Toxicol. Sci. [JOURNAL]
Sun
200 papers
Bee venom disrupts vascular homeostasis: apitoxin and melittin trigger vascular cell toxicity and aortic dysfunction in mice.
Bistué-Rovira À, Solé M, Anguera-Tejedor M … +6 more , Pérez B, García-Tercero L, Díaz-Pérez A, Martínez-Benitez Z, Delgado-Hernández R, Jiménez-Altayó F
Toxicol Sci · 2025 Sep · PMID 40498569 · Publisher ↗
Bee venom (apitoxin) is a mixture of bioactive molecules, with melittin as its principal component. Although its therapeutic potential is increasingly recognized, its toxic effects on vascular homeostasis remain underexp...
Bee venom (apitoxin) is a mixture of bioactive molecules, with melittin as its principal component. Although its therapeutic potential is increasingly recognized, its toxic effects on vascular homeostasis remain underexplored. We investigated the impact of apitoxin and melittin on vascular cell viability and mouse aortic function. Cytotoxicity was assessed in cultured endothelial and smooth muscle cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Aortic function was evaluated by mounting thoracic aortas from young male and female C57BL/6J mice in tissue baths. Isometric tension was measured during phenylephrine-induced contractions, as well as endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxations. To evaluate the roles of nitric oxide (NO) and oxidative stress, we used the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) and the antioxidant superoxide dismutase (SOD), respectively. High-performance liquid chromatography analysis revealed that melittin comprised 43.80% of apitoxin. Both apitoxin and melittin exhibited concentration-dependent cytotoxicity, significantly reducing endothelial cell viability at concentrations ≥5 µg/ml, whereas smooth muscle cells were affected at lower concentrations (≥2.5 µg/ml for apitoxin; ≥1.5 µg/ml for melittin). In functional experiments, apitoxin enhanced phenylephrine-induced contractions at 1 µg/ml and impaired both endothelium-dependent and -independent relaxations at ≥0.1 µg/ml, particularly in males. Although melittin mimicked these effects, higher concentrations (≥5 µg/ml) were required, suggesting that other venom components contribute to the vascular functional toxicity of apitoxin. L-NAME and SOD prevented apitoxin-induced vascular impairments, implicating the NO pathway and oxidative stress. These findings demonstrate that apitoxin impairs vascular cell viability and aortic function at clinically relevant concentrations, underscoring both its vascular risks and therapeutic potential.
Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses.
Alewel DI, Rentschler KM, Schladweiler MC … +6 more , Miller CN, Gavett SH, Evansky PA, Grindstaff R, Williams WC, Kodavanti UP
Toxicol Sci · 2025 Sep · PMID 40489674 · Full text
The contribution of neuroendocrine mechanisms of air pollution health effects in females and the extent to which such effects are related to estrogen signaling are unclear. To examine the interactive roles of estrogen (E...
The contribution of neuroendocrine mechanisms of air pollution health effects in females and the extent to which such effects are related to estrogen signaling are unclear. To examine the interactive roles of estrogen (ER) and glucocorticoid receptors (GR) in acrolein-induced respiratory and systemic effects, female Wistar-Kyoto rats were treated daily for 9 days with corn oil (vehicle, 1 ml/kg), fulvestrant (ER-antagonist/degrader, 20 mg/kg), mifepristone (GR antagonist, 30 mg/kg) or fulvestrant + mifepristone, and on days 8 and 9 post-drug-treatment start, rats were exposed nose-only to 0 or 3.2 ppm acrolein for ∼4 h/day. Glucose-tolerance testing was performed following the first exposure. Nasal and lung lavages and blood samples were collected following the second exposure. Fulvestrant and mifepristone pretreatments decreased serum estrogen and progesterone, respectively, and each drug increased adrenocorticotropic hormone in acrolein-exposed rats. Although acrolein-induced nasal and lung protein leakage was reduced in fulvestrant-treated rats, neutrophilic inflammation and pro-inflammatory cytokine increases were exacerbated. However, acrolein-induced airway inflammation was not observed in mifepristone or co-treated rats. Regarding systemic markers of hypothalamic-pituitary-adrenal (HPA) activity, fulvestrant and mifepristone each increased circulating basal leukocytes regardless of exposure, especially total white blood cells and neutrophils. Fulvestrant-induced neutrophilia was slightly dampened in acrolein-exposed females. Fulvestrant also primed multiple adverse acrolein-induced metabolic alterations. Importantly, systemic markers of acrolein-induced HPA activity were not impacted in mifepristone or fulvestrant + mifepristone co-treated rats. These data demonstrate that neuroendocrine co-regulation by ER and GR might explain acrolein susceptibility differences, contributing novel mechanistic information to the growing recognition of gonadal hormone influence in air pollution health effects susceptibility.
A cheminformatics workflow for higher-throughput modeling of chemical exposures from biosolids.
Kruse PM, Ring CL
Toxicol Sci · 2025 Sep · PMID 40489655 · Publisher ↗
The U.S. Environmental Protection Agency's Biosolids Screening Tool can predict potential human and ecological exposures to chemical contaminants in treated sewage sludge biosolids, but large quantities of chemical-speci...
The U.S. Environmental Protection Agency's Biosolids Screening Tool can predict potential human and ecological exposures to chemical contaminants in treated sewage sludge biosolids, but large quantities of chemical-specific physico-chemical data are required to parameterize the model. Here, an R workflow is presented that leverages publicly available databases of chemical information, particularly the U.S. EPA's CompTox Chemicals Dashboard, to prepare data for model simulations using the Biosolids Screening Tool. The workflow is publicly available at https://github.com/USEPA/CompTox-ExpoCast-autoBST. The automated Biosolids Screening Tool workflow (autoBST) reduces the time to gather data necessary to screen hundreds of chemicals from days to just a few minutes. autoBST is a practical example of the utility of leveraging the US EPA CompTox Chemicals Dashboard. autoBST provides transparent and reproducible data retrieval and input into existing models, allowing assessors to defensibly prioritize chemicals in biosolids that may pose a risk to human health or the environment.
Application of a metabolic network-based graph neural network for the identification of toxicant-induced perturbations.
Yuan K, Nault R
Toxicol Sci · 2025 Jul · PMID 40445920 · Full text
Transcriptomic analyses have been an effective approach to investigate the biological responses and metabolic perturbations by environmental contaminants in rodent models. However, it is well recognized that metabolic ne...
Transcriptomic analyses have been an effective approach to investigate the biological responses and metabolic perturbations by environmental contaminants in rodent models. However, it is well recognized that metabolic networks are highly connected and complex, and that traditional gene expression analysis methods, including pathway analyses, have a limited ability to capture these complexities. Given that metabolism can be effectively represented as a graph, this study aims to apply a network-based graph neural network (GNN) to uncover novel or hidden metabolic perturbations in response to a toxicant. A GNN model based on the mouse Reactome pathways was trained and validated on 7,689 transcriptomic samples from 26 mouse tissues curated from Recount3. This model was then used to identify important reactions in publicly available data from livers of mice treated with the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) achieving a performance of 100% when comparing a single dose to a control group. Integrated gradients and centrality analyses identified perturbation of the SUMOylation, cell cycle, P53 signaling, and collagen biosynthesis pathways by TCDD which were not identified using a pathway analysis approach. Collectively, our results demonstrate that GNNs can reveal novel mechanistic insights into toxicant-mediated metabolic disruption, presenting a putative strategy to characterize biological responses to toxicant exposures. Our studies illustrate how the use of a reaction-based graph neural network can support the discovery of toxicant-induced metabolic perturbations, and highlight strengths and challenges in the application of artificial intelligence methods for environmental health research.
A mixture of organophosphate esters sex-specifically impacts monocyte-macrophages in Sprague-Dawley rats.
Giles BH, Subramaniam NK, Caruana V … +3 more , Kukolj N, Robaire B, Mann KK
Toxicol Sci · 2025 Sep · PMID 40434910 · Full text
Exposure to individual organophosphate esters (OPEs) has been linked to immune dysfunction. However, the effect of OPEs as environmentally relevant mixtures on the immune system remains poorly understood. This study exam...
Exposure to individual organophosphate esters (OPEs) has been linked to immune dysfunction. However, the effect of OPEs as environmentally relevant mixtures on the immune system remains poorly understood. This study examines how parental exposure to an OPE mixture impacts the immune status of Sprague-Dawley rats and their offspring. Sprague-Dawley rats were fed a control or OPE-supplemented diet containing 13 OPEs detected in >85% of Canadian homes. Only male offspring of OPE-exposed animals showed a significant reduction in CD43lowHis48hi splenic monocyte-macrophages. There were no significant changes in CD43lowHis48hi splenic monocyte-macrophages in the F0 generation or female offspring. However, the OPE mixture significantly altered serum cytokine levels in both sexes and generations, with females and offspring experiencing more pronounced changes. Notably, female progeny had elevated levels of chemokines associated with monocyte recruitment. In vitro follow-up studies revealed that the OPE mixture delays monocyte-to-macrophage transition and monocyte migration in both sexes. These results indicate that an environmentally relevant OPE mixture disrupts immune function by affecting monocyte recruitment and differentiation but does not reveal clear sex differences. However, when combined with cytokine findings, these results support a hypothesis that OPE exposure causes male-specific decreases in CD43lowHis48hi monocyte-macrophages that are absent in females due to compensatory inflammation. These studies demonstrate that an environmentally relevant mixture of OPEs can alter basal immune status in the offspring of exposed animals. This work will be useful for risk assessment studies and regulations protecting human health.
Profiling the cytotoxic effects of naled and other pesticides in primary human placental cytotrophoblasts.
Li L, Chen H, Jigmeddagva U … +14 more , Le N, Kapidzic M, Gee S, Ali A, Levan J, Person R, Chen J, Gutierrez AM, Okorie CN, Wang M, Woodruff TJ, Fisher SJ, Gaw SL, Robinson JF
Toxicol Sci · 2025 Jul · PMID 40434365 · Full text
Placental cytotrophoblasts (CTBs) play critical roles in placentation, including implantation, barrier function, uterine invasion, and maternal endovascular remodeling. Impairment of CTB function is linked with common pr...
Placental cytotrophoblasts (CTBs) play critical roles in placentation, including implantation, barrier function, uterine invasion, and maternal endovascular remodeling. Impairment of CTB function is linked with common pregnancy complications. In this context, environmental chemicals can contribute to CTB dysfunction. Evidence suggests that prenatal exposures to pesticides affect the placenta and contribute to pregnancy complications and adverse developmental outcomes. Despite being restricted in the European Union, dimethyl 1,2-dibromo-2,2 dichloroethyl phosphate (naled), a common organophosphate pesticide, is widely used in vector control and agriculture in the United States and abroad. In this study, we investigated the placentotoxic activity of naled in second-trimester primary human CTBs. We assessed the cytotoxicity of naled and 67 pesticides using the neutral red lysosomal cellular uptake assay and the lactate dehydrogenase release assay. Naled was one of the most toxic compounds (∼15th percentile), impairing viability and inducing cell death at levels similar to federally restricted pesticides (methoxychlor and triclosan) and at lower concentrations than other commonly used compounds in the organophosphate class (e.g. chlorpyrifos, dichlorvos, and malathion). Naled significantly altered expression of 297 genes (unadjusted P < 0.01, absolute fold change >1.5 with 10 or 30 µM), including molecules important in regulating the environmental stress response and developmental processes. Using a benchmark modeling approach, we identified specific genes and related pathways that may serve as early indicators of naled-response in CTBs at physiologically relevant exposure levels. Thus, our data suggest that naled may alter critical human CTB functions in vivo.
Elucidating CD4+ and CD8+ T-cell involvement in patients with vancomycin-induced DRESS.
Gardner J, Martinez-Rivera S, Line J … +7 more , Thomson P, Clarke E, Gibson A, Krantz MS, Ardern-Jones M, Phillips EJ, Naisbitt DJ
Toxicol Sci · 2025 Aug · PMID 40424455 · Full text
Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing...
Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing HLA-A*32:01. Previous studies have identified the potential role of T-cells using HLA-A*32:01-positive healthy donor models. However, DRESS pathogenesis remains poorly defined, and a deeper mechanistic understanding is required to aid the diagnosis and prediction of vancomycin-induced DRESS. The present study aims to elucidate CD4+ and CD8+ T-cell involvement within the pathogenesis of vancomycin-induced DRESS following the isolation and functional study of cloned T-cells from hypersensitive patients. CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs) were generated by serial dilution from peripheral blood mononuclear cells collected from suspected vancomycin-DRESS patients. Functionality of drug-responsive TCCs was assessed using T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining, enzyme-linked immunospot assay, and LEGENDplex immunoassays. Vancomycin-responsive TCCs expressing CD4+ and CD8+ phenotypes were successfully generated from suspected vancomycin-DRESS patients (n = 3). CD45RO+ memory T-cells were the primary activated population, with both CD4+ and CD8+ T-cells associated with the release of IFN-γ, IL-5, IL-13, granzyme B, and perforin. Vancomycin-responsive CD4+ and CD8+ T-cells are activated by direct, pharmacological interactions, with antigen presentation possible through HLA class I and HLA class II molecules. This study provides in vitro evidence for the dual role of antigen-specific CD4+ and CD8+ T-cells within the pathogenesis of vancomycin-induced DRESS. This has been demonstrated following the generation of cloned T-cells with strong vancomycin specificity from patients presenting with vancomycin-DRESS and positive for expression of HLA-A*32:01.
Acetate derived from metabolism of ethanol affects gene expression in bone and contributes to delays in chondrogenic differentiation.
Pedersen KB, Del Valle Ponce de Leon C, Hang H … +7 more , Chen JR, Randolph CE, Zabaleta J, Taylor CM, Luo M, Denys A, Ronis MJJ
Toxicol Sci · 2025 Sep · PMID 40403335 · Full text
Alcohol intake is a risk factor for the development of osteopenia. Ethanol perturbs gene expression in osteoblasts and osteoclasts and disrupts growth plate morphology. Hepatic metabolism of ethanol to acetate elevates c...
Alcohol intake is a risk factor for the development of osteopenia. Ethanol perturbs gene expression in osteoblasts and osteoclasts and disrupts growth plate morphology. Hepatic metabolism of ethanol to acetate elevates concentrations of acetate in the circulation. We investigated whether acetate could, in part, mediate the toxicity of ethanol in bone and on chondrocyte differentiation. When ethanol and acetate were compared by gavage for 4 consecutive days, none of 11 selected genes involved in bone homeostasis were significantly affected by acetate, but acetate responses significantly correlated with ethanol responses. Intraperitoneal injection with acetate to transiently elevate serum acetate for 4 consecutive days significantly increased expression of 2 markers of osteoclast differentiation, calcitonin receptor (Calcr) and Ocstamp. Early chondrogenic differentiation of ATDC5 cells for 7 days in vitro, characterized by aggrecan (Acan) and collagen 2a1 (Col2a1) mRNA expression and proteoglycan production, was inhibited by both 50 mM ethanol and 5 mM acetate. Ethanol effects were not blocked by the alcohol dehydrogenase inhibitor 4-methylpyrazole. 50 mM ethanol retarded both ATDC5 cell growth and culture medium acidification. Inhibition of chondrogenic differentiation by 5 mM acetate was associated with elevated phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2 and decreased expression of transcription factors Sox9 and Runx2. In acetate-exposed cells, blocking of ERK1 and ERK2 phosphorylation with Trametinib prevented further reduction of Acan and Col2a1 mRNA expression. We conclude that ethanol-derived acetate mediates at least part of the induction of Calcr and Ocstamp expression and that acetate mimics the effects of ethanol on early chondrogenic differentiation.
Environmentally relevant lead exposure impacts gene expression in SH-SY5Y cells throughout neuronal differentiation.
Morgan RK, Tapaswi A, Polemi KM … +5 more , Tolrud EC, Bakulski KM, Svoboda LK, Dolinoy DC, Colacino JA
Toxicol Sci · 2025 Oct · PMID 40397994 · Full text
Lead (Pb) causes learning and memory impairments, but the molecular effects of continuous, environmentally relevant levels of exposure on key neurodevelopmental processes are not fully characterized. Here, we examine the...
Lead (Pb) causes learning and memory impairments, but the molecular effects of continuous, environmentally relevant levels of exposure on key neurodevelopmental processes are not fully characterized. Here, we examine the effects of a range of environmentally relevant Pb concentrations (0.16, 1.26, and 10 µM Pb) relative to control on neural differentiation in the SH-SY5Y cell model. Pb exposure began on differentiation day 5 and was continuous for the remaining days, and we assessed the transcriptome via RNA sequencing at several time points. The bulk of detected changes in gene expression occurred with the 10 µM Pb condition. Interestingly, changes associated with the lower 2 exposures were differentiation stage-specific, with aberrant expression of several genes (e.g. COL3A1, HMOX1, NQO1, and CCL2) observed during differentiation on days 9, 12, and 15 in both the 0.16 and 1.26 µM Pb conditions, which disappeared by the time differentiation concluded on day 18. We observed 6 co-expression clusters of genes during differentiation, and 10 µM Pb significantly perturbed 2 clusters, one involved in cell cycling and DNA repair and the other in protein synthesis. Benchmark concentration analysis identified many genes affected by levels of Pb at or below the current US reference value (3.5 µg/dl), and Pb-affected genes were enriched for pathways including stress responses, DNA repair, misfolded protein response, mitosis, and neurotransmitter production. This work highlights potential new mechanisms by which environmentally relevant concentrations of Pb impact gene expression throughout neural differentiation and may result in long-lasting implications for neural health and cognition.
Bayesian refinement of a physiologically based pharmacokinetic model for ethylbenzene pharmacokinetics in mice, rats, and humans.
Lin YS, Hsieh NH, Schlosser PM … +2 more , Dzierlenga MW, Ju H
Toxicol Sci · 2025 Aug · PMID 40378245 · Full text
Although several physiologically based pharmacokinetic (PBPK) models exist for ethylbenzene (EB), a systematic evaluation of variability and uncertainty across species is still missing. This study aims to develop and val...
Although several physiologically based pharmacokinetic (PBPK) models exist for ethylbenzene (EB), a systematic evaluation of variability and uncertainty across species is still missing. This study aims to develop and validate a universal, population-based Bayesian PBPK model to study EB inhalation kinetics for mice, rats, and humans using a Markov Chain Monte Carlo (MCMC) approach to enhance model parameterization and its predictions. A comprehensive database was used for calibration and evaluation. This refined model demonstrates a superior or comparable fit to the data when contrasted with earlier published PBPK models for EB. Except for mouse fat and lung tissues, the concentrations of EB in tissues and its metabolites were generally within residual errors of 3-fold across species. Specifically, urinary concentrations of mandelic acid, the primary downstream metabolite of EB, are generally well predicted in both rats and humans. Our approach offers a better characterization of pharmacokinetic variability and uncertainty than previous EB models, with strong agreement between predictions and experimental data. This supports efforts to adopt PBPK modeling for data extrapolation from animal studies to inform human health assessments, thereby greatly promoting public health. The confidence in applying the current refined PBPK model could be increased by confirming the predictions made by our analysis with additional targeted data collection. Impact Statement: This study presents a refined Bayesian PBPK model that captures EB pharmacokinetics across species. It outperforms previous EB models and improves interspecies extrapolation for human health risk assessment.
Quantitative and qualitative concordance between clinical and nonclinical toxicity data.
Weitekamp CA, Paul Friedman K, Harrill AH … +10 more , Auerbach S, Bandele O, Barton-Maclaren TS, Fitzpatrick S, Mezencev R, Santillo M, Simanainen U, Smith D, Whelan M, Thomas RS
Toxicol Sci · 2025 Aug · PMID 40378198 · Publisher ↗
Although rodent toxicity testing plays an important role in evaluating human hazards of environmental and industrial chemicals, evaluating the concordance of the rodent testing results with human effects is challenging b...
Although rodent toxicity testing plays an important role in evaluating human hazards of environmental and industrial chemicals, evaluating the concordance of the rodent testing results with human effects is challenging because these chemicals cannot be tested in humans. In this study, we evaluate the quantitative and qualitative concordance of lowest observed adverse effect levels (LOAELs) and adverse endpoints between in vivo and in vitro models of human health and human clinical trials of pharmaceuticals. Rodent human equivalent dose-adjusted LOAEL (LOAELHED) values and human LOAEL values for the sensitive effect in each species were moderately correlated in a protective context. When matched rodent and human effects were evaluated, the quantitative correlation in dose did not improve, and the qualitative balanced accuracy in effects was low, suggesting limited predictivity. Absolute differences in rodent LOAELHED and human LOAEL values were nearly 1 log10 unit with rodent LOAELHED values consistently higher; however, rodent LOAELHED values were less than the human LOAEL values for >95% of drugs when divided by typical composite uncertainty factors. In comparison, in vitro bioactivity administered equivalent dose (AED) values showed a similar moderate correlation and absolute differences with human LOAEL values, but in vitro bioactivity AED values were consistently lower. When in vitro bioactivity AED values were compared with rodent LOAELHED values, the correlation was lower and differences larger relative to human LOAEL comparison. Overall, the study expands previous efforts evaluating the concordance of rodent toxicological testing results with human responses and presents objective expectations for alternative toxicity testing approaches.
Integrating network analysis and machine learning to elucidate chemical-induced pancreatic toxicity in zebrafish embryos.
Schwartz AV, Sant KE, George UZ
Toxicol Sci · 2025 Aug · PMID 40373795 · Full text
Zebrafish (Danio rerio) are a popular vertebrate model for high-throughput toxicity testing, serving as a model for embryonic development and disease etiology. However, standardized protocols using zebrafish tend to expl...
Zebrafish (Danio rerio) are a popular vertebrate model for high-throughput toxicity testing, serving as a model for embryonic development and disease etiology. However, standardized protocols using zebrafish tend to explore pathologies and behaviors at the organism level rather than at the organ-specific level. This study investigates the effects of chemical exposures on pancreatic function in whole-embryo zebrafish by integrating network analysis and machine learning, leveraging widely available datasets to probe an organ-specific effect. We compiled transcriptomics data for zebrafish exposed to 53 exposures from 25 unique chemicals, including halogenated organic compounds, pesticides/herbicides, endocrine-disrupting chemicals, pharmaceuticals, parabens, and solvents. All raw sequencing data were processed through a uniform bioinformatics pipeline for re-analysis and quality control, identifying differentially expressed genes and altered pathways related to pancreatic function and development. Clustering analysis revealed 5 distinct clusters of chemical exposures with similar impacts on pancreatic pathways, with gene co-expression network analysis identifying key driver genes within these clusters, providing insights into potential biomarkers of chemical-induced pancreatic toxicity. Machine learning was utilized to identify chemical properties that influence pancreatic pathway response, including average mass and biodegradation half-life. The random forest model achieved robust performance (4-fold cross-validation accuracy: 74%) over eXtreme Gradient Boosting, support vector machine, and multiclass logistic regression. This integrative approach enhances our understanding of the relationships between chemical properties and biological responses in a target organ, supporting the use of zebrafish whole embryos as a high-throughput vertebrate model. This computational workflow can be leveraged to investigate the complex effects of other exposures on organ-specific development.
Nicotinamide mononucleotide ameliorates impaired testicular spermatogenesis in uranium-exposed mice by modulating glycolytic pathways.
Wu H, Huang B, Zhou Z … +7 more , Lei X, Zhang Y, She W, Peng Q, Zhu Y, Wang J, Dong M
Toxicol Sci · 2025 Aug · PMID 40372707 · Publisher ↗
Natural uranium is a ubiquitous element in the environment, and human exposure to low levels of uranium is unavoidable. Several concerns have recently been raised about the reproductive effects of chronic exposure to low...
Natural uranium is a ubiquitous element in the environment, and human exposure to low levels of uranium is unavoidable. Several concerns have recently been raised about the reproductive effects of chronic exposure to low levels of uranium. Therefore, the aim of this study was to investigate the protective effect of nicotinamide mononucleotide (NMN) on uranium exposure-induced testicular sperm function in mice. To this end, a research model was established in which testicular damage and spermatogenic dysfunction were induced in adult male mice by intraperitoneal injection of 2 different doses of uranyl nitrate. Following a week of intraperitoneal injection, the mice were given oral doses of 500 mg/kg of NMN. The results demonstrated a decline in testicular weight and epididymis weight, along with a reduction in sperm count, in comparison to the control group. Subsequent observation of testicular morphology revealed the presence of disorganized seminiferous tubules, characterized by reduced area and diameter. Concurrently, a downregulation of the anti-apoptotic factor (Bcl-2) and an upregulation of the apoptotic factor (Bax) were observed in the testis. In addition, significant changes in the testicular genetic expression levels of supporting cell (SCs) markers (WT1, SOX9, PCNA, and Vimentin) and the expression of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) were detected. NMN treatment resulted in a significant enhancement of testicular function compared with saline-treated uranium-exposed mice. Similar findings were similarly obtained in an in vitro cellular model validation.This study provides evidence that NMN has a positive effect on regulating sperm disorders in the testes of uranium-exposed mice.
Identifying environmental chemicals impacting neurodevelopment using a random mixture-based screening approach.
Hu W, Xing L, Park J … +7 more , Taylor-Blake B, Krantz JL, Hsiao YC, Liu CW, Lamberti SU, Lu K, Zylka MJ
Toxicol Sci · 2025 Aug · PMID 40347494 · Full text
Environmental exposures can impact brain development and contribute to neurodevelopmental disorder risk. In this study, we leveraged insights from in vitro high-throughput screening studies that examined the developmenta...
Environmental exposures can impact brain development and contribute to neurodevelopmental disorder risk. In this study, we leveraged insights from in vitro high-throughput screening studies that examined the developmental toxicity of environmental chemicals to select 47 chemicals for in vivo testing as complex random mixtures in pregnant female mice. Our objectives were to identify mixtures that impact key neurodevelopmental endpoints-embryonic body, brain, and placenta weight-and subsequently to use mass spectrometry to ascertain which chemicals from each active mixture entered the developing brain following gestational exposure. We identified 3 chemicals that entered the embryonic brain and reduced embryonic brain weight: Perfluorooctanoic acid (PFOA), fenpyroximate, and 4-tert-octylphenol. Given its effect on embryonic brain weight and its widespread presence in environmental samples, we selected PFOA for further study using single-nuclei RNA sequencing. We found that PFOA altered neural progenitor cell proliferation and neuronal differentiation in the developing mouse cerebral cortex. Furthermore, we found that gestational exposure to PFOA disrupted neurodevelopment by altering the cell cycle in neural progenitor cells of males and females. In conclusion, we identified environmental chemicals that impact neurodevelopmental processes in vivo and found that single-nuclei RNA sequencing can provide new insights into the cellular mechanisms of neurotoxicity.
Perfluorooctane sulfonate exposure and alcohol-associated liver disease severity in a mouse chronic-binge ethanol feeding model.
Ekuban FA, Gripshover TC, Ames P … +15 more , Biswas K, Bolatimi OE, Abramson J, Iyer M, Luo J, Ekuban A, Hwang JY, Park JW, Banerjee M, Watson WH, Wahlang B, Bello D, Schlezinger JJ, McClain CJ, Cave MC
Toxicol Sci · 2025 Aug · PMID 40347464 · Full text
Exposure to pollutants, including the ubiquitous "forever chemical," perfluorooctane sulfonate (PFOS) has increasingly been associated with metabolic dysfunction-associated steatotic liver disease. Recent epidemiological...
Exposure to pollutants, including the ubiquitous "forever chemical," perfluorooctane sulfonate (PFOS) has increasingly been associated with metabolic dysfunction-associated steatotic liver disease. Recent epidemiological evidence has identified associations between per- and polyfluoroalkyl substances (PFAS) exposure and increased liver injury in alcohol consumers, suggesting potential interactions between these exposures. However, the intersection of pollutant exposures and alcohol-associated liver disease (ALD) is not well studied. We hypothesize that pollutants may disrupt hepatic metabolism to modify ALD severity. Recently, we developed a two-hit (ethanol [EtOH] plus pollutant) mouse model, enabling testing of this hypothesis. Here, we elucidate the metabolic and disease-modifying effects of PFOS in this model. Male C57BL/6J mice were fed isocaloric control or 5% EtOH Lieber-DeCarli diet for 15 days. From day 6 of feeding, mice were concurrently gavaged with 1 mg/kg PFOS or 2% tween-80 vehicle for 10 days, followed by a 5 g/kg EtOH binge dose and euthanized 5 to 6 h later. Approximately 60% of the administered PFOS dose accumulated in the liver. PFOS exacerbated EtOH-induced hepatic steatosis and was associated by higher levels of plasma very low-density lipoprotein and alanine aminotransferase. PFOS upregulated hepatic EtOH-metabolizing enzymes and lowered blood alcohol levels. Ingenuity Pathway Analysis (IPA) Top Toxicity Functions/Lists associated with hepatic gene expression following PFOS co-exposure in EtOH-fed mice included: Fatty acid metabolism and liver steatosis; nuclear receptor activation, cytochrome P450, and reactive oxygen species; apoptosis; liver fibrosis; and hepatocellular carcinoma (HCC). Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses similarly revealed enrichment in fatty acid, xenobiotic, alcohol, or glutathione metabolic processes; and peroxisome proliferator-activated receptor (PPAR) signaling. PFOS upregulated hepatic expression of several nuclear receptors (e.g. Pparα, Car, and Pxr) and their P450 target genes (e.g. Cyp4a10, Cyp2b10, and Cyp3a11) by real-time-PCR or Western blot, confirming key IPA predictions. PFOS is a metabolism-disrupting chemical that worsens ALD severity. PFOS activated hepatic nuclear receptors and enriched hepatic transcriptional pathways associated with steatosis, xenobiotic metabolism, oxidative stress, cell death, fibrosis, and HCC. These data demonstrate a novel mechanism whereby PFOS exacerbates ALD through coordinated dysregulation of lipid homeostasis and liver injury, potentially mediated by nuclear receptor activation. The identification of PFOS as an ALD risk modifier highlights the critical need to evaluate environmental pollutants as potential contributors to liver disease progression. More data are required on environmental pollution as a disease-modifying factor in ALD. Impact Statement: The present study demonstrates that PFOS exacerbates alcohol-induced liver injury through nuclear receptor activation and metabolic disruption. These findings provide novel insights into how environmental pollutants can act as significant risk modifiers in ALD, how PFAS exposures may contribute to the growing public health burden of liver disease, and underscore the importance of considering combined risk factors in developing targeted interventions.
A Food and Drug Administration/Center for Drug Evaluation and Research nonclinical perspective on the use of human-induced pluripotent stem cell-derived cardiomyocyte data for cardiovascular safety assessment and regulatory decisions.
Simpson NE, Bourcier T, Sadrieh N
Toxicol Sci · 2025 Aug · PMID 40341948 · Publisher ↗
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a new approach methodology (NAM) used in regulatory submissions to the U.S. Food and Drug Administration (FDA). This article builds on the previo...
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a new approach methodology (NAM) used in regulatory submissions to the U.S. Food and Drug Administration (FDA). This article builds on the previous FDA analysis using a new search strategy to provide an updated landscape of hiPSC-CM studies submitted to the FDA for review. The current search method is more comprehensive than the previous ones, emphasizing the importance of standardized keywords in study titles for easier identification of NAMs submitted to the FDA. Here, the authors report an increase in hiPSC-CM studies submitted to the FDA, with most using the multielectrode array platform. In this new analysis, the authors observed that the study methodology, context of use, and reasons for submission are often unclear, despite their importance for regulatory acceptance and review. hiPSC-CM study results are not discussed in many archived reviews, suggesting limited impact on regulatory decisions. Detailed reporting to characterize the clinical relevance of findings and systematic submission of hiPSC-CM studies to better understand their predictivity compared with familiar nonclinical assessment methods are key components from a Pharmacology/Toxicology perspective to increase regulatory use of this subset of NAMs.
Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice.
Shukla R, Kannan A, Laws MJ … +4 more , Wagoner Johnson A, Flaws JA, Bagchi MK, Bagchi IC
Toxicol Sci · 2025 Jul · PMID 40323316 · Full text
Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. Although past research pre...
Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. Although past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed chronically to a mixture of phthalates for 12 mo through ad libitum chow consumption. Our studies revealed that continuous exposure to this phthalate mixture led to uterine hyperplasia with a significant increase in gland-to-stroma ratio. Endometrial hyperplasia is commonly caused by heightened estrogenic action and inflammatory response in the uterus, leading to increased proliferation of endometrial epithelial cells. Indeed, we observed a marked upregulation of several known estrogen-regulated genes, proinflammatory chemokines, elevated homing of macrophages, and increased KI67 staining in the endometrial epithelial cells upon phthalate exposure. Several signaling pathways, including the MAPK/ERK and Wnt/β-Catenin pathways, promote cell proliferation, leading to the hyperproliferative state of the endometrial cells. Our studies revealed no alteration of the MAPK/ERK pathway but a marked enhancement of the Wnt/β-Catenin signaling pathway in phthalate-exposed uteri. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.
4-Methylpyrazole-mediated inhibition of cytochrome P450 2E1 protects renal epithelial cells, but not bladder cancer cells, from cisplatin toxicity.
Akakpo JY, Abbott E, Woolbright BL … +4 more , Ramachandran A, Schnellmann RG, Wallace DP, Taylor JA
Toxicol Sci · 2025 Jul · PMID 40323313 · Full text
Cisplatin is an effective chemotherapeutic drug for the treatment of bladder cancer, though cisplatin-induced nephrotoxicity (CIN) occurs in ∼20% to 30% of patients, limiting its clinical use. Evidence has shown that cyt...
Cisplatin is an effective chemotherapeutic drug for the treatment of bladder cancer, though cisplatin-induced nephrotoxicity (CIN) occurs in ∼20% to 30% of patients, limiting its clinical use. Evidence has shown that cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme expressed in proximal tubules, mediates the production of reactive oxygen species during cisplatin-induced injury. Previously, we showed that the repurposed drug 4-methylpyrazole (4MP) blocks CYP2E1 activity. Here, we investigated the potential protective effects of 4MP against CIN. Male and female C57BL/6J mice were treated intraperitoneally (i.p.) with a single 20 mg/kg dose of cisplatin for 3 days or 9 mg/kg/wk for 4 wk with or without 50 mg/kg 4MP as a co-treatment. Our findings revealed that acute treatment with cisplatin induced severe histological tubular damage and elevated plasma BUN and creatinine levels in male but not female mice. This difference correlated with higher basal CYP2E1 expression in the kidneys of male mice compared with female mice. We also found that cisplatin increased renal CYP2E1 activity and that inhibition of CYP2E1 with 4MP significantly reduced cisplatin-induced cell death in male mice and primary normal human kidney cells. By contrast, human bladder cancer cells do not express CYP2E1, and treatment with 4MP did not interfere with cisplatin's anticancer effects in human bladder cancer HTB9 cells. This study highlights the critical role of CYP2E1 in CIN and suggests that its inhibition with 4MP in the kidney is a potential prophylactic therapeutic option to prevent CIN in bladder cancer patients without affecting its antineoplastic effect.
Developmental exposure to 1,4-dioxane, a volatile organic compound of emerging concern, induces immediate phenotypic, transcriptomic, and adult-onset neurodevelopmental effects.
Connell ML, Akemann C, Wu CC … +5 more , Kintzele E, Cavaneau E, Gonzalez GF, Baker BB, Baker TR
Toxicol Sci · 2025 Aug · PMID 40323311 · Full text
1,4-Dioxane, a synthetic volatile organic compound (VOC), has been found in products including paints, cosmetics, and pesticides as well as food products and drinking water. Contamination in groundwater poses significant...
1,4-Dioxane, a synthetic volatile organic compound (VOC), has been found in products including paints, cosmetics, and pesticides as well as food products and drinking water. Contamination in groundwater poses significant environmental and public health risks due to its high mobility and widespread human exposure through vapor intrusion and multiroute exposure pathways. Adverse health effects have been observed as a result of exposure to this compound; however, there is little research on the developmental and reproductive effects. Controlled VOC exposures [0.004, 0.40, and 40 parts per million (ppm)] of zebrafish embryos were conducted in sealed glass vials over a developmental period (120 h). Endpoints evaluated were mortality, abnormalities, larval behavior, transcriptomics, and adult-onset effects. The behavior of zebrafish larvae was significantly altered for the 40 ppm group. Expression of key genes (insig1, tbc1d10aa) was observed immediately following exposure and some persisted into adulthood. The top dysregulated diseases and disorders pathways in every concentration were cancer, organismal injury and abnormality, endocrine system disorders, gastrointestinal disease, and neurological disorders. Pathways of note enriched in larval and adult tissues include endocrine gland tumorigenesis, insulin resistance, movement disorders, cell survival, and cellular homeostasis. Specific reproductive pathways included pelvic, genital, uterine, and mammary tumors and carcinomas, however, there was no significant effect on adult zebrafish fertility. This study moves the field forward by integrating a novel zebrafish model and lifespan approach, shedding new light on understudied implications of low-level VOC exposure, ultimately informing public health policies to mitigate the risks associated with this ubiquitous environmental contaminant.
Incorporating Metabolic Competence into High-Throughput Profiling Assays.
Jurgelewicz A, Breaux K, Willis CM … +8 more , Harris FR, Byrd G, Witten J, Haggard DE, Bundy JL, Everett LJ, Deisenroth C, Harrill JA
Toxicol Sci · 2025 Aug · PMID 40317128 · Publisher ↗
High-throughput profiling assays such as high-throughput phenotypic profiling (HTPP) with Cell Painting and high-throughput transcriptomics (HTTr) with TempO-Seq have been used to characterize the bioactivity and potenti...
High-throughput profiling assays such as high-throughput phenotypic profiling (HTPP) with Cell Painting and high-throughput transcriptomics (HTTr) with TempO-Seq have been used to characterize the bioactivity and potential hazards associated with large inventories of chemicals. Although both methods offer broad coverage of molecular targets, a limitation is that the cell types used in these in vitro assays typically lack the xenobiotic metabolism capabilities of humans or laboratory animals used for in vivo testing. To address this limitation, this proof-of-concept study coupled the Alginate Immobilization of Metabolic Enzymes (AIME) platform to both assays and evaluated the impact of metabolism on chemical bioactivity in a breast cancer cell line, VM7Luc4E2. HTPP detected concentration-dependent increases in chemical bioactivity corresponding to increased estrogen receptor (ER) activation measured using an ER transactivation assay (ERTA) that had been previously coupled to the AIME platform in VM7Luc4E2 cells. Additionally, HTTr detected a greater number of active genes in the metabolic condition associated with increased ER activation. This corresponded to a greater number of active ER high-confidence (ERHC) gene signatures and/or metabolism-induced shifts in ERHC signature enrichment as a transcriptomic readout of ER activity. This study demonstrates that the high-throughput profiling assays can detect changes in chemical bioactivity between parent compounds and metabolites generated using the AIME platform in a reproducible way. Incorporating metabolic competence into high-throughput profiling assays will better inform next-generation risk assessment by capturing potential metabolite-based changes in bioactivity of test chemicals that may be missed by current screening approaches.
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