Chem. Res. Toxicol. [JOURNAL]
Sun
200 papers
Microbiota-Driven Metabolic Alterations Induced by BPA, TDCPP and PFOA in an Ex Vivo Human Fecal Fermentation Model.
Sabuz O, Folz J, Deepika D … +4 more , Blanco J, Schuhmacher M, Aichinger G, Kumar V
Chem Res Toxicol · 2026 Apr · PMID 41841412 · Full text
The gut microbiome is increasingly recognized as a key contributor to chemical toxicity. Endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and perfluorooctano...
The gut microbiome is increasingly recognized as a key contributor to chemical toxicity. Endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and perfluorooctanoic acid (PFOA) are widespread environmental contaminants with the potential to affect host health. To characterize microbiota-specific response to these compounds, we employed an ex vivo fecal fermentation model using samples from healthy adult donors. Fecal slurries were exposed to BPA, TDCPP and PFOA (75 μM) for up to 24 h under anaerobic conditions. Targeted LC-MS/MS quantified parent compounds over time, while untargeted metabolomics profiled microbial metabolic alterations at 4 and 24 h. TDCPP levels decreased similarly in fecal and abiotic controls, suggesting a nonmicrobial loss (e.g., instability or adsorption), whereas PFOA levels remained stable across donors. Untargeted metabolomics revealed compound- and time-dependent perturbations, with PFOA eliciting the strongest metabolic shifts. A curated set of 124 annotated metabolites indicated disruptions in bile acid transformation short-chain fatty acid production, nucleotide turnover, redox balance, and phytochemical catabolism. Several altered metabolites have been previously linked to immunomodulatory processes, suggesting potential implications for host-microbiota interactions. Overall, this study demonstrates the utility of ex vivo fermentation systems for assessing microbiota-mediated metabolic responses to xenobiotics and highlights the relevance of incorporating microbiome-related end points into chemical risk assessment.
Combining High-Throughput Screening and In Silico Modeling to Derisk Novel Agrochemicals for Androgen Receptor Binding.
Adamczewski M, Nisius B, Kausch-Busies N … +1 more , Tötsch N
Chem Res Toxicol · 2026 Apr · PMID 41821388 · Publisher ↗
Androgen receptor (AR) modulation is a critical safety concern for environmental chemicals, including agrochemicals, due to its role in endocrine disruption. Existing public data sets for AR modulation are limited in siz...
Androgen receptor (AR) modulation is a critical safety concern for environmental chemicals, including agrochemicals, due to its role in endocrine disruption. Existing public data sets for AR modulation are limited in size and diversity. Here, we report a large-scale high-throughput screening (HTS) campaign assessing AR binding for over 72,000 compounds from an agrochemical library using a fluorescence polarization displacement assay. Confirmatory dose-response testing identified 4,183 AR binders (5.7% hit rate) with substantial structural diversity and numerous novel scaffolds. To enable predictive modeling, we curated an unrestricted data set of 24,953 compounds with associated activity data, which we publish as part of this paper. Using this data set, we trained machine learning models based on molecular 1D and 2D descriptors and fingerprints. Gradient-boosted trees achieved the best performance, with a balanced accuracy of 0.77 and a negative predictive value of 0.98, making the model suitable for derisking large virtual libraries. External validation on existing publicly available AR data sets (CoMPARA and PubChem) demonstrated reasonable transferability (balanced accuracy 0.66 and 0.72), overcoming differences in experimental methods and composition of the compound sets. Our findings demonstrate the utility of combining HTS with machine learning for early safety assessment and provide a benchmark data set to advance AR binding prediction, complementing existing data sets.
Para-Benzoquinone (pBQ) Modifies Human Mitochondrial Phenylalanyl-tRNA Synthetase and Contributes to Mitochondrial Dysfunction.
Roy D, Bose S, Das A … +13 more , Manna R, Roy D, Verma SS, Bhattacharjee J, Das S, Tudu S, Steiner RE, Das M, Chaudhary N, Bhunia A, Ghosh A, Ibba M, Banerjee R
Chem Res Toxicol · 2026 Apr · PMID 41811228 · Publisher ↗
Para-benzoquinone (pBQ) is of growing concern as an emerging redox-active environmental pollutant due to its ubiquitous presence in smoke and combustion byproducts. Recent reports have highlighted its potential role as a...
Para-benzoquinone (pBQ) is of growing concern as an emerging redox-active environmental pollutant due to its ubiquitous presence in smoke and combustion byproducts. Recent reports have highlighted its potential role as a redox-driven mitotoxicant, although the involvement of specific mitochondrial protein targets remains unexplored. Here, we investigated the effects of pBQ on human mitochondrial phenylalanyl-tRNA synthetase (hmtPheRS), an essential enzyme required for mitochondrial protein synthesis and linked to severe neurodevelopmental disorders. Our biophysical analyses revealed that pBQ enhanced the formation of covalently modified higher-ordered structures of hmtPheRS by 75% and induced conformational instability, thereby significantly reducing its aminoacylation activity. NMR spectroscopy and molecular docking analyses further supported interactions between pBQ and residues within the catalytic domain of hmtPheRS, indicating the formation of a protein adduct. In parallel, exposure of HEK293 cells to sublethal concentrations of pBQ (20-40 μM) resulted in altered cellular redox homeostasis. It also impaired mitochondrial membrane potential and respiration, disrupted mitochondrial dynamics, and activated mitophagy. Consistent with the broad reactivity of pBQ and its ability to induce oxidative stress, these findings suggest that hmtPheRS is a vulnerable mitochondrial target whose modification may contribute to mitochondrial dysfunction, together with other redox-dependent pathways. Together, this work highlights mitochondrial aminoacyl-tRNA synthetases as an underexplored class of proteins susceptible to redox-active environmental pollutants.
Low Mutagenicity of Phosphate and Sugar Modifications Used in Donor DNA for Genome Editing.
Tsai H, Kawai H, Shoji T … +2 more , Koizumi M, Kamiya H
Chem Res Toxicol · 2026 Apr · PMID 41808288 · Publisher ↗
Genome editing with combinations of an artificial nuclease and donor nucleic acid is expected to cure genetic diseases, including cancers. Chemically modified oligodeoxyribonucleotides constitute a class of donor nucleic...
Genome editing with combinations of an artificial nuclease and donor nucleic acid is expected to cure genetic diseases, including cancers. Chemically modified oligodeoxyribonucleotides constitute a class of donor nucleic acids, and phosphorothioate (P-S) and locked nucleic acid (LNA/2',4'-BNA) modifications to the donor nucleic acid have been successfully employed. However, the genotoxicities of the P-S and LNA in DNA have not been evaluated. In this study, the two modifications were separately introduced into the reporter gene, and their mutagenicities were examined in human cells. The ethyl phosphotriester (P-OEt) modification was also examined for comparison. These modified plasmid DNAs were introduced into human U2OS cells, and the replicated DNAs were electroporated into indicator bacterial cells. The mutant frequencies of these plasmids were examined by next-generation sequencing (NGS). No difference was observed in the mutant frequencies and mutation spectra, suggesting that these modifications are safe for genome editing therapies.
Correction to "Identification of Butyrylcholinesterase-Derived Small Molecule Peptides Indicative of Novichok Nerve Agent Exposures".
Kim SO, Lansing TT, Perez JW … +4 more , Boles SL, Pantazides BG, Crow BS, Blake TA
Chem Res Toxicol · 2026 Apr · PMID 41790514 · Publisher ↗
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Selective Toxicity of Nicotinic Insecticides: Responsibility of Varied Amino Acid(s) in the Ligand-Docking Pocket between Insect versus Mammalian Nicotinic Acetylcholine Receptors.
Terajima T, Uehara K, Suzuki T … +2 more , Shimomura K, Tomizawa M
Chem Res Toxicol · 2026 Mar · PMID 41785389 · Publisher ↗
Nicotinic insecticides are utilized throughout the world for crop protection and animal care. The selective toxicity of nicotinic insecticides is principally attributable to the specificity of insect versus mammalian nic...
Nicotinic insecticides are utilized throughout the world for crop protection and animal care. The selective toxicity of nicotinic insecticides is principally attributable to the specificity of insect versus mammalian nicotinic acetylcholine receptors (nAChRs). The goal of this investigation is to evaluate the responsibilities of varied amino acids in the insecticide-binding spheres (located at an interface connecting α and non-α subunits) between insect and mammalian nAChR subtypes. Insect nAChR loop C region on the α subunit has Ser or Val, which is replaced by Glu on the mammalian α4 subunit, and insect loop D on the β subunit has Arg, whereas Thr takes this position on the mammalian β2 subunit. The present study, therefore, provides six recombinant nAChRs consisting of peach-potato aphid α2 and β2 subunits (WT, V225S, V225E, T77R, V225S+T77R, and V225E+T77R) to compare the binding affinity of nicotinic insecticides in an equilibrium state. [H]imidacloprid (IMI) specifically binds to the six recombinant nAChRs with a single dissociation constant in each mutant, i.e., 3.2, 2.7, 6.0, 3.5, 2.2, or 8.2 nM for the WT, V225S, V225E, T77R, V225S+T77R, or V225E+T77R receptor, respectively. Relative to the binding affinity of the nicotinic ligand as a displacer of [H]IMI binding, an insecticide with a -nitroimine, -cyanoamidine, -cyanosulfoximine, or butenolide moiety (IMI, acetamiprid, sulfoxaflor, or flupyradifurone, respectively) fundamentally prefers nAChRs providing Ser (or Val) on the loop C region over those with Glu. Intriguingly, flupyrimin with a -trifluoroacetamide pharmacophore shows higher affinities for the nAChRs having Arg on loop D than those with Thr. These results prompt us to establish the selective molecular recognition models of nicotinic insecticides at the insect nAChR.
Inhibition of Four Anaplastic Lymphoma Kinase Inhibitors on the Activity of Human UDP-Glucuronosyltransferases and Prediction of Drug-Drug Interactions.
Yin H, Wang X, Wang Z … +5 more , Wang Z, Lv X, Jiang L, Cao J, Liu Y
Chem Res Toxicol · 2026 Mar · PMID 41755788 · Publisher ↗
Anaplastic lymphoma kinase (ALK) inhibitors have shown remarkable efficacy in targeted therapy for non-small cell lung cancer (NSCLC). However, it is worth noting that they may cause clinical drug-drug interactions (DDIs...
Anaplastic lymphoma kinase (ALK) inhibitors have shown remarkable efficacy in targeted therapy for non-small cell lung cancer (NSCLC). However, it is worth noting that they may cause clinical drug-drug interactions (DDIs) by inhibiting the activities of drug-metabolizing enzymes, thereby leading to unnecessary side effects. This study sought primarily to characterize the inhibition effects of four well-known ALK inhibitors, crizotinib, ceritinib, alectinib, and brigatinib, on human UDP-glucuronosyltransferases (UGTs) and to assess their potential DDI risks . Initial studies demonstrated that all tested ALK inhibitors exhibited a varying extent of inhibition profile on UGTs at starting test concentrations (100 or 60 μM). Subsequent kinetic experiments indicated that alectinib was a selective potent inhibitor for UGT1A4 in a competitive manner with a value of 0.07 μM. Ceritinib exhibited a potent noncompetitive inhibition against UGT1A1 and UGT1A7 with values of 1.28 and 3.08 μM, respectively, and a competitive inhibition against UGT2B7 with of 1.16 μM. Crizotinib and brigatinib demonstrated potent inhibition against UGT2B7 and UGT1A8, respectively. - extrapolation (IVIVE) suggested that all four ALK inhibitors have potential for DDIs due to their inhibitory effects on UGTs. Among them, the DDI risks of alectinib and brigatinib were much higher than the FDA standard, which may have an impact on the safety of clinical drug use.
Relationship of Urinary Mercapturic Acids of Selected Tobacco Smoke Constituents to Chronic Obstructive Pulmonary Disease in Cigarette Smokers of the Singapore Chinese Health Study.
Hecht SS, Chen M, Carmella SG … +3 more , Wang R, Koh WP, Yuan JM
Chem Res Toxicol · 2026 Mar · PMID 41730674 · Full text
α,β-Unsaturated carbonyl compounds in cigarette smoke, such as acrolein and acrylamide, are considered as possible causative factors for chronic obstructive pulmonary disease (COPD) in people who smoke cigarettes. A majo...
α,β-Unsaturated carbonyl compounds in cigarette smoke, such as acrolein and acrylamide, are considered as possible causative factors for chronic obstructive pulmonary disease (COPD) in people who smoke cigarettes. A major route of metabolism of these compounds is reaction with glutathione to form adducts that are further metabolized and excreted in the urine as mercapturic acids, which serve as useful dosimeters of exposure. In this study, we analyzed urine samples from the Singapore Chinese Health Study, a prospective epidemiology study of 63,257 men and women 45-74 years old with Chinese origin who were permanent residents or citizens of Singapore when they were enrolled in 1993-1998. A case-control study with 100 incident cases of COPD and 100 matched controls, all of whom were current cigarette smokers, was conducted within this cohort. Urine samples of the study subjects were collected during follow-up I (2000-2005) and the COPD cases were identified in follow-up II interviews (2006-2010). Urinary mercapturic acids of acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA, ), acrylamide (2-carbamoylethyl mercapturic acid, 2-CaEMA, ), acrylonitrile (2-cyanoethyl mercapturic acid, 2-CyEMA, ), crotonaldehyde (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA-1, ), methacrolein (3-hydroxy-2-methylpropyl mercapturic acid, HMPMA-2, ), and methyl vinyl ketone (3-hydroxy-3-methylpropyl mercapturic acid, HMPMA-3, ) were quantified using a LC-MS/MS method. Urinary levels of 2-CaEMA, the mercapturic acid of acrylamide, were significantly higher in cases (geometric mean 361.0 pmol/mg creatinine) than in controls (293.7 pmol/mg creatinine) and the increasing level of 2-CaEMA in tertiles was significantly associated with increased odds of developing COPD (both <0.05), after adjustment for cigarettes per day and years of cigarette smoking. For the mercapturic acid of acrylonitrile, a weak trend of increasing 2-CyEMA with the COPD status was observed ( trend = 0.033), while none of the other mercapturic acids were significantly related to the risk of COPD. These results indicate that acrylamide in cigarette smoke should be given strong consideration as a cause of COPD in people who smoke.
Naphthalene-DNA Adduct Formation in a Lung Airway Explant Model: The Role of Bioactivation and Naphthalene Metabolites.
Domanico MC, Carratt SA, Collette N … +6 more , Ubick EA, Edwards PC, Yang W, Buchholz BA, Ding X, Van Winkle LS
Chem Res Toxicol · 2026 Mar · PMID 41730518 · Full text
Humans are widely exposed to naphthalene. Once inhaled or ingested, naphthalene is metabolized by cytochrome P450 and other enzymes to form toxic metabolites known to harm lung epithelial cells. Naphthalene metabolites c...
Humans are widely exposed to naphthalene. Once inhaled or ingested, naphthalene is metabolized by cytochrome P450 and other enzymes to form toxic metabolites known to harm lung epithelial cells. Naphthalene metabolites circulate in the blood. Chronic naphthalene inhalation promotes lesions in the epithelium of the mouse lung and rat nose. Oral naphthalene exposure leads to DNA adduct formation in mouse lung, but the contributions of different enzymatic pathways and the metabolites they generate are not fully understood. This study explores the influence of naphthalene metabolites on DNA adduct formation in the lungs of two species (mice and primates). To isolate the lung response, conducting airway explants containing Club cells, a target for pulmonary naphthalene toxicity, were microdissected from live lung tissue and incubated with C-naphthalene or its metabolites: C-1,2-naphthoquinone or C-naphthalene-1,2-dihydrodiol. Explants were incubated for 1 h, then processed immediately (T1), or were transferred to clean media for the remainder of the 24 h (T24), to monitor C in DNA over time. Accelerator mass spectrometry analysis revealed the formation of DNA adducts by all three radiolabeled compounds by T24. Our results support the notion that P450 enzymes of the subfamily contribute to naphthalene-induced DNA adduct formation (approximately 4-fold reduction in male mice lacking the genes, < 0.01). The finding that naphthalene-1,2-dihydrodiol, a stable metabolite, formed DNA adducts (102-117 adducts/10 nucleotides) at 24 h following addition to the culture media validates the concern that circulating naphthalene metabolites can contribute to DNA adduct formation in the lung. DNA adducts persisted to 24 h after exposure in both mouse and primate airways and at comparable levels between species (77.8 vs 129 adducts/10 nucleotides, respectively). Together, these results support the importance of a potential genotoxic mechanism of naphthalene and its metabolites in vivo in both mice and nonhuman primates, and possibly also in humans.
Correction to "Interindividual Variability in Cytochrome P450 3A and 1A Activity Influences Sunitinib Metabolism and Bioactivation".
Burnham EA, Abouda AA, Bissada JE … +5 more , Nardone-White DT, Beers JL, Lee J, Vergne MJ, Jackson KD
Chem Res Toxicol · 2026 Mar · PMID 41725313 · Publisher ↗
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Modulation of the Toxicity of Three Red Tattoo Pigments by Artificial Aging.
Aubry L, Blanchemanche M, Breuillé L … +2 more , Rabilloud T, Douki T
Chem Res Toxicol · 2026 Mar · PMID 41723704 · Publisher ↗
Pigments used in tattoos represent a unique case of voluntary, long-term exposure to particles trapped in the skin. Evidence is accumulating that these compounds, and in particular red pigments, are associated with skin...
Pigments used in tattoos represent a unique case of voluntary, long-term exposure to particles trapped in the skin. Evidence is accumulating that these compounds, and in particular red pigments, are associated with skin disorders and possibly cutaneous cancers. In the present work, we tested the hypothesis of degradation of pigments in the dermis that would lead to the release of diffusible nanoparticles or soluble degradation products. These species could then reach the epidermis and trigger physiological responses by impacting keratinocytes. Two degradation pathways of tattoo pigments were investigated in the present work, which combined physicochemical characterization and toxicological assessment in the HaCaT human keratinocyte cell line. The first pathway was the photodegradation of pigments that we explored in a previous work on Pigment orange 13 (PO13) and extended here to Pigment red 254 (PR254) and Pigment red 122 (PR122). While PR254 was photostable, PR122 was found to release toxic photoproducts. The second studied pathway was the possible degradation in the phagolysosomes of macrophages where pigment particles are stored in the skin. We did not observe degradation upon incubation in reconstructed phagolysosomal medium but rather found that the added immunoglobulins completely inhibited the cytotoxicity of PO13, PR254, and PR122. The observation of a drastic decrease in ζ potential strongly suggested the creation of a protein corona, which led to a decrease in cellular toxicity.
Cytochrome P4501A1-Catalyzed Regioselective Activation Mechanism of PAHs and Their Nitrogen-Containing Derivatives.
Hou Z, Tong C, Zheng M … +4 more , Zhang W, Zhang Q, Wang W, Li Y
Chem Res Toxicol · 2026 Mar · PMID 41717807 · Publisher ↗
Polycyclic aromatic hydrocarbons (PAHs) and their nitrogen-containing derivatives are persistent environmental pollutants prevalent in combustion byproducts and industrial waste. Human cytochrome P4501A1 (CYP1A1), a key...
Polycyclic aromatic hydrocarbons (PAHs) and their nitrogen-containing derivatives are persistent environmental pollutants prevalent in combustion byproducts and industrial waste. Human cytochrome P4501A1 (CYP1A1), a key isoform within the cytochrome P450 enzyme family, plays a pivotal role in its oxidative metabolism. Here, a high-level quantum mechanics/molecular mechanics (QM/MM) computational approach was employed to elucidate the regioselective activation mechanisms of three representative compounds: carbazole, fluorene, and 2-aminofluorene. We show that CYP1A1 preferentially activates these compounds through competitive electrophilic addition and hydrogen abstraction pathways. We identify different regioselectivities among the three model compounds. Correlation analyses reveal that distance , , and angle are the principal determinants of regioselectivity. The calculated reactivity order is 2-aminofluorene > carbazole > fluorene. These findings provide mechanistic insight into the enzymatic transformation of PAHs and their nitrogen-containing derivatives in human cells, contributing to a more accurate assessment of their potential health risks.
Binding of -(1,3-Dimethylbutyl)--phenyl--phenylenediamine Quinone (6PPDQ) to Mitochondrial Proteins Provokes Mitochondria Dysfunction.
Wei N, Yan X, Yu M … +7 more , Li R, Xiao Z, Chen S, Yang L, Wang Q, Liu Q, Jiang G
Chem Res Toxicol · 2026 Mar · PMID 41714849 · Publisher ↗
-(1,3-Dimethylbutyl)-'-phenyl--phenylenediamine Quinone (6PPDQ) not only causes acute mortality in salmon but also induces toxicities in other living organisms. The electrophilic quinone moiety in the 6PPDQ molecular str...
-(1,3-Dimethylbutyl)-'-phenyl--phenylenediamine Quinone (6PPDQ) not only causes acute mortality in salmon but also induces toxicities in other living organisms. The electrophilic quinone moiety in the 6PPDQ molecular structure can participate in binding to the cysteine residues that ubiquitously exist in protein nucleophiles, which are responsible for its toxicities. Out of the 82 6PPDQ-bonded proteins found in the human model cell line A549 on the sulfhydryl-reactive proteomics platform, which enables the precise identification of covalent binding protein targets of a pollutant, we discovered three 6PPDQ-bonded mitochondrial proteins─NDUS6, COX5B, and ATP5PB─that are involved in mitochondrial dysfunction for the first time. They impede the function of mitochondria, as witnessed by the decreased enzymatic activities of mitochondrial respiratory chain Complexes I (27.63%) and IV (23.11%), the decreased cellular ATP content (19.94%), and the reduced mitochondrial membrane potential (3.2-fold), as well as the elevated mitochondrial ROS level (2.2-fold) under the environmentally relevant 8.9 μg/L 6PPDQ exposure compared to the controls. Our findings provide experimental evidence for elucidating 6PPDQ's toxicities at the molecular level, and the knowledge learned will enhance the public's awareness of the adverse impacts of environmental pollution on health.
Endogenous DNA Damage and Its Role in Human Disease.
Bryan EM, Lauderback C
Chem Res Toxicol · 2026 Jun · PMID 41706912 · Full text
Endogenous DNA damage from metabolism and genome dynamics drives mutation, instability, and disease. New insights from ACS Fall 2025 reveal chemical diversity, metabolic drivers, and repair limits that shape cancer risk...
Endogenous DNA damage from metabolism and genome dynamics drives mutation, instability, and disease. New insights from ACS Fall 2025 reveal chemical diversity, metabolic drivers, and repair limits that shape cancer risk and biomarker development.
Toxicological Evaluation of Ionic Liquids: QSAR Approach for Acetylcholinesterase Enzyme Inhibition.
Ebrahimpoor Gorji A, Uusi-Kyyny P, Alopaeus V
Chem Res Toxicol · 2026 Mar · PMID 41699781 · Full text
A "quantitative structure-activity relationship" (QSAR) model is developed to predict the toxicity of ionic liquids (ILs) based on the effect on the acetylcholinesterase (AChE) enzyme. A data set of 243 ILs was compiled...
A "quantitative structure-activity relationship" (QSAR) model is developed to predict the toxicity of ionic liquids (ILs) based on the effect on the acetylcholinesterase (AChE) enzyme. A data set of 243 ILs was compiled and randomly divided into training (183 ILs) and test (60 ILs) sets to enable both internal and external validations. To optimize the model performance, a breaking point analysis was performed to identify the most relevant molecular descriptors. The analysis revealed that a set of 11 COSMO-RS quantum chemical descriptors provided near-optimal predictive power, with additional descriptors offering minimal improvement. A multiple linear regression (MLR) model was developed by using these descriptors, incorporating both cationic and anionic molecular features. Internal validation using Leave-One-Out and Leave-Many-Out cross-validation ( = 0.79, = 0.78) as well as Y-scrambling confirmed the robustness of the model. External validation on the test set yielded acceptable = 0.75 and low RMSE = 0.35 values, indicating strong predictive performance. The developed model outperformed previous models, particularly by accounting for the influence of anion structures, which have been largely neglected in earlier works. The final MLR-QSAR model not only demonstrated statistical reliability but also provided mechanistic insights into the structural contributions of both ionic components to IL's toxicity. Predicted toxicity values (Log 1/EC50) for novel ILs are also presented, expanding our understanding of IL safety profiles.
A Computational Framework to Evaluate Interactions of BPA and Its Analogs with Human Liver X Receptor-Beta for Health Risk Assessment.
Pathak RK, Kumar S, Kumar V
Chem Res Toxicol · 2026 Mar · PMID 41696937 · Full text
Bisphenols are widely used in industrial applications to produce plastics and other consumer products. Among them, bisphenol A (BPA) is the most extensively studied due to its well-documented endocrine-disrupting effects...
Bisphenols are widely used in industrial applications to produce plastics and other consumer products. Among them, bisphenol A (BPA) is the most extensively studied due to its well-documented endocrine-disrupting effects and its association with various health conditions, including metabolic disorders and liver disease. Due to its known toxicity, BPA use has been restricted in many countries, leading to the emergence of several structural analogs. Recent studies have shown that BPA can interfere with normal liver metabolism by interacting with Liver X Receptor-beta (LXRβ). Although some BPA analogs have also been reported to cause toxicity, their exact effects on LXRβ remain unclear. In this study, we investigated the interaction between BPA analogs and LXRβ using molecular docking. BPA and the known LXRβ ligand G58 were used as reference compounds. The top 10 BPA analogs were further evaluated for their pharmacokinetics and pharmacodynamics properties. Molecular dynamics simulations over 100 ns were performed to study the dynamic behavior of LXRβ in complex with these analogs. Binding free energies were then calculated using the MM-PBSA method. Our results showed that several BPA analogs exhibited predicted stronger binding activities to LXRβ than BPA. Although some analogs shared similar pharmacokinetic and pharmacodynamic profiles with BPA, their stronger interaction with LXRβ raises concerns about their potential hepatotoxicity. This study employs a robust framework to predict that commonly used BPA alternatives may pose a greater potential hepatotoxic risk than the banned parent compound, highlighting the value of computational approaches in prioritizing chemicals for further experimental assessment.
Dynamic Chemistry and Toxicity of E-Cigarette Aerosols and Their Product Waste.
Woo W, Tran LN, Tian L … +2 more , Canchola A, Lin YH
Chem Res Toxicol · 2026 Mar · PMID 41678326 · Publisher ↗
The rapid rise of e-cigarette (vape) use over the past decade has raised significant public health and environmental concerns. While marketed as safer alternatives to combustible cigarettes, e-cigarettes generate complex...
The rapid rise of e-cigarette (vape) use over the past decade has raised significant public health and environmental concerns. While marketed as safer alternatives to combustible cigarettes, e-cigarettes generate complex aerosols that expose both users and nonusers to potentially harmful compounds. Vaping produces aerosols containing active ingredients (such as nicotine or cannabinoids), flavoring agents, metals, carbonyls, reactive oxygen species, and ultrafine particles that can deposit throughout the respiratory tract. Beyond direct inhalation, nonusers are also subject to secondhand and thirdhand exposure through inhalation of exhaled aerosols and contact with surface-deposited residues. These aerosols undergo dynamic physicochemical transformations, including gas-particle partitioning, oxidation, and aging processes, that may enhance their toxicity by increasing the abundance of reactive and oxygenated species. Emerging evidence suggests that passive exposure may pose disproportionate risks to vulnerable populations, such as children, adolescents, pregnant women, and the elderly. In addition, the rapid expansion of disposable e-cigarette products introduces new environmental hazards. Improper disposal of devices containing plastics, metals, lithium batteries, and residual e-liquids contributes to electronic waste, microplastic pollution, and leaching of toxicants, such as nicotine, heavy metals, and persistent organic pollutants. Despite growing research, critical gaps remain in understanding the long-term health effects of passive vaping, the environmental transformation of e-cigarette emissions, and the ecological consequences of disposable device waste. This review highlights current evidence on the composition, transformation, and toxicity of e-cigarette aerosols, examines the environmental burden of e-cigarette waste, and outlines future research priorities needed to inform regulatory policies and protect public health.
The Mechanism of Combined Exposure of Polystyrene Microplastics and Cadmium Inducing Hepatic Injury through the Modulation of PI3K/AKT/mTOR-Mediated Autophagy.
Li S, Zhang Q, Hao Y … +5 more , Liu X, Li Y, Yan L, Pan G, Sun W
Chem Res Toxicol · 2026 Mar · PMID 41677865 · Full text
Recent studies indicate that microplastics and nanoplastics (MNPs) act as key vectors for contaminants including cadmium (Cd). However, the bioavailability induced by their interaction remains controversial. Since both M...
Recent studies indicate that microplastics and nanoplastics (MNPs) act as key vectors for contaminants including cadmium (Cd). However, the bioavailability induced by their interaction remains controversial. Since both MNPs and Cd primarily accumulate in the liver after ingestion by organisms, hepatotoxicity induced by coexposure to MNPs (100 mg/kg body weight (BW)), 100 nm and 1 μm polystyrene (PS), and Cd (5 mg/kg BW) was examined in this study. Single or combined exposure models were established, and gavage was performed 5 times a week for 5 weeks. We observed that polystyrene (PS) accumulated in the mice liver. In comparison to the control group, all exposure groups exhibited significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, altered hepatic antioxidant enzyme activities, decreased P62 protein expression, and elevated Beclin-1 expression and LC3II/I ratios, indicating that PS alone or in combination with Cd disrupted liver structures and induced excessive autophagy and oxidative damage. Specifically, the 1 μm PS group induced significantly stronger hepatotoxic effects than the 100 nm PS group. In contrast, for 100 nm PS, although it was less toxic when administered alone, it significantly enhanced the Cd-induced liver injury. Notably, triple exposure to 100 nm PS, 1 μm PS, and Cd resulted in the most severe liver dysfunction, histopathological alterations, and activated cellular autophagy. Mechanistic investigations revealed that PS exposure alone or in combination with Cd triggered excessive autophagy and oxidative stress in hepatocytes by interfering with the PI3K/AKT/mTOR signaling pathway, thereby mediating liver injury. This study innovatively demonstrates that coexposure to different-sized PS particles and Cd can lead to complex liver injury patterns while particle size influences their combined hepatotoxicity with Cd.
Insights into the Biochemical and Immune Mechanisms in Drug-Induced Liver Injury Pathogenesis.
Saville E, Wells G, Farrell L … +2 more , Naisbitt DJ, Meng X
Chem Res Toxicol · 2026 Mar · PMID 41677797 · Full text
DILI is the leading cause of drug failure in clinical trials and withdrawal from the market. Certain intrinsic mechanisms of injury have been characterized such as the direct cytotoxicity exerted by NAPQI, a reactive met...
DILI is the leading cause of drug failure in clinical trials and withdrawal from the market. Certain intrinsic mechanisms of injury have been characterized such as the direct cytotoxicity exerted by NAPQI, a reactive metabolite of acetaminophen. However, presentation of DILI is highly heterogeneous with several idiosyncratic presentations being observed in patients. Such manifestations are often linked to aberrant immune activation although the biochemical mechanisms directing such responses currently evade complete understanding. This review consolidates current literature findings into potential mechanisms of immune-mediated DILI as well as risk factors which may polarize both the liver itself and certain individuals toward a drug-reactive phenotype. Current theories implicate neoantigen formation as a result of the generation of drug-protein adducts by both parent drugs and reactive metabolites. Responses to such adducts can be restricted to the presence of certain HLA alleles though these associations are identified through epidemiological means rather than mechanistic investigations. Further, susceptibility to DILI can be linked to nuance in the T-cell responses to HLA displayed antigens where basal levels of effector molecules and inflammation as well as the presence of liver resident immune cells, such as natural killer T-cells, can augment drug-specific immune responses.
Size-Segregated Incense Aerosols Drive ROS-Mitochondrial Dysfunction and Programmed Cell Death Across Human Cell Types.
Tseng YE, Teng MC, Huang YS … +5 more , Selvam P, Pan CH, Chang YP, Wang CC, Fan HF
Chem Res Toxicol · 2026 Mar · PMID 41661689 · Full text
Incense burning is a major indoor source of fine and ultrafine particulate matter (PM), yet the size-chemistry determinants of its cellular toxicity remain underdefined. We characterized aerosols from three commonly used...
Incense burning is a major indoor source of fine and ultrafine particulate matter (PM), yet the size-chemistry determinants of its cellular toxicity remain underdefined. We characterized aerosols from three commonly used incense types using Aerodynamics Particle Sizer (APS)/Scanning Mobility Particle Sizer (SMPS) for sizing, Micro-Orifice Uniform Deposit Impactor (MOUDI) for size segregation, and water-soluble phase (WP) or organic-phase (OP) extraction to generate incense aerosol extracts (IAEs). Across A549, HEK293T, and SH-SY5Y cells, OP-IAEs from fraction III (0.18-0.10 μm) and IV (<0.10 μm) exhibited the strongest cytotoxicity, oxidative responses, and mitochondrial dysfunction. Type A incense (sandalwood-dominant) IAEs consistently showed the highest potency among the investigated incenses. Mechanistic assays revealed that ultrafine OP-IAEs, elevated intracellular HO, decreased mitochondrial membrane potential (MMP), depleted ATP, and activated apoptosis (caspase-3), pyroptosis (caspase-1), and autophagy-associated pathways. Moreover, ≥80% of all emitted particles were <0.18 μm and were disproportionately enriched in OP constituents across incense types. Collectively, these results identify ultrafine, lipophilic aerosol fractions as key drivers of oxidative-mitochondrial injury and programmed cell death, establishing a size- and phase-resolved framework for assessing incense-related health risks and for guiding exposure mitigation in incense-rich indoor environments.
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