further research into the carcinogenic potential of AA-III and its role in renal and urinary bladder cancer associated with traditional herbal medicines.
Halogen Atoms in Bisphenol A Derivatives Enhance the Inhibitory Potency against Human and Rat Placental 3β-Hydroxysteroid Dehydrogenases.
Wang S, Fu X, Ren X … +4 more , Yi P, Wu Z, Ge RS, Peng B
Chem Res Toxicol · 2025 Jul · PMID 40511817 · Publisher ↗
Halogenated bisphenol A (BPA) derivatives are extensively utilized in industrial production and have been detected in the environment, as well as in human samples. The 3β-HSDs are important for the catalytic transformati...
Halogenated bisphenol A (BPA) derivatives are extensively utilized in industrial production and have been detected in the environment, as well as in human samples. The 3β-HSDs are important for the catalytic transformation of pregnenolone into progesterone. But inhibition by BPA derivatives on 3β-HSD activity is still unclear. The inhibition of 3β-HSD by 8 halogen BPA derivatives was assessed by means of an in vitro test. Tetrachloro BPA was found to be the strongest 3β-HSDs in both human and rat models with IC values of 1.48 and 3.81 μM. Other derivatives, including 3-chloro BPA, bisphenol C, 3,3',5-trichloro BPA, tetrabromo BPA, and 4,4'-thiodiphenol, also exhibited inhibitory effects on human and rat placental 3β-HSD activity, albeit with lower potency. 3-Chloro BPA and bisphenol C exerted mixed inhibition against human 3β-HSD1, while the others functioned as competitive inhibitors. These compounds significantly suppressed progesterone secretion in human JAr cells. The inhibitory effects were inversely correlated with the Log P (lipophilicity) and halogen atoms. Docking analysis showed hydrophobic and hydrogen bond interactions that played key roles in the inhibition mechanism. In this paper, a new pharmacological model, which includes both hydrophobic and aromatics, has been proposed for the prediction of inhibition of BPA derivatives. In summary, some halogen-containing derivatives are strong suppressors of 3β-HSDs in placenta, and the inhibition effect of these compounds is mainly dependent on the lipophilicity.
Toxicokinetics and Perfluorooctanesulfonic Acid-Induced Liver Protein Expression Are Markedly Altered in Mice Lacking Albumin.
Kaye EM, Becanova J, Vojta S … +3 more , Lohmann R, Fischer FC, Slitt A
Chem Res Toxicol · 2025 Jul · PMID 40492927 · Full text
Perfluorooctanesulfonic acid (PFOS) is a ubiquitous perfluoroalkyl substance (PFAS) linked to liver disease and obesity in humans. Binding studies suggest that albumin is a crucial blood protein influencing PFOS toxicoki...
Perfluorooctanesulfonic acid (PFOS) is a ubiquitous perfluoroalkyl substance (PFAS) linked to liver disease and obesity in humans. Binding studies suggest that albumin is a crucial blood protein influencing PFOS toxicokinetics and hepatotoxicity; however, its role has not been mechanistically tested in vivo. This study used an albumin-deficient mouse model to investigate the relevance of albumin in PFOS tissue distribution and liver disease end points. Adult male C57BL/6J wild-type (Alb) and albumin-deficient (Alb) mice were orally gavaged daily for 7 days with either vehicle or PFOS at 0.5 or 10 mg/kg body weight. The measured PFOS concentrations in plasma were significantly lower in Alb mice compared to those in Alb mice, while liver concentrations were significantly higher in Alb mice. Binding experiments confirmed these findings, indicating that PFOS toxicokinetics are driven by plasma and tissue binding. Significant changes in liver protein expression did not translate into differences in liver disease end points between genotypes, suggesting the need for chronic exposure studies. Our data imply that disease-related albumin deficiency in humans can influence PFAS toxicokinetics and susceptibility to hepatotoxicity. Our framework using knockout mice can be adapted in future studies to assess the relevance of protein binding and membrane transporters in PFAS distribution and elimination.
Facile Biological Oxidation of Dopamine to 6-Hydroxydopamine -Quinone in a Sequential Two-Step Process: Implications for Parkinson's Disease.
Jiang XR, Zhu BT
Chem Res Toxicol · 2025 Jun · PMID 40468542 · Publisher ↗
6-Hydroxydopamine (6-OHDA), a hydroxyl-derivative of the endogenous neurotransmitter dopamine, can selectively induce Parkinsonian symptoms in animal models. At present, most researchers consider 6-OHDA a man-made neurot...
6-Hydroxydopamine (6-OHDA), a hydroxyl-derivative of the endogenous neurotransmitter dopamine, can selectively induce Parkinsonian symptoms in animal models. At present, most researchers consider 6-OHDA a man-made neurotoxicant, due to the lack of strong evidence for its presence and/or formation in biological systems. The present study aims to determine whether 6-OHDA can be formed under physiologically relevant conditions. Here, we report in the Fenton reaction system (containing 15 μM Fe, 142 μM ascorbic acid and 80 μM EDTA in 50 mM phosphate buffer, pH 7.4), dopamine can undergo facile oxidation to 6-OHDA -quinone (a stable, oxidized form of 6-OHDA) in a sequential two-step process: the first step involves dopamine oxidation to its -quinone (DAQ), and this process is facilitated by oxidants like transition metal ions Fe and Mn; and the second step involves the further oxidization of DAQ to 6-OHDA -quinone by hydroxyl radical or hydrogen peroxide. The chemical mechanism by which HO oxidizes DAQ to 6-OHDA -quinone likely results from the attack of HO-derived OOH at the C-6 position of DAQ. We also demonstrate that while catalase abolishes 6-OHDA -quinone formation by removing hydrogen peroxide or hydroxyl radical, glutathione and cysteine provide effective protection by forming conjugates with DAQ and 6-OHDA -quinone. The results of this study demonstrate that 6-OHDA can be readily formed from dopamine under physiologically relevant conditions, and thus provide important tangible support for the long-held speculation that 6-OHDA is an intrinsic etiological factor in Parkinson's disease.
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