Toxicol. Sci. [JOURNAL]
Sun
200 papers
β-lactoglobulin-per- and polyfluoroalkyl substance-binding interactions identifies the calyx domain as a determinant of contaminated milk exposure and the calycin protein family as potential mediators of per- and polyfluoroalkyl substance toxicity.
McLean ZS, Thomas ME, Belcher SM
Toxicol Sci · 2026 Feb · PMID 41460158 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly fluorinated persistent synthetic chemical pollutants. Major routes of human exposure include ingestion of contaminated drinking water and foods inc...
Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly fluorinated persistent synthetic chemical pollutants. Major routes of human exposure include ingestion of contaminated drinking water and foods including dairy. Consumption of PFAS-contaminated milk and dairy is especially concerning for infants and children who are particularly sensitive and most highly exposed. Here, we report findings of quantitative analysis of PFAS binding to β-lactoglobulin (β-Lg), the major whey protein in bovine milk, using differential scanning fluorimetry to determine binding affinities for 17 PFAS; except for uncharged fluorotelomer alcohols, β-Lg bound each PFAS congener tested, supporting a key role of charged functional groups in binding. The perfluoroalkyl carboxylic acid trifluoroacetic acid (TFA) bound with lowest affinity (Kd=8.6 mM) and long-chain congeners PFNA, PFDA, and PFUnDA bound with highest affinities. Evidence of significant cooperative binding was found for TFA, PFDA, PFUnDA, and PFOS. Molecular docking was used to define molecular mechanisms of PFAS binding by β-Lg and across the calycin super family of lipocalins and fatty acid-binding proteins. All calycins were predicted to bind PFAS in the calyx domain with ΔG of binding ranging from -5.3 to -9.4 kcal/mol, revealing that the binding affinity for many PFAS is greater than those for binding albumin. In total, this study has identified the calycin protein superfamily as PFAS-binding proteins, most of which have well-characterized functions related to key endocrine and toxicological pathways associated with the adverse consequences of PFAS exposure.
A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.
Murphy SV, Rajan SAP, Lindert K … +41 more , Young T, Jiao Y, Zhou Y, Khoury O, McSwain M, Sittadjody S, Hamid Z, Clapp PW, Leach TS, Orr TC, Shankle D, Whitaker E, Sutton K, Albertson SE, Stumpf K, Mutkus L, Simon T, Kulkarni G, Chan J, Lee J, Cox LA, Li G, Campbell C, Olivier M, Puppala S, Reeves TE, Langefeld CD, Ainsworth HC, Ziegler J, Zinnia A, Khan MS, Marini FC, Walker SJ, Shupe TD, Jacobson A, Furdui CM, Bishop AC, Hall AR, Seeds MC, Reeves KD, Atala A
Toxicol Sci · 2026 Mar · PMID 41442163 · Full text
There is a critical need to understand pathophysiological mechanisms involved in injury from acute chlorine gas (Cl2) exposure. Limited information is available regarding the time course and mechanisms of injury after ac...
There is a critical need to understand pathophysiological mechanisms involved in injury from acute chlorine gas (Cl2) exposure. Limited information is available regarding the time course and mechanisms of injury after acute Cl2 exposure due to a lack of human clinical data and limited fidelity of pre-clinical animal models. We designed and integrated a Cl2 exposure platform to generate and deliver precise concentrations of Cl2 to a microfluidic human airway-on-a-chip microphysiological system. Chemical, biological, structural, and functional airway-on-a-chip responses to Cl2 exposure were characterized across multiple concentrations, exposure times, and post-exposure timepoints. Transcriptomics and metabolomics analyses delineated key molecular, cellular, and physiological pathways involved in the acute response to Cl2 exposure. This work represents a significant advancement towards high-throughput, human-relevant characterization of pulmonary toxicants and medical countermeasure development, addressing critical gaps in toxicology modeling while reducing reliance on animal studies.
Advantages of long-term evaluation of doxorubicin-induced cardiotoxicity using human iPSC-derived cardiomyocyte sheet tissues with continuous contractile force measurement under constant pacing.
Hinata Y, Kagawa Y, Seno T … +7 more , Kubo H, Kato E, Baba A, Sasaki D, Matsuura K, Shimizu T, Sawada K
Toxicol Sci · 2026 Feb · PMID 41418477 · Publisher ↗
With advancements in anticancer therapy, concerns over delayed cardiotoxicity are increasing, creating demand for precise in vitro systems to evaluate long-term cardiotoxic effects in drug discovery. In this study, we ex...
With advancements in anticancer therapy, concerns over delayed cardiotoxicity are increasing, creating demand for precise in vitro systems to evaluate long-term cardiotoxic effects in drug discovery. In this study, we examined the impact of doxorubicin on the contractility of cell sheet tissues made from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) maintained at a steady pacing rate of 1 Hz. Using our system for continuous contractile force measurement over 5 days, tissues exposed to 0.3 µM doxorubicin exhibited progressive force decline and arrhythmias, despite no significant changes in 4 biomarkers, ANP, BNP, NT-proBNP, and cTnT, sampled post-measurement. These findings suggest that indirect biomarker-based assessment of the cardiotoxicity of doxorubicin may be challenging. Notably, an increased slope during the relaxation stage preceded reduction in contraction amplitude in 0.3 µM-exposed tissues. Further analysis, dividing the relaxation into early, middle, and terminal phases, indicated that doxorubicin induces a rapid force decline during the early phase, followed by a gradual decrease in the terminal phase. We discussed the mechanistic basis of this toxicity based on intracellular Ca2+ dynamics. These insights derive from a system that enables stable, long-term measurement of contractile force under a consistent beating rate, and such technological advancements promise to enable more reliable evaluation of delayed cardiotoxicity in future drug development. Thus, our rate-controlled, continuous force platform reveals early relaxation-phase changes not detected by soluble biomarkers and offers a more sensitive in vitro approach for preclinical cardiotoxicity screening.
A computational model of inflammation reveals crosstalk among energy metabolism, oxidative stress, insulin, and cytokines in hepatocytes during early MASLD progression.
Miura Y, Sakai Y, Nishikawa M … +1 more , Leclerc E
Toxicol Sci · 2026 Feb · PMID 41405848 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent liver disorders, affecting approximately one-third of the global adult population. The disease begins with hepatic fat accumul...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent liver disorders, affecting approximately one-third of the global adult population. The disease begins with hepatic fat accumulation (steatosis) and can progress to inflammation, fibrosis, and hepatocellular carcinoma. To elucidate the complex mechanisms underlying MASLD, we have developed a novel mathematical model that integrates glucose and lipid metabolisms, oxidative stress, insulin signaling and insulin resistance, and cytokines functions. We demonstrated that variations in extracellular fatty acid and lactate levels, along with changes in the activities of key glycolytic and triglyceride-synthesizing enzymes observed in actual patients, exert a substantial impact on oxidative stress and subsequent cellular damage. Moreover, this model enabled us to evaluate daily metabolic dynamics associated with protein expression patterns specific to steatotic livers. Importantly, it also allowed simulation of cytokine release from hepatocytes into the bloodstream (autocrine and endocrine effects) and the impact of locally elevated cytokines concentrations derived from immune cells (paracrine effects). Our model revealed the dynamics of the early stages of MASLD progression in response to alterations in blood metabolite levels, hepatic enzyme activities, insulin profiles, and cytokine patterns. Furthermore, we identified specific combinations of these factors that may mitigate hepatic fat accumulation or oxidative stress, highlighting the importance of patient-specificity. This study presents the first mechanistic framework grounded in experimental data to describe the crosstalk among hepatic metabolism, insulin, and cytokines, serving as a powerful tool for elucidating disease mechanisms and developing therapeutic strategies.
Rethinking the microenvironment's role in chemical-induced malignancy.
Bisson WH, Currie RA, Lim EL … +4 more , Mlynarczyk C, Tokar EJ, Colacci A, Colacino JA
Toxicol Sci · 2026 Feb · PMID 41405843 · Publisher ↗
Why and how does cancer start? Building from a Symposium at the 2025 Society of Toxicology meeting, we convened a group of international experts to answer this seemingly simple question. As experimental evidence has evol...
Why and how does cancer start? Building from a Symposium at the 2025 Society of Toxicology meeting, we convened a group of international experts to answer this seemingly simple question. As experimental evidence has evolved, perspectives on cancers' origins have shifted from the accumulation of DNA mutations in single cells to complex processes involving signals from an altered tissue microenvironment which promote tumorigenesis. Carcinogen exposures impact the biology of the microenvironment in complex and tissue-specific ways. These changes can include the infiltration of inflammatory cells that produce growth factors, neo-angiogenesis, morphological changes, and immune tolerance that avoids immune-mediated elimination. In this in-depth review, we discuss the evidence linking chemical-driven microenvironmental changes in the development of a range of solid and liquid tumors. We discuss specific phenotypic alterations, such as selection pressure driving clonal expansion and cellular plasticity and reacquisition of stem cell states, linked to carcinogen-induced changes in the microenvironment. We describe assays and biomarkers which can allow us to experimentally assess links between chemical exposures, the microenvironment, and cancer phenotypes. We end by discussing how understanding the role of the microenvironment and malignancy in toxicology is essential for accurate cancer hazard evaluation, development of next-generation risk assessment frameworks, identifying new strategies for cancer prevention, and improving patient care.
Withdrawn as duplicate: Cobalt Mediates Stage-Specific Toxicity of Metal Mixtures in Cardiovascular-Kidney-Metabolic Syndrome.
Zhang W, Jiang G, Liu Z … +6 more , Duan L, Liang J, Wang Z, Kang H, Huang D, Gao A
Toxicol Sci · 2026 Jun · PMID 41397916 · Full text
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Computational integration of in vivo single cell and in vitro bulk transcriptomics across 236 human and mouse datasets differentiates physiological versus non-physiological hepatic cell lines for hepatotoxicity screening.
Kowal T, Wang S, Cheng M … +3 more , Liu R, Blencowe M, Yang X
Toxicol Sci · 2026 Feb · PMID 41390973 · Publisher ↗
New approach methods (NAMs), including in vitro paradigms, are needed to increase throughput, sustainability, and ethicality in toxicity research. However, selecting optimal cell culture models that mimic in vivo physiol...
New approach methods (NAMs), including in vitro paradigms, are needed to increase throughput, sustainability, and ethicality in toxicity research. However, selecting optimal cell culture models that mimic in vivo physiological conditions is challenging. To identify cell lines that best recapitulate physiological cells, we compared gene expression signatures of cell lines and in vivo tissues. We curated 214 transcriptomics datasets from 17 human and mouse hepatic cell lines representing hepatocytes, hepatic stellate cells, and cholangiocytes and determined basal gene expression profiles for each. We also collected 7 in vivo single-cell RNA sequencing (scRNAseq) datasets from human and mouse livers, which provide physiologically relevant transcriptome profiles for hepatic cell types. We compared cell line transcriptome profiles to liver scRNAseq data to determine which cell lines best represent in vivo physiology for each cell type and compared genes, regulatory networks, and biological pathways between cell lines and hepatic cell types. We further analyzed 15 cell lines, in vivo, and primary hepatocyte datasets from hepatotoxicity studies to relate baseline patterns to toxicological responses. We identified HepaRG as optimal to model hepatocytes both at baseline and in hepatotoxicity application studies of diverse toxicants, and further provided biological insights into the key differences of some of the widely used hepatic cell lines from in vivo biology. Overall, we present a new in silico approach that leverages existing big data to guide the selection of cell lines with better functional relevance, which can be applied to in vitro modeling of other tissues and broad biomedical applications.
Lung injury, oxidative stress, and impaired functioning in a model of prolonged ozone exposure in female mice are associated with macrophage proinflammatory and profibrotic activation and altered bioenergetics.
Sunil VR, Vayas KN, Radbel J … +9 more , Smith LC, Meshanni JA, Lee JM, Weinstock D, Abramova E, Shmarakov IO, Gow AJ, Laskin JD, Laskin DL
Toxicol Sci · 2026 Feb · PMID 41390972 · Full text
Prolonged exposure to ozone causes lung injury and persistent inflammation, pathologies associated with emphysema and asthma. Herein, we characterized inflammatory cells in the lungs using a murine model of prolonged ozo...
Prolonged exposure to ozone causes lung injury and persistent inflammation, pathologies associated with emphysema and asthma. Herein, we characterized inflammatory cells in the lungs using a murine model of prolonged ozone exposure, with the long-term goal of assessing their role in disease pathogenesis. Mice were exposed to air or ozone (1.5 ppm, 2 h, 2×/wk, 6 wk). Bronchoalveolar lavage fluid (BAL) and cells and lung tissue were collected 24 h after the final exposure. Alveolar/bronchiolar hyperplasia, epithelial degeneration, and mononuclear cell infiltration were observed following ozone exposure; BAL protein, cells, fibrinogen, and SP-A and SP-D were also increased, along with markers of oxidative stress, and impaired pulmonary function. Flow cytometric analysis of infiltrating myeloid cells revealed that after ozone exposure, the majority of these cells were mature infiltrating macrophages. These were comprised mainly of anti-inflammatory/profibrotic macrophages, with a smaller number of proinflammatory macrophages. Proinflammatory genes (Il1β, Ccl3, Ccl17, Ccl22, Tnfα) and NF-κB activity were increased in BAL cells from ozone-exposed mice (>97% macrophages); profibrotic genes (Mmp12, Mmp28, Tgfβ), but not anti-inflammatory genes (Il10, Arg1), were also upregulated. Following ozone exposure, glycolytic activity and oxidative phosphorylation increased in BAL cells, consistent with proinflammatory and profibrotic activation, respectively. These findings are important as they provide a rationale for evaluating the role of inflammatory macrophages in the pathophysiological response to prolonged ozone exposure. Impact statement: These studies are significant as they may lead to the identification of novel therapeutic approaches for reducing inflammatory lung disease caused by long-term exposure to inhaled ozone.
Developmental toxicology profile of the IRAK4 degrader KT-474.
Enerson BE, Cappon G, Shi Y … +14 more , Walther DM, Campbell V, Chen D, Kuhn E, Massa V, Ho C, Zheng X, Yuan J, Sharma K, Hohlbaum AM, Slavin A, Ji N, Mainolfi N, Weiss MM
Toxicol Sci · 2026 Feb · PMID 41385308 · Publisher ↗
KT-474 is a first-in-class IRAK4 heterobifunctional degrader that utilizes cereblon (CRBN) for E3 ligase recruitment and was rationally designed to be devoid of immunomodulatory imide drug (IMiD)-related neosubstrate deg...
KT-474 is a first-in-class IRAK4 heterobifunctional degrader that utilizes cereblon (CRBN) for E3 ligase recruitment and was rationally designed to be devoid of immunomodulatory imide drug (IMiD)-related neosubstrate degradation. Like KT-474, most degraders in clinical trials to date rely on CRBN for E3 ligase recruitment to harness the ubiquitin-proteasome system to selectively degrade disease-associated proteins. Structural similarities of the CRBN-binding portion of these degraders to IMiDs (e.g., thalidomide) have raised safety concerns due to potential degradation of CRBN neosubstrates implicated in teratogenicity, such as SALL4. To address this theoretical concern, the potential of KT-474 to degrade CRBN neosubstrates in vitro and cause developmental toxicity in vivo was evaluated. Proteomic analyses across 3 human cell systems (peripheral blood mononuclear cells [PBMCs], induced pluripotent stem cells, and SK-N-DZ cells) demonstrated that KT-474 selectively degraded IRAK4 without affecting SALL4 or other detected CRBN neosubstrates. In embryo-fetal development studies, no KT-474-related malformations or embryo-fetal toxicity were observed in rats or rabbits at the highest doses tested. Associated exposures (AUC) provided 23- to 9-fold multiples, respectively, over exposures at the clinical dose of KT-474 associated with robust degradation of IRAK4 and early signals of efficacy. Deep IRAK4 degradation by KT-474 in primary rat cells, rabbit PBMCs, and a range of tissues provides confidence in the appropriateness of the animal species tested. Taken together, these data clearly differentiate KT-474 from IMiDs, support that CRBN-mediated teratogenicity seen with IMiD drugs is neosubstrate-driven, and demonstrate that structure-based design can generate highly selective degraders devoid of teratogenic risk.
7-OH and kratom vaping products: an emerging public health threat.
Schichlein KD, Kim HH, Porter NA … +1 more , Jaspers I
Toxicol Sci · 2026 Feb · PMID 41385306 · Publisher ↗
Abstract loading — click title to view on PubMed.
Cobalt mediates stage-specific toxicity of metal mixtures in cardiovascular-kidney-metabolic syndrome.
Zhang W, Jiang G, Liu Z … +6 more , Duan L, Liang J, Wang Z, Kang H, Huang D, Gao A
Toxicol Sci · 2026 Feb · PMID 41385298 · Full text
Cardiovascular-Kidney-Metabolic (CKM) syndrome imposes a rising global health burden, yet the link between environmental metal mixtures and CKM progression remains unclear. To assess the joint effects of metal mixtures o...
Cardiovascular-Kidney-Metabolic (CKM) syndrome imposes a rising global health burden, yet the link between environmental metal mixtures and CKM progression remains unclear. To assess the joint effects of metal mixtures on CKM syndrome staging and identify critical toxic drivers through advanced mixture analysis. National Health and Nutrition Examination Survey data (2011 to 2016) from 1,816 participants were analyzed via Weighted Quantile Sum (WQS) regression, generalized linear models (GLMs), ridge regression, Shapley Additive exPlanations (SHAP) analysis, and polynomial regression. An adverse outcome pathway (AOP) framework was utilized to characterize the mechanisms of metal-mediated CKM. The WQS model revealed an association between mixed metal exposure and CKM (β = 0.502, P = 0.013). Subsequently, GLMs and ridge regression further identified the associative characteristics of individual metals, with all 3 models pointing to cobalt as the key driver. The SHAP model validated cobalt's dominant contribution from the perspective of marginal feature importance. Additionally, a polynomial equation analysis showed that cobalt exhibited a linear dose-response relationship with CKM syndrome. Based on these findings, the AOP framework further identified that early CKM stages are linked with cobalt-related metabolic and immune dysregulation. In contrast, late stages involve disruptions in calcium homeostasis, lipid metabolism, and cell apoptosis-survival balance. Our findings highlight the impact of metal exposure on the progression of CKM syndrome; the AOP framework has deciphered stage-specific mechanisms of cobalt, revealing distinct toxicological pathways in early versus late CKM.
Interlaboratory validation of the human thyroid microtissue assay.
Deisenroth C, Foley B, Rogers E … +11 more , Kühnlenz J, Chen W, Feshuk M, Bianchi E, McKenna J, Hill BN, Larocca J, LeCluyse EL, Kleinstreuer N, Thomas RS, Hogberg HT
Toxicol Sci · 2026 Feb · PMID 41344865 · Publisher ↗
The U.S. Environmental Protection Agency (EPA) continues to evaluate strategies to implement new approach methods (NAMs) for screening chemicals that disrupt the thyroid endocrine system. Validation of NAMs is a critical...
The U.S. Environmental Protection Agency (EPA) continues to evaluate strategies to implement new approach methods (NAMs) for screening chemicals that disrupt the thyroid endocrine system. Validation of NAMs is a critical milestone toward establishing confidence in data sources that could be used in a regulatory decision-making context. The objective of this study was to conduct an interlaboratory validation of the human thyroid microtissue assay to evaluate its relevance and reliability. In coordination with the US validation authority, NICEATM, and collaboration with industry partners (LifeNet Health, Bayer Crop Science, Corteva Agrisciences), the study aims were to (1) define the study design and establish standard operating procedures, (2) conduct test method transfer, training, and within-laboratory model performance evaluation, (3) perform interlaboratory reference chemical testing and assay performance evaluation. Progress was independently monitored by a validation management team comprised of an international group of experts in thyroid physiology, in vitro test methods, and regulatory toxicology. Results indicated the thyroid microtissue model could be reliably transferred to new laboratories with reproducible effects on thyroid hormone synthesis. Interlaboratory testing of 4 blinded reference chemicals (3 true positive, 1 true negative) across 3 independent human donors revealed consistent bioactivity across the reference set and performance metrics (dynamic range, precision, screening quality) that met acceptance criteria and shed insight into areas for improvement. In the context of a NAM-based testing strategy, a validated human thyroid microtissue assay enables direct measurement of thyroid hormone synthesis perturbations, reducing reliance on animal testing and addressing a critical mode-of-action that is of regulatory concern.
Nrf2 contributes to the protective effect of iron overload on thioacetamide-induced chronic liver injury in rats.
Hamada N, Ito Y, Niimi H … +5 more , Atarashi M, Kuwamura M, Taguchi K, Yamamoto M, Izawa T
Toxicol Sci · 2026 Feb · PMID 41344862 · Publisher ↗
Chronic liver disease (CLD) is a global health concern that progresses to liver cirrhosis and cancer. This progression can be partly replicated in rodents through experimental administration of thioacetamide (TAA). Hepat...
Chronic liver disease (CLD) is a global health concern that progresses to liver cirrhosis and cancer. This progression can be partly replicated in rodents through experimental administration of thioacetamide (TAA). Hepatic iron accumulation is a relatively common finding in CLD patients, as excess intracellular iron promotes the progression of CLD by generating reactive oxygen species. We previously reported that dietary iron overload abrogates TAA-induced liver cirrhosis in rats, raising a possibility that hepatic iron accumulation exerts a cytoprotective function. Here we investigated the role of Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (Keap1-Nrf2) system in the protective effects of iron overload in TAA-induced chronic liver injury. The suppression of TAA-induced liver cirrhosis by dietary iron overload, demonstrated in wild-type rats, was cancelled in Nrf2 knockout (KO) rats, suggesting that Nrf2 contributes to the protective effect. In wild-type rats treated with both TAA and iron, major Nrf2-target gene products, NAD(P)H quinone dehydrogenase 1 and placental glutathione S-transferase (GSTP), were specifically overexpressed in hepatocytes around the fibrotic lesions. This overexpression was accompanied by iron accumulation and expression of cytochrome P450 2E1, which converts TAA into its toxic metabolites. In addition, wild-type rats treated with TAA alone developed multiple GSTP-positive preneoplastic foci, characterized by strong activation of Nrf2, partially involved by p62-dependent selective autophagy. GSTP expression was absent in hepatocytes of Nrf2 KO rats. These results suggest that Nrf2 protects liver cirrhosis and promotes formation of preneoplastic hepatocellular nodules during TAA-induced chronic liver injury depending on the hepatic iron condition.
A novel constrained drop surfactometer demonstrates inhibition of lung surfactant function by PFAS aerosols in vitro.
Klein LM, Heyman JD, Murray JR … +6 more , Sørli JB, Smeltz MG, Monsees ME, Krantz QT, Puckett ET, Gavett SH
Toxicol Sci · 2026 Feb · PMID 41289147 · Full text
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in both indoor and outdoor air, and there is an increasing need to effectively screen this diverse class of chemicals for inhalation toxicity potential. Because P...
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in both indoor and outdoor air, and there is an increasing need to effectively screen this diverse class of chemicals for inhalation toxicity potential. Because PFAS have strong surface-active properties, we hypothesized they may interfere with lung surfactant (LS) activity. We investigated the ability of 17 PFAS delivered as liquid aerosols to inhibit LS function in a newly developed constrained drop surfactometer. Using both fluorescent tracers and mass spectrometry techniques, deposition of PFAS aerosols onto exposed LS was determined. Nine of the 17 PFAS increased surface tension (ST) above the inhibition threshold, defined as mean minimum post-exposure ST above 10 mN/m. Inhibitory compounds included legacy PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS]), emerging compounds (hexafluoropropylene oxide dimer acid, perfluoro-2-methoxyacetic acid), perfluorooctyltriethoxysilane, and perfluorooctane-sulfonamides and -sulfonamidoethanols. These compounds represent a wide range of molecular weights and functional head groups (carboxylic and sulfonic acids, sulfonamides, and siloxane). Among these compounds, the lowest modeled inhibitory doses were for N-methyl-perfluorooctane-sulfonamidoethanol (0.34 ppm) and N-ethyl-perfluorooctane-sulfonamidoethanol (0.14 ppm). Concentrations of PFOA and PFOS required to inhibit LS were significantly lower when aerosolized than when directly mixed with LS, demonstrating the importance of interactions with surfactant at the air-liquid interface. Our results show that a combination of size, functional groups, and hydrophobicity influence the ability of PFAS to inhibit LS function. Under high exposure conditions, inhaled PFAS may initiate an adverse outcome pathway through surfactant inhibition, which may ultimately produce a reduction of lung function.
Position-specific methyl substitution on benzo[a]pyrene drives AHR-dependent fin duplication in zebrafish.
Morshead ML, Truong L, Tanguay RL
Toxicol Sci · 2026 Jan · PMID 41264521 · Full text
Polycyclic aromatic hydrocarbons (PAHs) are a contaminant class characterized by fused aromatic rings, formed through the incomplete combustion of organic materials and petrogenic sources. Despite the abundance and toxic...
Polycyclic aromatic hydrocarbons (PAHs) are a contaminant class characterized by fused aromatic rings, formed through the incomplete combustion of organic materials and petrogenic sources. Despite the abundance and toxicity of alkyl-substituted PAHs, most research and regulation focus on unsubstituted parent PAHs. Alkyl substitution of Benzo[a]pyrene (BaP), one of the most well-studied parent PAHs, drastically alters its bioactivity in zebrafish. In larval zebrafish exposed from 6 h post-fertilization (hpf), BaP caused behavioral effects but no morphological effects up to 50 µM at 120 hpf. In contrast, 8-methylbenzo[a]pyrene caused a distinct fin duplication phenotype by 0.26 µM and additional morphological effects by 1 µM. Alkyl substitution in different positions (7-, 6-, 9-, and 10-MBaP) did not elicit morphological effects at similar concentrations. This study characterized the morphological effects of 8-MBaP in zebrafish and investigated its mechanism(s) of action. Using knock-out lines, we demonstrated that 8-MBaP toxicity is Ahr2 dependent and that Cyp1a served a protective role. To identify underlying transcriptomic changes, embryos were exposed to 3 concentrations of BaP, 6-MBaP, and 8-MBaP. Whole embryos/larvae were collected at 48 and 72 hpf, which was before and during phenotype onset, respectively. Collecting RNA and morphological effects across concentration, time, and chemicals facilitated the identification of concentration-dependent transcriptional responses linked to the downstream morphological phenotypes unique to BaP methylation at the eighth position. This study improves environmental and human health hazard assessment by identifying critical structural features and mechanisms of action contributing to the toxicity of PAH mixtures in the environment.
Advancing transcriptomics-based mechanistic assessment of nephrotoxicity in vitro using the human RPTEC/TERT1 TXG-MAPr gene co-expression network.
van Kessel HW, Kunnen SJ, Callegaro G … +1 more , van de Water B
Toxicol Sci · 2026 Jan · PMID 41264515 · Full text
Traditional animal-based chemical safety assessments often fall short in accurately predicting human toxicities, highlighting the need for more human-relevant testing strategies. In response to this challenge, new approa...
Traditional animal-based chemical safety assessments often fall short in accurately predicting human toxicities, highlighting the need for more human-relevant testing strategies. In response to this challenge, new approach methodologies have emerged, with high-throughput in vitro transcriptomic screening playing a pivotal role in elucidating mechanisms of toxicity. In this study, we developed the first human kidney in vitro toxicogenomic co-expression network using transcriptomic profiles from immortalized human renal proximal tubule epithelial cells (RPTEC/TERT1) exposed to a curated panel of nephrotoxicants. Through weighted correlation network analysis, we identified distinct gene co-expression modules and conducted comprehensive downstream analyses at the module, sample, and transcription factor levels. We integrated these insights into the human in vitro RPTEC/TERT1 TXG-MAPr, an interactive R Shiny platform designed to facilitate the interpretation of gene co-expression networks. Our findings demonstrate that module-based analysis enables the differentiation of distinct mechanisms of action. By linking transcriptional modules to KE within the nephrotoxicity adverse outcome pathway network, we reinforce the potential of gene co-expression network approaches to advance mechanism-based risk assessment and support next-generation chemical safety assessment.
Endocrine-disrupting chemical exposure during differentiation alters the proliferation-maturation balance in stem-cell islets.
Gudmestad JH, Unger L, Paulo JA … +2 more , Ghila L, Legøy TA
Toxicol Sci · 2026 Jan · PMID 41264466 · Full text
Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a risk factor for diabetes, primarily through disruption of pancreatic beta-cell function and insulin signaling. These effects can arise not...
Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a risk factor for diabetes, primarily through disruption of pancreatic beta-cell function and insulin signaling. These effects can arise not only from adult exposure but also during development, as many EDCs can cross the placental barrier. However, models that accurately mimic human pancreatic islet development are limited. In this study, we reported the first toxicological application of stem cell islets (SC-islets) to investigate the developmental effect of EDCs. Using human-induced pluripotent stem cells (iPSCs), we generated SC-islets and exposed them to a mixture of bisphenol A, bisphenol S, and trans-nonachlor during differentiation. EDC exposure resulted in SC-islets with an altered transcriptional profile, characterized by reduced expression of beta-cell maturity markers, increased proliferation markers, and elevated KI67-positive cell counts. These features resembled earlier developmental stages and deviated from mature human islet profiles, suggesting a delay in differentiation. Our findings establish SC-islet differentiation as a novel and relevant in vitro model for assessing the developmental toxicity of EDCs, with outcomes consistent with in vivo studies. This model opens new avenues for mechanistic studies and chemical safety assessment in endocrine development.
Machine learning modeling of zebrafish toxicity endpoints after exposure to PROTACs.
Yogodzinski C, Harris JS, Lane TR … +7 more , Barnes M, Vignaux PA, Raman R, Truong L, Tanguy RL, Kullman SW, Ekins S
Toxicol Sci · 2026 Jan · PMID 41259055 · Full text
Zebrafish (Danio rerio) are an ideal system for understanding developmental toxicity as they display similar toxicity outcomes to other vertebrates. Further, many molecules have been tested for developmental toxicity in...
Zebrafish (Danio rerio) are an ideal system for understanding developmental toxicity as they display similar toxicity outcomes to other vertebrates. Further, many molecules have been tested for developmental toxicity in zebrafish, providing an opportunity for machine learning model development. We curated 1,345 small molecules from ToxCast, flame retardant compounds, per- and polyfluoroalkyl substances (PFAS), and industrial chemicals published by the Superfund Research Program (SRP). Following curation, we trained machine learning models on the zebrafish toxicity endpoints ANY_ = any effect including mortality, ANY_BUT_MORT = any effect excluding mortality, MORT = mortality, i.e. did the embryo die, EDEM = did an edema form, and CRAN = Craniofacial malformation. We demonstrated that these models were better than random when compared with shuffled data. We also fine-tuned the molecular SMILES encoder MolBART to predict on all zebrafish toxicity endpoints and found it generally matched the performance of classical machine learning models for ANY_BUT_MORT, CRAN, and EDEM endpoints. We present new toxicity data for Proteolysis Targeting Chimeras (PROTACs) in zebrafish and machine learning models for these data by fingerprinting different parts of the molecule individually, yielding predictive performance (AUROC 0.6 to 0.7). If we are to reduce animal testing with new approach methodologies like these zebrafish toxicity models they need to be able adapt to new molecular classes like PROTACs.
circZNF462 inhibits cadmium-induced DNA damage in bronchial epithelial cells by regulating chromatin accessibility.
Li M, Lin Q, Chen W … +10 more , Chen Y, Wang Y, Fu P, Zheng Q, Wu Z, Yang D, Lin T, Shang K, Ling Y, Jiang Y
Toxicol Sci · 2026 Jan · PMID 41247323 · Publisher ↗
Genetic damage is an early effect of altered cell function and tumorigenesis. Analysis of epigenetic alterations in genetic damage in the context of environmental heavy metal-induced cytotoxicity highlights the importanc...
Genetic damage is an early effect of altered cell function and tumorigenesis. Analysis of epigenetic alterations in genetic damage in the context of environmental heavy metal-induced cytotoxicity highlights the importance of environment-epigenetics-genetics interactions. The mechanism through which circular RNA (circRNA), an important molecule in epigenetics, regulates cadmium (Cd)-induced DNA damage is unknown. Herein, we report that circRNA circZNF462 regulates chromatin accessibility and inhibits DNA damage after Cd exposure. Downregulation of circZNF462 was associated with DNA damage in a model of 10 μM Cd-exposed bronchial epithelial cells. Chromatin accessibility increased after Cd exposure. Downregulation of circZNF462 significantly increased chromatin accessibility, thereby increasing DNA damage. MCM5 was significantly upregulated after Cd exposure and was negatively correlated with circZNF462. Furthermore, in the Cd exposure model, downregulated circZNF462 increased the levels of MCM5 and facilitated chromatin opening. Reduction of MCM5 reversed the induction of DNA damage after Cd exposure by low levels of circZNF462. These findings underscore the role of circZNF462-regulated chromatin accessibility in Cd-induced DNA damage and suggest that the epigenetic molecule circZNF462 might serve as a potential biomarker and early intervention target for preventing environmentally related genetic damage events.
E-cigarette exposure during pregnancy impairs uterine artery blood flow and feto-placental function.
Olverson ZA, Saldaña SJ, Miller RA … +1 more , Gorr MW
Toxicol Sci · 2026 Jan · PMID 41247316 · Publisher ↗
The popularity of electronic cigarettes (e-cigs) has risen in recent years, largely due to perceptions of reduced harm compared with traditional tobacco cigarettes. E-cig use has spread into vulnerable populations such a...
The popularity of electronic cigarettes (e-cigs) has risen in recent years, largely due to perceptions of reduced harm compared with traditional tobacco cigarettes. E-cig use has spread into vulnerable populations such as adolescents and individuals of reproductive age, yet their safety during pregnancy remains poorly understood. E-cigs differ from conventional cigarettes in composition, and their aerosolized components may uniquely affect the uterine environment and placental function. Proper placental development, maternal vascular remodeling, and tone are essential for healthy pregnancy outcomes, but it remains unclear how e-cig aerosol components affect these processes. To address this gap, we investigated how in utero exposure to sub-ohm e-cig aerosols, with and without nicotine, affects maternal and fetal cardiovascular function, uterine vascular function, and placental morphology. Pregnant female FVB/J mice were exposed to filtered air, vehicle (propylene glycol/vegetable glycerin; PG:VG or PV), or vehicle with nicotine (PV + Nicotine) from embryonic day (E) 0.5 to E17.5 (4 h/day, 5 days/week). Maternal and fetal cardiovascular parameters were assessed at E16.5 via echocardiography and ultrasound. At E17.5, maternal, fetal, and placental tissues were collected for histological and molecular analysis. E-cig exposure resulted in maternal diastolic dysfunction, reduced uterine artery blood flow, fetal bradycardia, structural alterations in the placenta, and reduced placental sufficiency. These effects were observed in both e-cig exposure groups, with some differences between the PV and PV + Nicotine groups, suggesting that exposure to aerosolized e-cig vehicle components alone can also contribute to gestational impairments. Our findings demonstrate that e-cig exposure during pregnancy disrupts cardiovascular adaptation and fetal development, highlighting the need for reevaluation of e-cig safety during pregnancy and guiding future mechanistic studies of its effects on placental and vascular dysfunction.
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