Chem. Res. Toxicol. [JOURNAL]
Sun
200 papers
Nitrogen Mustard Disrupts Bioenergetics and Activates Oxidative Stress-Induced Cell Death Pathways in Human Keratinocytes.
Jan YH, Michniak-Kohn B, Joseph LB … +2 more , Laskin DL, Laskin JD
Chem Res Toxicol · 2026 Jun · PMID 42205054 · Full text
Nitrogen mustard (HN2) is a highly reactive bifunctional alkylating agent that causes severe skin injury. To define its impact on keratinocyte bioenergetics and stress responses, we examined mitochondrial function, metab...
Nitrogen mustard (HN2) is a highly reactive bifunctional alkylating agent that causes severe skin injury. To define its impact on keratinocyte bioenergetics and stress responses, we examined mitochondrial function, metabolism, and cell death signaling in human HaCaT cells. Seahorse analysis showed that HN2 caused time- and concentration-dependent suppression of oxidative phosphorylation, including reductions in basal, adenosine 5'-triphosphate-linked, and maximal oxygen consumption. Glycolytic activity was similarly impaired, with decreased extracellular acidification, reduced glucose-stimulated glycolysis, and loss of glycolytic capacity and reserve, indicating broad metabolic dysfunction. HN2-induced bioenergetic impairment triggered rapid nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulation of antioxidant and mitochondrial regulatory genes (HO-1, NQO1, GSTA4, and PGC1α). In parallel, HN2 activated multiple programmed cell death pathways, including apoptosis, autophagy, and ferroptosis, as evidenced by corresponding alterations in Bax, Bcl-xL, LC3-II, SQSTM1/p62, caspase-2, caspase-9, GPx4, TFRC, and ACSL4. Cell cycle analysis identified cells in G2/M as particularly susceptible to HN2, which exhibited enhanced apoptotic signaling. -acetylcysteine attenuated Nrf2 activation, preserved mitochondrial and glycolytic function, and reduced activation of cell death pathways, demonstrating a central role for oxidative and electrophilic stress in HN2 toxicity. These findings reveal a novel mechanism by which HN2 disrupts keratinocyte bioenergetics to drive stress-dependent cell death and highlight antioxidant intervention as a potential strategy to mitigate HN2-induced skin injury.
A Benchmark Evaluation of Chemical Structure Extraction from Patents: Insights and Challenges in Chemical Structure Recognition.
Tariq F, Ylipää E, Jiang L … +2 more , Ryden P, Andersson PL
Chem Res Toxicol · 2026 May · PMID 42186716 · Publisher ↗
Early warning systems (EWSs) are currently being developed by various authorities aiming at identifying potentially hazardous chemicals before they become a threat to the environment and human health. In this context, pa...
Early warning systems (EWSs) are currently being developed by various authorities aiming at identifying potentially hazardous chemicals before they become a threat to the environment and human health. In this context, patents provide an excellent data source for exploring novel chemistry or the use of chemicals in materials and products. However, analysis of patents is challenging, including unraveling molecular structures presented as graphics depicting various elements, functional groups, and molecular bonds. Our study aims to improve EWS using automated artificial intelligence-based molecular structure recognition methods for encoding these for further hazard analysis. Current structure extraction tools are primarily trained on chemical structures collected from publicly available data sets, and the application of these tools to patent-specific chemical data has received little attention. This paper presents a field study utilizing the three tools Decimer, Molscribe, and Mathpix and assesses their performance in recognizing chemical structures in patents. Two data sets were compiled and curated including (1) diverse organic chemicals and (2) per- and polyfluoroalkyl substances (PFAS). It was revealed that these tools perform well on simpler molecular structures, whereas they struggle with more complex structural features, including repetitive units, cross-bonding, and Markush structures. Furthermore, it was discovered that these tools are extremely sensitive to image artifacts such as noise from lines and dots or distortions. Overcoming these challenges will be critical before implementation in automated EWS and thereby enable screening of patents for rapid and effective identification of potentially hazardous emerging chemicals.
Physicochemical Characterization and Metabolites Identification of the Synthetic Cannabinoid MDMB-5'Br-PINACA Using and Approaches.
Godoi AB, Antunes NJ, da Silva JCC … +3 more , Cordeiro G, Castro TFD, Costa JL
Chem Res Toxicol · 2026 Jun · PMID 42177656 · Full text
MDMB-5'Br-PINACA is a recently identified brominated synthetic cannabinoid that was detected in herbal materials seized in Brazil in 2025, raising concerns regarding further potential intoxication cases. In this sense, t...
MDMB-5'Br-PINACA is a recently identified brominated synthetic cannabinoid that was detected in herbal materials seized in Brazil in 2025, raising concerns regarding further potential intoxication cases. In this sense, the evaluation of physicochemical properties and metabolic fate may improve its analytical detectability. Therefore, an integrated and approach was employed to investigate the physicochemical properties and phase I metabolism of MDMB-5'Br-PINACA. Physicochemical parameters and predicted metabolic pathways were first evaluated using BioTransformer 3.0 and XenoSite, providing complementary insights into likely sites of metabolism. metabolism was subsequently assessed using pooled human liver microsomes associated with liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) analysis. MS-based molecular networking (MN) was applied as an exploratory and confirmatory strategy to guide metabolite annotation by clustering structurally related features and prioritizing candidates linked to MDMB-5'Br-PINACA. A total of twenty-seven metabolites were level 2 annotated, encompassing aliphatic and aromatic hydroxylation, sequential alcohol oxidation to ketone, aldehyde, and carboxylic acid derivatives, ester hydrolysis, intramolecular lactone formation, and -dealkylation with loss of the pentyl side chain. Hydroxylations of the pentyl chain and -butyl moiety and secondary oxidative reactions emerged as the predominant pathways under the experimental conditions, in agreement with predictions. However, lactone formation was exclusively revealed by experiments, demonstrating limitations of current prediction approaches. The integration of computational prediction, LC-HRMS, and MN substantially enhanced metabolite coverage and confidence of structural assignment. These findings provide a detailed metabolic map of MDMB-5'Br-PINACA and underscore the value of combining and approaches to improve metabolite identification, supporting forensic and clinical investigations of intoxication involving this synthetic cannabinoid.
Sensitive Quantification of the Ethylene Oxide Hemoglobin Adduct -(2-Hydroxyethyl)-l-valine from Minimal Blood Volumes.
Liu CW, Feng J, Peng J … +7 more , Zhao H, Wang X, Gollapudi BB, Li AA, Bus JS, Kirman C, Lu K
Chem Res Toxicol · 2026 Jun · PMID 42175963 · Publisher ↗
Ethylene oxide (EtO) assessment relies on detecting the hemoglobin adduct -(2-hydroxyethyl)-l-valine (HE-V). However, current methods require large blood volumes, limiting small-animal exposure studies and reliable detec...
Ethylene oxide (EtO) assessment relies on detecting the hemoglobin adduct -(2-hydroxyethyl)-l-valine (HE-V). However, current methods require large blood volumes, limiting small-animal exposure studies and reliable detection of endogenous background levels of HE-V. We optimized a highly sensitive analytical workflow including hemoglobin extraction from microliter-scale blood samples, HE-V purification, and targeted LC-MS/MS quantitative analysis. This workflow reliably quantifies endogenous HE-V levels of unexposed mice from only 50 μg of purified hemoglobin (10 μL of blood) and is demonstrated to detect significant HE-V increases at EtO exposures as low as 0.05 ppm. Our platform enables practical EtO biomonitoring in volume-constrained experimental and environmental settings.
The Role of HGF/c-Met/PI3K/AKT Pathway Regulated by α7-nAChR/β2-AR in Nicotine-Promoted Malignant Progression of Nonsmall Cell Lung Cancer A549 Cells.
Li Z, Xie B, Liu X … +5 more , He Z, Zhang Z, Zhou J, Zhou T, Wang H
Chem Res Toxicol · 2026 Jun · PMID 42160188 · Publisher ↗
As the most frequently occurring cancer worldwide, lung cancer is notoriously diagnosed at advanced stages, resulting in high mortality rates. The primary factor underlying this persistent global health burden remains to...
As the most frequently occurring cancer worldwide, lung cancer is notoriously diagnosed at advanced stages, resulting in high mortality rates. The primary factor underlying this persistent global health burden remains tobacco consumption. Nicotine, a key component of cigarette smoke, is one of the major contributing factors to the development of lung cancer, but the molecular mechanisms remain incompletely elucidated. α7-nAChR, β2-AR, and HGF/c-Met are known to contribute to lung cancer development, respectively. However, the specific signaling cascade through which they interact in nicotine-induced malignancy is unclear. In this study, using CCK-8 assays across a range of concentrations (0-5 μM), we determined that 1 μM nicotine treatment for 48 h optimally enhances A549 cell proliferation, establishing this condition for subsequent experiments. This study uncovers nicotine's role in driving malignant behaviors including proliferation, migration, and invasion in nonsmall cell lung cancer A549 cells. Notably, nicotine potently stimulated migration and invasion, accompanied by upregulation of Cyclin D1 and MMP-2, and downregulation of BAX, BAD, and Caspase-3. Mechanistically, nicotine induced synergistic engagement of α7-nAChR and β2-AR, leading to activation of the HGF/c-Met/PI3K/AKT axis and enhancing the secretion of both HGF and MMP-2. Importantly, we reveal a previously unrecognized bidirectional regulatory loop between α7-nAChR and β2-AR that functionally converges on the HGF/c-Met axis, which acts as a critical signaling hub to drive the downstream PI3K/AKT pathway and facilitate tumor progression. Our findings provide the first evidence of a coordinated α7-nAChR/β2-AR interface regulating HGF/c-Met signaling that orchestrates both intracellular signaling and extracellular secretory programs in nicotine-promoted lung cancer progression. This offers innovative insights for identifying potential antitumor therapeutic targets and presents novel perspectives for the prevention and clinical management of lung cancer, particularly in smokers with nonsmall cell lung cancer.
QSAR in the AI Era: Reflections for Advancing Chemical Safety Assessment.
Kovarich S, Gissi A, Browne P … +6 more , Fuart-Gatnik M, Moncho S, Mostrag-Szlichtyng A, Myatt G, Pavan M, Bassan A
Chem Res Toxicol · 2026 Jun · PMID 42159267 · Publisher ↗
Quantitative Structure-Activity Relationship (QSAR) models are increasingly discussed in the broader context of artificial intelligence (AI). Indeed, they formally meet certain regulatory definitions of AI as data-driven...
Quantitative Structure-Activity Relationship (QSAR) models are increasingly discussed in the broader context of artificial intelligence (AI). Indeed, they formally meet certain regulatory definitions of AI as data-driven inference systems. However, in the context of chemical safety assessment, QSARs represent a distinct, domain-specific class of models shaped by decades of dialogue between computational toxicology and regulatory science. This work summarizes roundtable discussions from the 21st International workshop on QSAR in Environmental and Health Sciences (QSAR2025) held in Milan in June 2025, addressing structural similarity and local performance assessment, model selection, integration of multiple predictions, and challenges posed by black-box models that demand careful consideration of the balance between predictive performance and explainability. These discussions highlight the experience of integrating QSAR approaches into regulatory frameworks, supported by internationally harmonized OECD principles, standardized reporting formats (QMRF, QPRF, QRRF), and the OECD QSAR Assessment Framework (QAF). The QAF provides a structured basis for evaluating the reliability and regulatory relevance of QSAR predictions through transparent documentation, consideration of applicability domain, and expert-driven interpretation. The discussion is then broadened to examine how modern AI, particularly Large Language Models, may support toxicological risk assessment beyond QSAR modeling itself. Building on both the conference insights and this extended analysis, this work reflects on how principles established through decades of QSAR development and regulatory integration (including considerations on data quality, applicability domain, uncertainty, and expert judgment) may inform the governance of emerging AI applications in chemical safety assessment.
AB-Free Kava and Dihydromethysticin Inhibit Chronic Hexavalent Chromium Exposure-Induced Cell Malignant Transformation through Down-Regulating RNA Splicing Factor SNRPA1 Expression.
Li E, Bian T, Finkelberrg M … +6 more , Liu Z, Bi Z, Carlson D, Xing C, Yang C, Wang Z
Chem Res Toxicol · 2026 Jun · PMID 42135982 · Full text
Hexavalent chromium [Cr(VI)] is a common occupational and environmental toxicant and an established carcinogen causing lung cancer in humans. The mechanism through which Cr(VI) exposure causes lung cancer remains to be c...
Hexavalent chromium [Cr(VI)] is a common occupational and environmental toxicant and an established carcinogen causing lung cancer in humans. The mechanism through which Cr(VI) exposure causes lung cancer remains to be clearly defined. No effective strategies are currently available to prevent lung cancer resulting from chronic Cr(VI) exposure. Kava is traditionally consumed by South Pacific Islanders to reduce anxiety. Epidemiology and experimental studies suggest that kava has anticancer potential and may be used as a preventive agent to reduce the risk of various cancers including lung cancer. The purpose of this study is to determine the effect of AB-Free Kava and its active component dihydromethysticin (DHM) on chronic Cr(VI) exposure-induced cell malignant transformation and the underlying mechanism. The study was performed by pretreating immortalized but nontumorigenic human bronchial epithelial cells (BEAS-2B) with AB-Free Kava (25 μg/mL) or DHM (10 μM) followed by exposing cells to 0.25 μM Cr(VI) (KCrO) for 20 weeks to determine the impact of AB-Free Kava or DHM on chronic Cr(VI) exposure-induced cell transformation, cancer stem cell (CSC)-like properties, and tumorigenesis. The extent of cell transformation was evaluated by soft agar colony formation assays, Western blot analysis of cancer stemness marker expression levels, and nude mouse xenograft tumorigenesis assays. It was found that AB-Free Kava or DHM pretreatment significantly reduces Cr(VI)-induced cell transformation, CSC-like properties, and tumorigenesis. Mechanistically, it was determined that AB-Free Kava or DHM impairs Cr(VI)-induced cell transformation by down-regulating RNA splicing factor small nuclear ribonucleoprotein polypeptide A' (SNRPA1) expression to reduce the protooncogene, cancer stemness marker, and driver c-MYC expression. It was further determined that DHM and SNRPA1 regulate c-MYC expression through affecting c-MYC protein stability. It was concluded that AB-Free Kava or DHM inhibits Cr(VI)-induced cell transformation, CSC-like properties, and tumorigenesis by down-regulating RNA splicing factor SNRPA1 expression to increase the protooncogene c-MYC protein degradation.
Few-Shot Prediction of Toxicity of Ionic Liquids Supported by Attentive Model-Agnostic Meta-Learning.
Baran K, Derron T, Eichenlaub J … +1 more , Kloskowski A
Chem Res Toxicol · 2026 Jun · PMID 42135212 · Full text
Prediction of chemical compounds' toxicity enables efficient and rapid screening at the cost of utilizing experimental data as a foundation for artificial intelligence (AI) models. Given the constraints of limited data a...
Prediction of chemical compounds' toxicity enables efficient and rapid screening at the cost of utilizing experimental data as a foundation for artificial intelligence (AI) models. Given the constraints of limited data availability, few-shot learning techniques, like those based on meta-learning models, may be beneficial. In this study, the ionic liquid (IL) toxicity dataset was employed. Initially, models underwent pretraining on data from related domains before being adapted in a few-shot manner, adhering to the Model-Agnostic Meta-Learning (MAML) algorithm. The MAML algorithm utilized a neural network to predict toxicity based on the descriptors of the molecular structure. MAML enhanced the accuracy of IL toxicity prediction even with limited data, particularly when similar tasks were provided during meta-training, such as between and . Its effectiveness, however, is dependent on the diversity of the chemical space of the task for which adaptation is performed. As the final part of the study, a new version of MAML (i.e., attentive MAML) was proposed to address the limitations of the basic method. In our Att-MAML modified version of the algorithm, a part of the neural network was dedicated to adapting the importance of latent features with respect to the given test task. This approach allowed a significant reduction in standard deviation and overall improvement of the performance metrics in the low-data regime. This work advances the toxicity prediction in extremely low-data regimes beyond the current state of the art. Incorporation of attentive latent feature scaling (with Att-MAML) handles the limitations inherent to extremely low-data regimes. This novel method allows reductions in the standard deviation of metric values even while adapting on sets as small as four records.
Di-2-ethylhexyl Phthalate Reprograms Epithelial-Mesenchymal Transition and Lenvatinib Responsiveness in Hepatoma Cells via SPAG4-Dependent MAPK/ERK Signaling.
Yang Q, Yu L, Tang R … +12 more , Peng Y, Huang T, Chen H, Zhu W, Yuan Q, Wang W, Jiang X, Ma Z, Yuan L, Wang S, Wang X, Wang G
Chem Res Toxicol · 2026 Jun · PMID 42126986 · Publisher ↗
Environmental chemical exposure has emerged as an important modulator of cancer progression and therapeutic outcomes. Di-2-ethylhexyl phthalate (DEHP), a ubiquitous environmental plasticizer, has been widely recognized f...
Environmental chemical exposure has emerged as an important modulator of cancer progression and therapeutic outcomes. Di-2-ethylhexyl phthalate (DEHP), a ubiquitous environmental plasticizer, has been widely recognized for its endocrine-disrupting effects; however, its impact on intracellular signaling reprogramming and cancer drug responsiveness remains incompletely understood. In this investigation, we aimed to elucidate the toxicological mechanisms by which DEHP alters cellular phenotypes and therapeutic sensitivity in hepatocellular carcinoma (HCC) cells. We demonstrate that DEHP exposure does not primarily promote cancer cell proliferation but instead induces epithelial-mesenchymal transition (EMT), leading to enhanced migratory and invasive capacities and reduced responsiveness to the tyrosine kinase inhibitor lenvatinib. Notably, integrative bioinformatic analyses combined with functional validation identified sperm-associated antigen 4 (SPAG4) as a key DEHP-responsive regulator mediating toxicant-induced cellular reprogramming. Mechanistic studies revealed that DEHP-induced upregulation of SPAG4 activates the MAPK/ERK signaling pathway, thereby driving EMT and attenuating lenvatinib responsiveness. Genetic silencing of SPAG4 or pharmacological inhibition of MAPK/ERK signaling effectively reversed DEHP-induced EMT and drug resistance. In conclusion, we highlight DEHP as a signaling-disrupting environmental toxicant that reprograms cancer cell states and modulates therapeutic responses through a SPAG4-dependent MAPK/ERK pathway. These findings provide mechanistic insight into how environmental chemical exposure can reshape intracellular signaling networks and influence cancer treatment outcomes, underscoring a previously underappreciated aspect of chemical toxicology.
Gold Nanoparticles Size Dependence on DNA Damage under X-rays.
Huwaidi A, Abdo RA, Lessard F … +3 more , Guérin B, Sanche L, Wagner JR
Chem Res Toxicol · 2026 Jun · PMID 42126127 · Publisher ↗
Combining gold nanoparticles (AuNPs) with 10-100 keV X-rays has shown considerable potential for radiotherapy. The uptake of AuNPs in cancer tissues is influenced by their size, with smaller sizes exhibiting enhanced pen...
Combining gold nanoparticles (AuNPs) with 10-100 keV X-rays has shown considerable potential for radiotherapy. The uptake of AuNPs in cancer tissues is influenced by their size, with smaller sizes exhibiting enhanced penetration capabilities into deeper layers of cancer tissue compared to larger AuNPs. In this study, we examine the effect of nanoparticle (NP) size with respect to the formation of various types of DNA damage upon X-ray exposure of dried AuNP-oligo-DNA mixtures. The type and yield of DNA damage is measured using LC-MS/MS. The most important type of damage involves the release of nucleobases (Cyt > Ade ≈ Thy > Gua), which accounts for 82% of the total measured damage. The remaining 18% includes reduction products of pyrimidines (5,6-dihydrothymidine and 5,6-dihydro-2'-deoxyuridine), oxidative products (8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxoG) and 5-hydroxymethyl-2'-deoxyuridine (5hmU)), and novel electron-specific products, including eight 2',3'- and 2',5'-dideoxynucleosides (ddNs). The presence of AuNP in close contact with DNA results in a shift of radiation-induced damage toward that mediated by electrons. Moreover, the yield of damage depends on the size of the NP, with much more damage (7-10-fold) observed for NPs with a small diameter (5 nm) compared to those with a large diameter (110 nm). The dependence of DNA damage with NP size is partly attributed to the energy of electrons emitted from the surface of AuNPs and the distance required to reach available sites of electron attachment. This study contributes to elucidate the mechanisms of AuNP radiosensitization and should aid in designing optimal NP sizes for radiotherapy.
Sex-Specific Modulation of Drug Metabolizing Enzymes, Transporters, and Pro-Inflammatory Cytokines by Arsenic Trioxide in C57Bl/6 Mice.
El-Mahrouk SR, El-Kadi AOS
Chem Res Toxicol · 2026 Jun · PMID 42099285 · Publisher ↗
Arsenic trioxide (ATO) is both a life-saving therapy for acute promyelocytic leukemia and a systemic toxicant whose hepatic effects remain incompletely defined. This study examined how a single clinically relevant ATO do...
Arsenic trioxide (ATO) is both a life-saving therapy for acute promyelocytic leukemia and a systemic toxicant whose hepatic effects remain incompletely defined. This study examined how a single clinically relevant ATO dose (8 mg/kg, i.p.) acutely remodels hepatic xenobiotic-metabolizing enzymes, arsenic transporters, and pro-inflammatory mediators in male and female C57Bl/6 mice. Mice were treated with ATO or saline and livers were collected at 6 and 24 h for integrated mRNA and protein profiling of major Cytochrome P450 (CYP) families, aquaglyceroporins (), ATP-binding cassette () transporters, and cytokines (). ATO induced highly sex-, time-, and isoform-specific reprogramming. Females exhibited a wider and earlier decline in several female-predominant CYP2, CYP3, and CYP4 isoforms, including a more pronounced reduction in hepatic CYP3A, CYP4A, and CYP4F protein abundance. In contrast, males showed mainly transcriptional induction of specific genes (, , , and ), accompanied by comparatively modest decreases in overall CYP protein levels. and transporters were differentially modulated, with males displaying early, relatively monotonic upregulation of efflux systems, while females exhibited higher basal expression but more complex, biphasic regulation of both influx () and efflux pathways. These transcriptional changes paralleled a transient inflammatory response, including early induction and female-specific elevation. Collectively, these findings highlight sex-dependent modulation of hepatic ATO handling and drug metabolizing capacity, with important implications for risk assessment and individualized ATO containing regimens.
Drug-Induced Liver Injury: Mitochondrial Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.
Verma BK, Bhalgama D, Thakur P … +1 more , Banerjee D
Chem Res Toxicol · 2026 May · PMID 42096259 · Publisher ↗
Drug-induced liver injury (DILI) remains a major challenge in drug development and clinical pharmacology, contributing significantly to late-stage attrition and regulatory failure. Growing experimental evidence implicate...
Drug-induced liver injury (DILI) remains a major challenge in drug development and clinical pharmacology, contributing significantly to late-stage attrition and regulatory failure. Growing experimental evidence implicates mitochondrial dysfunction as a central mechanism underlying chemically induced hepatotoxicity. This review provides an integrated analysis of mitochondrial pathways involved in DILI, including disruption of oxidative phosphorylation, inhibition of fatty acid β-oxidation, mitochondrial permeability transition, and mitochondrial DNA damage. We synthesize data from in vitro systems, animal models, and human studies to illustrate how diverse xenobiotics converge on mitochondrial targets to trigger hepatocellular injury. Emerging mitochondrial biomarkers, such as glutamate dehydrogenase, circulating mitochondrial DNA, and microRNAs, are discussed in the context of mechanistic relevance and translational utility. In addition, advances in experimental models including humanized mice and liver organoids are evaluated for their predictive value in drug safety assessment. The review further highlights mitochondria-centered intervention strategies as mechanistic tools to validate injury pathways and inform pharmacological risk mitigation. By integrating mitochondrial biology with applied toxicology, this review provides a mechanistic framework to improve early detection, mechanistic understanding, and prevention of drug-induced liver injury during drug development.
Frequent Detection of Abasic Sites and -Methyl-2'-Deoxyguanosine and Absence of Substituted Aromatic DNA Adducts in Colorectal Tissue of Smokers and Meat-Eaters with Colorectal Cancer.
Brandt K, Konorev D, Bellamri M … +8 more , Yao L, Villalta PW, Burnett T, Abe J, White K, Wilkens L, Le Marchand L, Turesky RJ
Chem Res Toxicol · 2026 May · PMID 42095780 · Publisher ↗
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Epidemiological studies have linked the consumption of processed and cooked red meat, as well as tobacco smoking, to increased CRC risk. Processed...
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Epidemiological studies have linked the consumption of processed and cooked red meat, as well as tobacco smoking, to increased CRC risk. Processed meats cured with nitrite contain genotoxic -nitroso compounds (NOCs), and the consumption of both processed and unprocessed red meats can lead to endogenous NOC formation. High-temperature cooking of processed and unprocessed red meats produces genotoxic heterocyclic aromatic amines (HAAs) and polycyclic aromatic hydrocarbons (PAHs), many of which also arise in tobacco smoke. These chemicals form pro-mutagenic DNA adducts, some of which destabilize glycosidic bonds, leading to apurinic/apyrimidinic (AP) abasic sites that are potentially mutagenic and cytotoxic if unrepaired. These DNA lesions may contribute to CRC development; however, the chemicals responsible for the damage and the DNA adduct structures that lead to mutations in the colorectum remain uncertain. We applied nanoflow liquid chromatography-Orbitrap mass spectrometry to profile DNA adducts in nontumorous colorectal tissue of CRC patients. AP sites and the NOC-related DNA adduct -methyl-2'-deoxyguanosine (-MedG) were frequently detected. AP sites, but not -MedG, were significantly elevated in current smokers compared to former and never smokers. In contrast, the NOC related -carboxymethyl-2'-deoxyguanosine (-CMedG) adduct, and DNA adducts associated with high-temperature meat cooking, including several common HAAs and benzo[]pyrene, were not detected in colorectal tissue of current, former, or never smokers, nor among meat-eaters. The frequent detection of AP sites and their co-occurrence with -MedG demonstrates that alkylating agents contribute to colorectal DNA damage and may play an important role in CRC risk.
In Silico ApoE Isoform Interactions with Methylmercury (MeHg) and In Vivo MeHg Intoxication Effects on Epididymal White Fat Tissue and Liver Function in Young ApoE Knockout Mice.
Lopes SC, Monteiro VKF, Leocádio PCL … +14 more , Rodrigues MVF, Maciel d'Auriol Souza M, de Paiva MJN, Zandonadi F, Sussulini A, Raposo R, da Silva FL, Zampieri D, Coppi AA, Martins AMA, Alvarez-Leite J, Lopes da Silva ÁR, Monteiro NKV, Oriá RB
Chem Res Toxicol · 2026 May · PMID 42085539 · Full text
MeHg neurotoxicity is well recognized; however, less is known about its effects on metabolism. Here, we integrated in silico and in vivo approaches to investigate MeHg interactions with apolipoprotein E (ApoE) and their...
MeHg neurotoxicity is well recognized; however, less is known about its effects on metabolism. Here, we integrated in silico and in vivo approaches to investigate MeHg interactions with apolipoprotein E (ApoE) and their metabolic consequences. Computational analyses revealed that human ApoE2 and ApoE3 isoforms establish stable Hg-S bonds with MeHg, while ApoE4 showed no stable binding, suggesting reduced mercury retention capacity. In addition, we evaluated the impact of MeHg intoxication (20 mg/L in drinking water for 20 days) on the liver and epididymal white fat (EWF) in young ApoE knockout (ko) and wild-type mice. Hg levels in hair, liver, and EWF were measured. We also evaluated body weight gain, plasma triglycerides, total cholesterol, and liver injury by assessing steatosis score, SOD, TBAR, AST, and ALT activities. To evaluate EWF, we analyzed adipocyte diameter, plasma leptin levels, and metabolomics. Hg levels were markedly higher among intoxicated mice. ApoE ko mice had higher Hg concentrations in hair but lower levels in liver and EWF than wild-type controls. Among wild-type mice, MeHg compromised weight gain and increased liver TBAR compared to nonchallenged controls. Among nonintoxicated mice, ApoE deficiency significantly increased triglycerides, cholesterol, and liver transaminases, accompanied by reduced EWF wet weight, SOD activity, and leptin levels. MeHg, together with ApoE deficiency, elevated cholesterol, triglycerides, hepatic transaminases, and TBARS. We found distinct EWF metabolite activity in different scenarios of ApoE deficiency and MeHg intoxication, highlighting increased cardiovascular risk when both challenges occur. Further studies are needed to clarify these mechanisms and identify key nutritional interventions.
Vegetable Activated Charcoal for Human Consumption Reduces Selected PFAS Levels in a Bile Secretion Model: Cues on Its Possible Clinical Use.
Bonetto A, De Toni L, Di Nisio A … +4 more , Pagnin L, Ferlin A, Marcomini A, Foresta C
Chem Res Toxicol · 2026 May · PMID 42083736 · Full text
Perfluoroalkyl substances (PFAS) are pollutants with relevant accumulation in humans, and the enterohepatic circulation of PFAS secreted in bile sustains their persistence. A significant increase in fecal excretion has b...
Perfluoroalkyl substances (PFAS) are pollutants with relevant accumulation in humans, and the enterohepatic circulation of PFAS secreted in bile sustains their persistence. A significant increase in fecal excretion has been experimentally assessed with the use of oral adsorbents with negligible gut absorption. Here, we evaluated the use of activated charcoal (AC) for human consumption, as sorption material for a panel of PFAS, such as, perfluoro-butanoic acid (PFBA), perfluoro-butanesulfonic acid (PFBS), perfluoro-hexanoic acid (PFHxA), perfluoro-hexanesulfonic acid (PFHxS), perfluoro-octanoic acid (PFOA), and perfluoro-octanesulfonic acid (PFOS), in an experimental simulated bile juice (SBJ). The aim was to obtain preliminary data for possible clinical applications to reduce PFAS blood levels in humans. PFAS concentrations in experimental samples were quantified by liquid chromatography-mass spectrometry. In kinetic tests, equimolar solutions of single PFAS in SBJ were incubated with AC at 37 °C up to 120 min, and the time-dependent reduction of PFAS concentration was monitored. In thermodynamic tests, PFAS solutions in SBJ were incubated at increasing concentrations with AC for 24 h at 37 °C and the concentrations at equilibrium evaluated. Results were finally fitted with available models in order to characterize the PFAS interaction with AC. All PFAS showed more than 80% sorption on activated charcoal from simulated bile juice within 120 min. This suggests rapid and nearly complete removal. Modeling analysis indicated that the pseudo-first-order kinetic model best described short-chain PFAS, while PFOS and PFOA fitted better with the Elovich model. Thermodynamic analysis showed a general fitting with the Freundlich model, presumptive of a heterogeneous binding model. PFOS binding was concentration-dependent and was better described by the Sips model. These data are suggestive of a potential noninvasive intervention strategy to increase fecal PFAS excretion through the dietary use of AC, in order to mitigate health issues associated with PFAS exposure.
Glycerolphosphorylethanolamine and Several Other Biochemical Amines Are Targets of Furan's Reactive Metabolite in Rodents.
Vevang KR, Trinh A, Raj M … +4 more , Ocasio-Ramirez C, Zhao Y, von Weymarn LB, Peterson LA
Chem Res Toxicol · 2026 May · PMID 42083458 · Full text
Furan, a potent toxicant and liver carcinogen, is present in tobacco smoke and may contribute to smoking-related adverse health effects. Furan requires metabolic activation to its reactive metabolite, cis-2-butene-1,4-di...
Furan, a potent toxicant and liver carcinogen, is present in tobacco smoke and may contribute to smoking-related adverse health effects. Furan requires metabolic activation to its reactive metabolite, cis-2-butene-1,4-dial (BDA), to exert its toxic effect. Chemical characterization of hepatocellular and urinary metabolites indicates that the reaction of BDA with glutathione (GSH) generates a reactive GSH conjugate, 2-(-glutathionyl)succinaldehyde (GSH-BDA), that targets protein lysine residues and polyamines to form GSH-BDA-amine cross-links. In this report, five additional amine targets of BDA following its reaction with GSH are identified as GSH-BDA-amine cross-links in furan-exposed rodent hepatocytes. They are ethanolamine, glutamic acid, citrulline, glycerolphosphorylethanolamine (GPE), and taurine. Furthermore, the corresponding mercapturic acid metabolites and their sulfoxides were identified in urine from furan-treated rats and mice, indicating that these amines are targets in vivo. Of particular interest is the modification of GPE, which is an important component of lipids. Since other reactive dialdehydes target GPE and the result of its alkylation is linked to toxicity, lipid alkylation by furan metabolites may play an important role in the toxicity associated with furan exposure. This study generates important new possible biomarkers of effect that can be used in human epidemiological studies to assess furan's human health effects.
An Integrated AIVIVE-PBPK-QIVIVE Framework with HTTK Validation for Probabilistic Risk Assessment of Neodymium Nitrate.
Wang N, Leng J, Zhang HM … +7 more , Xu J, Qian KL, Chang XL, Sun NN, Xiao P, Hong XY, Lu DS
Chem Res Toxicol · 2026 May · PMID 42083101 · Full text
Rare earth elements (REEs) are critical to modern industries but pose growing health risks due to increasing environmental release, and neodymium nitrate (Nd(NO)), a representative REE compound, lacks comprehensive toxic...
Rare earth elements (REEs) are critical to modern industries but pose growing health risks due to increasing environmental release, and neodymium nitrate (Nd(NO)), a representative REE compound, lacks comprehensive toxicological data. To address this, we developed an integrated computational toxicology framework combining artificial intelligence-enhanced in vitro to in vivo extrapolation (AIVIVE), physiologically based pharmacokinetic (PBPK) modeling, quantitative in vitro to in vivo extrapolation (QIVIVE), and high-throughput toxicokinetic (HTTK) validation for mechanism-based risk assessment. A closed-loop "model-informed experimental design" was employed, where AIVIVE, using conditional generative adversarial networks (cGAN) predicted toxicity pathways from multiomics data, experimental determination of key toxicokinetic parameters (plasma protein binding and partition coefficients) calibrated HTTK predictions, and a PBPK-QIVIVE framework incorporating nonlinear features extrapolated in vitro EC to human equivalent doses (HED), with Monte Carlo simulation and Sobol sensitivity analysis quantifying uncertainty. Results showed AIVIVE predicted transcriptomic responses with high fidelity (cosine similarity = 0.9986) and identified p53, apoptosis, and ferroptosis pathways with >85% accuracy. Experimental calibration revealed significant nonlinearity: plasma unbound fraction (fu) exhibited a U-shaped concentration dependence (0.556 at 1 μg/mL → 0.176 at 10 μg/mL → 0.965 at 100 μg/mL), while cellular partition coefficients () displayed an inverted U-shape (0.048-0.079). HTTK substantially underestimated fu (∼15-fold) and partition coefficients (2.4-5.5-fold). The integrated framework predicted a median HED of 0.032 mg/kg/day (95% CI: 0.012-0.098), with an 18% probability of exceeding the high-risk threshold (0.1 mg/kg/day). Sensitivity analysis identified fu (65%), K (22%), and EC (11%) as the dominant uncertainty sources. Probabilistic integration with exposure data indicated a high safety margin for the general population but concerns for mining area residents (100% probability of margin of exposure <100). This framework addresses the challenges of evaluating metals with nonlinear kinetics, reduces reliance on animal testing, and supports regulatory decisions, proposing an occupational exposure limit of 0.05 mg/m for neodymium nitrate.
Identification of a Potential Direct-Acting DNA Ethylating Agent Originating from the Synthetic Cooling Agent -Ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-3).
Ostlund T, Dameh NF, Luedtke MW … +2 more , Carmella SG, Hecht SS
Chem Res Toxicol · 2026 May · PMID 42081608 · Publisher ↗
Previous studies have reported the existence of a direct-acting DNA ethylating agent in tobacco products; it is known that ethyl DNA adducts such as 7-ethylguanine (7-Et-Gua) are elevated in tissues of smokers, but the i...
Previous studies have reported the existence of a direct-acting DNA ethylating agent in tobacco products; it is known that ethyl DNA adducts such as 7-ethylguanine (7-Et-Gua) are elevated in tissues of smokers, but the identity of the ethylating agent is unknown. In the study reported here, we investigated the possibility that -ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-3), a synthetic cooling agent used in tobacco and other products as a menthol alternative, could be nitrosated to produce the reactive DNA ethylating agent -nitroso--ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (NO-WS-3). We synthesized NO-WS-3 and investigated its formation and stability, as well as its ability to ethylate DNA. Formation of NO-WS-3 is favored under acidic conditions that are likely to be found in the gastrointestinal tract, along with endogenous nitrite. The half-life of NO-WS-3 under biological conditions was about 16 h, ample time for its reaction with DNA to create potentially mutagenic ethyl DNA adducts which have been associated with tobacco use. Reaction of NO-WS-3 with calf-thymus DNA resulted in the formation of 7-Et-Gua (167 adducts per 10 nucleotides), 3-Et-Ade (437 adducts per 10 nucleotides), and -Et-Gua (148 adducts per 10 nucleotides) well above background DNA levels in control incubations without NO-WS-3. This is the first identification of an agent potentially present in consumer products or formed that can directly ethylate DNA, providing a novel source of ethyl DNA adducts present in humans.
The Expanding Landscape of ADP-Ribosylation: Protein, DNA, RNA, and Mitochondrial Regulation.
Sin YC, Zhao L
Chem Res Toxicol · 2026 May · PMID 42080600 · Full text
ADP-ribosylation is an essential post-translational modification that contributes to key cellular processes, such as DNA damage repair, cell-cycle progression, chromatin remodeling, mitochondrial function, and immune res...
ADP-ribosylation is an essential post-translational modification that contributes to key cellular processes, such as DNA damage repair, cell-cycle progression, chromatin remodeling, mitochondrial function, and immune responses in mammalian cells. This modification derives from NAD and is regulated by dedicated writer, eraser, and reader proteins that govern its installation, removal, and recognition. Traditionally viewed as a protein-centered modification, ADP-ribosylation has recently been extended to nucleic acids, with ADP-ribosylated DNA and RNA now identified in both mammalian and bacterial systems. These discoveries reveal previously underappreciated layers of nucleic acid-based regulation and suggest that NAD-dependent chemistry integrates genome maintenance, RNA metabolism, and cellular stress responses. In this review, we first outline the major mammalian ADP-ribosylation machineries, including the families of writer, eraser, and reader proteins, and discuss how their activities are coordinated. We then examine emerging roles of ADP-ribosylation in mitochondria, with a focus on mitochondrial DNA repair and metabolic control. Finally, we highlight recent advances in understanding NAD-dependent modifications of DNA and RNA in mammalian and bacterial cells, including terminal and nucleobase-linked ADP-ribosylation and NAD capping, and discuss outstanding questions regarding their physiological functions and interplay with protein post-translational modification and other nucleic acid modifications.
Evaluating Dermal Bioactivity of Metal Additive Manufacturing Powders Using Human and Skin Models.
Persson A, Łyczyńska Z, Shahata M … +7 more , Kotlyar O, Engwall M, Särndahl E, Ehrström M, Melican K, Odnevall I, Alijagic A
Chem Res Toxicol · 2026 May · PMID 42070096 · Full text
Metal additive manufacturing (AM) relies on alloy feedstock powders that may come into contact with the workers' skin during handling, yet skin-relevant data on metal release and biological reactivity remain limited. Her...
Metal additive manufacturing (AM) relies on alloy feedstock powders that may come into contact with the workers' skin during handling, yet skin-relevant data on metal release and biological reactivity remain limited. Here, we assessed the cutaneous bioactivity of the fine particle fraction of four gas-atomized Fe-based AM powders (316L stainless steel, Fe-powder A, and tooling steels B and C). Powders were sieved to <10 μm and characterized by scanning electron microscopy and X-ray photoelectron spectroscopy before and after incubation in artificial sweat (ASW). Metal biodissolution was quantified in ASW and keratinocyte culture medium using atomic absorption spectrophotometry. Cellular responses were evaluated in HaCaT keratinocytes using Cell Painting-based phenomics and multiplex cytokine/chemokine profiling and in an full-thickness human skin explant model, including superficial barrier disruption, IL-8/CXCL8 quantification, and histological assessment. ASW exposure induced marked shifts in the outermost surface composition across powders, indicating sweat-driven surface transformation. Biodissolution was low and medium-dependent, with Fe dominating the release in ASW, and with an overall metal release remaining limited in cell culture medium. In HaCaT cells, MCP-1/CCL2, IL-6, and IL-8/CXCL8 were quantifiable but showed no significant changes following powder exposure. Cell Painting revealed subtle, shared phenotypic signatures, primarily involving mitochondrial-associated features, without evidence of broad cellular stress. In the skin model, AM powders did not increase IL-8/CXCL8 secretion, the particles remained localized to the skin surface without detectable penetration, and coexposure with did not enhance bacterial colonization or induce inflammation. To the best of our knowledge, this is the first study that applies a human skin explant model to evaluate dermal responses to metal AM powders. Overall, the tested AM powders showed low short-term cutaneous reactivity under skin-relevant conditions, providing human-relevant evidence to inform occupational risk assessment in AM environments.
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