Toxicol. Sci. [JOURNAL]
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200 papers
Reader comment on: Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing.
Shafer TJ, Perron M, Mendez E … +3 more , Tan Y, Lowit A, Barone S
Toxicol Sci · 2025 Sep · PMID 40692290 · Publisher ↗
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AIVIVE: a novel AI framework for enhanced in vitro to in vivo extrapolation (IVIVE) of toxicogenomics data.
Chandra M, Li T, Tong W
Toxicol Sci · 2025 Oct · PMID 40692113 · Full text
In vitro to in vivo extrapolation (IVIVE) of toxicogenomics (TGx) data is essential for enhancing mechanism-based toxicity evaluations and minimizing animal use. However, translating in vitro findings to in vivo response...
In vitro to in vivo extrapolation (IVIVE) of toxicogenomics (TGx) data is essential for enhancing mechanism-based toxicity evaluations and minimizing animal use. However, translating in vitro findings to in vivo responses remains challenging. Generative adversarial networks (GANs) show potential in synthesizing gene expression data but often miss subtle, toxicologically relevant signals. We developed AIVIVE (artificial intelligence-aided IVIVE), a novel framework integrating GANs with local optimizers guided by biologically relevant gene modules to improve prediction accuracy. AIVIVE was trained using rat liver in vitro and in vivo transcriptomic data from the Open TG-GATEs (Toxicogenomics Project-Genomics-Assisted Toxicity Evaluation System) database. AIVIVE was evaluated using cosine similarity, root mean squared error (RMSE), and mean absolute percentage error (MAPE), demonstrating synthetic profiles comparable to real biological replicates. Notably, the model showed high overlap with differentially expressed genes, including Cytochrome P450 enzymes, which are often underrepresented in vitro. AIVIVE recapitulated in vivo CYP expression patterns, overcoming in vitro limitations. Further analysis revealed that AIVIVE captured liver-related pathways like bile secretion, steroid hormone biosynthesis, hepatitis C, and chemical carcinogenesis. It also captured gene expression changes linked to liver-specific adverse outcome pathways, such as Cyp2e1 upregulation in non-alcoholic fatty liver disease. Additionally, AIVIVE slightly outperformed real data in necrosis classification tasks, suggesting its potential for advancing toxicology predictions. These findings support AIVIVE as a tool for generating biologically relevant, in vivo-like profiles from in vitro data to enhance risk assessment, drug safety, and the 3Rs (reduce, replace, refine) principle.
Refining high-throughput in vitro-in vivo extrapolation modeling through incorporation of intestinal toxicokinetics.
Korol-Bexell E, Jarnagin AS, Brennan A … +5 more , Ford J, Bounds J, MacMillan DM, Hughes MF, Wetmore BA
Toxicol Sci · 2025 Oct · PMID 40692089 · Publisher ↗
UNLABELLED: New approach methods (NAMs) that combine high-throughput toxicity and toxicokinetic data have gained prominence as federal entities attempt to evaluate tens of thousands of commercial chemicals for human heal...
UNLABELLED: New approach methods (NAMs) that combine high-throughput toxicity and toxicokinetic data have gained prominence as federal entities attempt to evaluate tens of thousands of commercial chemicals for human health hazards. In vitro-in vivo extrapolation employing a generic high-throughput toxicokinetic (HTTK) model to convert in vitro points of departure (POD) to human equivalent doses (i.e. PODNAMs) has proven successful in translating in vitro data to real-world exposures; however, conservative assumptions, including consideration of only hepatic metabolism, have resulted in PODNAMs that are 10- to 100-fold more conservative when compared to available in vivo-based PODs. This effort evaluates the impact of incorporating intestinal metabolism through consideration of cytochrome P450 monooxygenase isozyme 3A4 (CYP3A4), a cytochrome P450 isozyme responsible for over 80% of intestinal clearance. For 11 chemicals, intrinsic clearance rates were derived in human liver and intestinal microsomes with and without inhibition of CYP3A4 to quantitate relative CYP3A4 contribution. Physiologically based TK simulations were conducted using Simcyp Simulator to (i) recapitulate the HTTK approach and (ii) incorporate CYP3A4 contribution into the elimination model, which by extension incorporates intestinal clearance occurring via CYP3A4. CYP3A4 contribution ranged from 0% to 71% across the chemicals tested, and estimates of oral bioavailability, steady-state concentration, and fraction escaping gut metabolism typically decreased with increasing CYP3A4 involvement. Further, incorporation of in vitro PODs with this refined model showed a concomitant increase in PODNAMs, indicating that incorporating such information into HTTK provides more predictive risk-based prioritization of the commercial chemical space. IMPACT STATEMENT: The toxicokinetic model presented herein incorporates intestinal metabolism into an established generic toxicokinetic model designed for New Approach Method application. Considering CYP3A4 contribution as a surrogate for intestinal metabolism is sufficient and results in improved estimates of NAM-based POD for risk prioritization.
Response to reader comment on: Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing.
Newell AJ, Patisaul HB
Toxicol Sci · 2025 Sep · PMID 40692088 · Publisher ↗
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Detection of developmental toxicity of the anti-COVID-19 drug molnupiravir using gastruloid-based in vitro assays.
Huntsman MC, Marikawa Y
Toxicol Sci · 2025 Sep · PMID 40692086 · Full text
In pharmaceutical drug development, animal tests are traditionally required to conduct comprehensive toxicity assessments before initiating human clinical trials. However, animal tests are time-consuming and can hinder t...
In pharmaceutical drug development, animal tests are traditionally required to conduct comprehensive toxicity assessments before initiating human clinical trials. However, animal tests are time-consuming and can hinder the rapid development of drugs needed to combat urgent health crises, such as the COVID-19 pandemic. Therefore, faster non-animal alternatives are critical to accelerating preclinical toxicity assessments. Molnupiravir, an antiviral medication authorized for emergency use to treat COVID-19, is an oral pro-drug that is metabolized into its active form, N4-hydroxycytidine (NHC). The developmental toxicity of molnupiravir was initially identified in preclinical animal studies. The present study aims to determine whether in vitro assays using gastruloids-three-dimensional aggregates of pluripotent stem cells that mimic axial elongation morphogenesis of early embryos-can effectively detect the developmental toxicity of molnupiravir in a clinically relevant context. In our experiments, NHC at 20 μM significantly impaired the morphological progression and altered the gene expression profiles in gastruloids derived from mouse P19C5 stem cells. Similarly, in a human embryonic stem cell-based morphogenesis model, NHC reduced the aggregate size at 10 μM and induced significant gene expression changes at concentrations as low as 2.5 μM. Notably, these NHC concentrations are comparable to the plasma levels observed in humans (approximately 10.8 μM) following administration of the clinically recommended dose of molnupiravir. These findings demonstrate that gastruloid-based assays can reliably detect the developmental toxicity of NHC at clinically relevant concentrations, supporting their utility as non-animal tools for expediting preclinical developmental toxicity assessments.
Computationally informed point of departure evaluation for proarrhythmic cardiotoxicity assessment using 3D engineered cardiac microtissues from human iPSC-derived cardiomyocytes.
Daley MC, Bronk P, Kim TY … +5 more , Soepriatna AH, Tran CT, Mende U, Coulombe KLK, Choi BR
Toxicol Sci · 2025 Sep · PMID 40692085 · Full text
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising new approach for in vitro proarrhythmic cardiotoxicity assessment. However, variation due to differentiation batch, individual sample...
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising new approach for in vitro proarrhythmic cardiotoxicity assessment. However, variation due to differentiation batch, individual sample variation, and non-linear responses to test drugs complicate the prediction of proarrhythmic drug concentrations. This study combines a computational human action potential (AP) model of hERG channel block with experimental data from three-dimensional hiPSC-CM engineered microtissues to optimize point of departure (POD) estimation of drug-induced prolongation of AP duration (APD). Computer simulations predicted that APD prolongation from hERG block follows a logistic curve and that >81% hERG block induced early afterdepolarizations (EADs), which significantly shifted the APD response curve. Curve fitting of APD response by logistic, bilinear breakpoint, and maximal curvature was more accurate prior to EAD onset. Goodness-of-fit testing indicated that logistic regression with ≥6 test concentrations was sufficient to accurately estimate PODs. Power analysis, based on experimental variations between batches (n = 14), molds (n = 57), and microtissues (n = 1701), predicted that PODs from 2 ∼ 3 batches with 10 microtissues per mold using a 5% threshold for APD prolongation detected proarrhythmic cardiotoxicity with a negligible false positive rate. We then applied this POD analysis to hiPSC-CM microtissue data after treatment with well-characterized drugs (i.e. cisapride, ranolazine, quinidine, and verapamil). Using bootstrapping, we estimated PODs and confidence intervals that matched concentrations known to cause proarrhythmic effects in patients. This study identified a robust method for calculating PODs for proarrhythmic cardiotoxicity risk in vitro and developed a framework for experimental design in this and other in vitro platforms.
Characterizing oxidative metabolites of 6-methylnicotine (6MN; aka Metatine): divergent metabolism from nicotine and identification of urinary biomarkers of exposure.
Xie Z, Conklin DJ, Jin L … +6 more , Miller A, Stowers H, Gallagher J, Keith RJ, Chen JY, Lorkiewicz P
Toxicol Sci · 2025 Oct · PMID 40690396 · Full text
The emergence of synthetic nicotine analogs in "tobacco-free" products, such as 6-methylnicotine (6MN; aka Metatine) in SPREE BAR, presents new regulatory and public health challenges. Alarmingly, little is known about t...
The emergence of synthetic nicotine analogs in "tobacco-free" products, such as 6-methylnicotine (6MN; aka Metatine) in SPREE BAR, presents new regulatory and public health challenges. Alarmingly, little is known about the metabolism of 6MN, its potential biomarkers of exposure, or its toxicity. In this study, we systematically characterized oxidized metabolites of 6MN in the urine of mice exposed to 6MN (via intraperitoneal or inhalation route) using liquid chromatography-high resolution mass spectrometry. Similarly, human urine samples were analyzed for 6MN metabolites after use of the SPREE BAR (Blue Razz Ice) product. Nine 6MN metabolites were identified in mouse urine, and each metabolite corresponded with a known nicotine metabolite, albeit with increased mass (i.e. m/z + 14 Da). Although 6MN and nicotine share oxidative routes, the metabolism of 6MN was dominated via N-oxidation (likely FMO3-mediated) rather than C-oxidation (likely CYP2A6-dependent) pathways, whereas nicotine metabolism is vice versa. Six 6MN metabolites were detected in human urine after SPREE BAR use, demonstrating strong cross-species metabolic concordance. Among these 6MN human metabolites, 6-methylcotinine, 6-methyl-3'-hydroxycotinine, and 6-methylcotinine-N-oxide emerged as potential urinary biomarkers of exposure due to their prevalence. Importantly, 6MN, yet not an equimolar dose of nicotine, induced acute neurotoxic effects in mice, highlighting distinct toxicological risks of 6MN compared with nicotine. This research revealed a distinct metabolic profile of 6MN and established a framework for biomonitoring of 6MN exposure. Together, these findings advanced our understanding of the metabolism of synthetic nicotine analogs and emphasized the importance of compound-specific profiling to support regulatory oversight of emerging nicotine-like products.
Orthogonal screening for thyroid stimulating hormone receptor modulators in human thyroid assays.
Foley B, Breaux K, Shobair M … +5 more , Feshuk M, Richard AM, Thomas RS, Paul Friedman K, Deisenroth C
Toxicol Sci · 2025 Oct · PMID 40690393 · Publisher ↗
The US Environmental Protection Agency has evaluated thousands of environmental chemicals within the ToxCast and Toxicology in the 21st Century (Tox21) programs using high-throughput screening (HTS) assays for molecular...
The US Environmental Protection Agency has evaluated thousands of environmental chemicals within the ToxCast and Toxicology in the 21st Century (Tox21) programs using high-throughput screening (HTS) assays for molecular targets across the hypothalamic-pituitary-thyroid axis. The thyroid stimulating hormone receptor (TSHR) is a critical regulator of thyroid development and function and essential for thyroid hormone synthesis. Hundreds of chemicals have been identified as potential modulators of the TSHR in a Tox21 HTS assay, but the mechanistic and biological relevance to humans is uncertain. The objectives of this study were to select a subset of active chemicals from the Tox21 TSHR assay, screen for agonist or antagonist activity in human primary thyrocyte assays to evaluate mechanistic effects on the native TSHR, and then extend screening to assess functional effects on thyroid hormone synthesis in human thyroid microtissues. A total of 72 (agonist mode) and 64 (antagonist mode) chemicals were selected for screening. A conventional two-dimensional screening assay was implemented as a primary screening strategy to evaluate thyroglobulin protein production as a biomarker for TSHR-dependent bioactivity in primary thyrocytes. Active chemicals were triaged for secondary screening in three-dimensional thyroid microtissue assays to evaluate the functional relevance to thyroid hormone synthesis. Final results revealed 2 agonist and 13 antagonist chemicals that demonstrated concordant activity across the 2 assay formats. The results support a strategic tiered testing paradigm whereby chemicals flagged for hazard potential from targeted HTS assays are evaluated in assays with enhanced biological relevance to the target tissue of interest to inform hazard characterization for putative thyroid-disrupting chemicals in humans.
Targeted RNA-sequencing of testes from fetal rats exposed to dicyclohexyl phthalate informs potency and adverse outcome pathway development.
Waterbury CR, Crockett MN, Conley JM … +2 more , Lambright CS, Wehmas LC
Toxicol Sci · 2025 Oct · PMID 40690386 · Publisher ↗
There is growing interest in introducing efficiencies in chemical safety assessment by reducing reliance on conventional chronic toxicity tests. One approach involves benchmark dose (BMD) analysis of gene expression data...
There is growing interest in introducing efficiencies in chemical safety assessment by reducing reliance on conventional chronic toxicity tests. One approach involves benchmark dose (BMD) analysis of gene expression data from short-term adult animal studies to assess chronic toxicity. Whether this approach applies to chemicals that cause developmental and reproductive toxicity (DART), such as dicyclohexyl phthalate (DCHP), is unknown. The present study aimed to (i) investigate how well BMD analysis of gene expression data performed at indicating DART potency using an in utero rat exposure (gestational days 14 to 18 at 0, 100, 300, 600, and 900 mg DCHP/kg-day), and (ii) inform new key events in phthalate syndrome through use of targeted RNA-sequencing. A sub-aim evaluated the consistency of existing polymerase chain reaction array vs. targeted RNA-sequencing data, which were relatively similar. BMD analysis identified gene set points-of-departure (PODs) of 10.4 and 24.7 mg/kg-day, which were similar to some of the lowest PODs for DCHP DART endpoints at 10 mg/kg-day. Further analysis of targeted RNA-sequencing results identified Testin (found in Sertoli cell junctions) as one of a few significantly upregulated genes. Upstream regulator analysis predicted inhibition of SREBPs and gonadotropins, consistent with downregulation of steroidogenesis genes and testosterone production. These results show that transcriptomics can quickly identify a gene set POD comparable to that of DART PODs while also discovering upregulation of Testin as a putative mediator of rodent phthalate syndrome. These data present an important first step to evaluating a transcriptomic approach as an efficient and cost-effective means to assess chemical impacts related to DART.
Neurotoxicants driving glial aging: role of astrocytic aging in non-cell autonomous neurodegeneration.
Reina-Gonzalez P, Ay M, Langley M … +6 more , Plunk E, Strazdins R, Abu-Salah A, Anchan A, Shah A, Sarkar S
Toxicol Sci · 2025 Sep · PMID 40680177 · Full text
Astrocytes, the most abundant glial cells in the central nervous system (CNS), play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can un...
Astrocytes, the most abundant glial cells in the central nervous system (CNS), play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can undergo senescence-a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors-in response to aging and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype. A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence, such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.
Correction to: Repeated exposure to eucalyptus wood smoke alters pulmonary gene and metabolic profiles in male Long-Evans rats.
Toxicol Sci · 2025 Dec · PMID 40570135 · Full text
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Adapting existing toxicokinetic models to relate perfluoroalkyl and polyfluoroalkyl intake to biomarkers in humans.
Dean KJ, Pouillot R, Van Doren JM … +1 more , Santillana Farakos SM
Toxicol Sci · 2025 Sep · PMID 40570094 · Full text
Exposures to per- and polyfluoroalkyl substances (PFAS) are associated with various adverse health outcomes, and a wide range of PFAS compounds have been detected in human serum, the environment, and food. Toxicokinetic...
Exposures to per- and polyfluoroalkyl substances (PFAS) are associated with various adverse health outcomes, and a wide range of PFAS compounds have been detected in human serum, the environment, and food. Toxicokinetic models, however, have been developed for only a subset of the compounds of interest. To facilitate reverse dosimetry and risk assessment for the less studied PFAS compounds in food, we developed and evaluated an approach to adapt existing toxicokinetic models for nonhuman primates to predict human serum levels. The approach was validated with perfluorooctanoic acid and perfluorooctanesulfonic acid data and applied to perfluorohexanesulfonate. Results indicate that the approach yields similar dosimetry estimates to those of other models, particularly those used for regulatory purposes, suggesting the methodology can be leveraged to inform decision-making in data-sparse spaces. Applying and adapting the framework will improve our ability to connect dietary PFAS exposures to endpoints of concern for a wide range of PFAS compounds.
The pyrethroid insecticide deltamethrin disrupts neuropeptide and monoamine signaling pathways in the gastrointestinal tract.
White AC, Krout IN, Mouhi S … +5 more , Blackmer-Raynolds L, Chang J, Kelly SD, Caudle WM, Sampson TR
Toxicol Sci · 2025 Sep · PMID 40569082 · Full text
Enteroendocrine cells (EECs) are a rare cell type of the intestinal epithelium. Various subtypes of EECs produce distinct repertoires of monoamines and neuropeptides, which modulate intestinal motility and other physiolo...
Enteroendocrine cells (EECs) are a rare cell type of the intestinal epithelium. Various subtypes of EECs produce distinct repertoires of monoamines and neuropeptides, which modulate intestinal motility and other physiologies. EECs also possess neuron-like properties, suggesting a potential vulnerability to ingested environmental neurotoxicants. One such group of toxicants is pyrethroids, a class of prevalent insecticides used residentially and agriculturally. Pyrethroids agonize voltage-gated sodium channels (VGSCs), inducing neuronal excitotoxicity, and affect the function of monoamine-producing neurons. Given their anatomical location at the interface with the environment and their expression of VGSCs, EECs likely represent a vulnerable cell type to oral pyrethroid exposure. In this study, we used the EEC cell line, STC-1 cells, to evaluate the effects of the common pyrethroid deltamethrin on the functional status of EECs. We find that deltamethrin impacts both the expression of serotonergic pathways and inhibits the adrenergic-evoked release of an EEC hormone, glucagon-like peptide 1, in vitro. In a mouse model of oral exposure, we found that deltamethrin induced an acute, yet transient, loss of intestinal motility in both fed and fasted conditions. This constipation phenotype was accompanied by a significant decrease in peripheral serotonin production and an inhibition of nutrient-evoked intestinal hormone release. Together, these data demonstrate that deltamethrin alters monoaminergic signaling pathways in EECs and regulates intestinal motility. This work demonstrates a mechanistic link between pyrethroid exposure and intestinal impacts relevant to pyrethroid-associated diseases, including inflammatory bowel disease, neurodegenerative disease, and metabolic disorders.
ToxPoint: Chemical risks and children's health-building on progress based on science, not panic.
Cohen SM, Rietjens IMCM, Levy L … +1 more , Alliance of Scientists for Evidence-Based Risk Assessment
Toxicol Sci · 2025 Jul · PMID 40567060 · Full text
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Maternal α-cypermethrin and permethrin exert differential effects on fetal growth, placental morphology, and fetal neurodevelopment in mice.
Elser BA, Hing B, Eliasen S … +8 more , Afrifa MA, Meurice N, Rimi F, Chimenti M, Schulz LC, Dailey ME, Gibson-Corley KN, Stevens HE
Toxicol Sci · 2025 Sep · PMID 40517329 · Full text
Pyrethroid insecticides represent a broad class of chemicals used widely in agriculture and household applications. Human studies show mixed effects of maternal pyrethroid exposure on fetal growth and neurodevelopment. A...
Pyrethroid insecticides represent a broad class of chemicals used widely in agriculture and household applications. Human studies show mixed effects of maternal pyrethroid exposure on fetal growth and neurodevelopment. Assessment of shared pyrethroid metabolites as a biomarker for exposure obscures effects of specific chemicals within this broader class. To better characterize pyrethroid effects on fetal development, we investigated maternal exposure to permethrin, a type I pyrethroid, and α-cypermethrin, a type II pyrethroid, on fetal development in mice. Pregnant CD1 mice were exposed to permethrin (1.5, 15, or 50 mg/kg), α-cypermethrin (0.3, 3, or 10 mg/kg), or corn oil vehicle via oral gavage on gestational days (GDs) 6 to 16. Effects on fetal growth, placental toxicity, and neurodevelopment were evaluated at GD 16. Cypermethrin, but not permethrin, significantly reduced fetal growth and altered placental layer morphology. Placental RNAseq analysis revealed downregulation of genes involved in extracellular matrix remodeling in response to α-cypermethrin. Both pyrethroids induced shifts in fetal dorsal forebrain microglia morphology from ramified to ameboid states; however, the effects of α-cypermethrin were more pronounced. The α-cypermethrin transcriptome of fetal dorsal forebrain implicated altered glutamate receptor signaling, synaptogenesis, and c-AMP signaling. Coregulated gene modules in individual placenta and fetal dorsal forebrain pairs were correlated and overlapped in biological processes characterizing synapses, mitotic cell cycle, and chromatin organization, suggesting placenta-fetal brain shared mechanisms with α-cypermethrin exposure. In summary, maternal exposure to the type II pyrethroid α-cypermethrin, but not type I pyrethroid permethrin, significantly affected placental development, fetal growth, and neurodevelopment, and these effects were linked.
Environmental exposome meets muscle wasting: unraveling the VOC-sarcopenia nexus through urinary metabolomics, inflammatory mediation, and network pharmacology in the NHANES cohort.
Shi M, Wei Y, Zhang W … +3 more , Wei W, Guo R, Luo F
Toxicol Sci · 2025 Aug · PMID 40504669 · Publisher ↗
Volatile organic compounds (VOCs) are pervasive environmental pollutants. However, their impact on sarcopenia, a condition characterized by progressive muscle loss and closely linked to numerous adverse health outcomes,...
Volatile organic compounds (VOCs) are pervasive environmental pollutants. However, their impact on sarcopenia, a condition characterized by progressive muscle loss and closely linked to numerous adverse health outcomes, remains poorly understood. Using data from the National Health and Nutrition Examination Survey (NHANES, 2011 to 2018), we analyzed 16 urinary metabolites of VOCs, adjusted for creatinine, to explore potential associations between VOC exposure and sarcopenia. Our findings consistently revealed a positive correlation across statistical models, with 2-aminothiazoline-4-carboxylic acid (a cyanide metabolite) contributing the greatest weight to the overall association. Subgroup analyses revealed particularly robust associations among younger women (≤50 years) and individuals with obesity (BMI ≥30), with inflammatory pathways emerging as key mediators. Through network toxicology, we identified pivotal targets and pathways involved in immune response, infection defense, apoptosis, and metabolic regulation. Notably, natural compounds such as quercetin have emerged as promising candidates for mitigating sarcopenia risk or slowing its progression. Together, these findings not only advance our understanding of the environmental determinants of sarcopenia but also highlight opportunities for targeted interventions.
Identification of four mechanisms of toxicity for per- and polyfluoroalkyl substances through transcriptomic profiling in human liver spheroids exposed to 24 PFAS.
Addicks GC, Rowan-Carroll A, Leingartner K … +5 more , Williams A, Meier MJ, Lorusso L, Yauk CL, Atlas E
Toxicol Sci · 2025 Sep · PMID 40504556 · Full text
Per- and polyfluoroalkyl substances (PFAS) are persistent and widespread contaminants. Epidemiological effects of PFAS include increased serum cholesterol, decreased immune response to vaccination and disease, and increa...
Per- and polyfluoroalkyl substances (PFAS) are persistent and widespread contaminants. Epidemiological effects of PFAS include increased serum cholesterol, decreased immune response to vaccination and disease, and increased incidence of cancer; however, PFAS modes of action remain unclear. Herein, we analyzed gene expression data from human liver spheroids that were exposed to several concentrations of 24 different PFAS. Benchmark concentration (BMC) response modeling was used to identify the 250 lowest gene BMCs for each PFAS. Hierarchical clustering analysis revealed 4 functionally diverse gene sets. Each gene set was affected by a distinct group of PFAS, whereas individual PFAS were usually part of more than 1 PFAS group. The biological roles of these gene sets relate to: (1) cholesterol biogenesis and cholesterol clearance (downregulated by 7 fluorocarbon or longer PFAS), putatively through discordance of cholesterol sensing by SCAP and LXR due to membrane integration of PFAS; (2) lipolysis (upregulated by 8 carbon or shorter PFAS); (3) innate immunity (downregulated by most PFAS); and (4) adaptive immunity (downregulated by sulfonate-type PFAS). The distinctions between the 4 PFAS groups suggest that PFAS can act through at least 4 independent mechanisms. The molecular characteristics of each PFAS group may be useful for understanding the molecular interactions leading to their effect on gene expression. Inclusion of some PFAS congeners in more than one PFAS group suggests that individual PFAS can act through multiple unrelated molecular interactions. This transcriptomic analysis offers a major advancement to the understanding of the molecular mechanisms underlying the effects of PFAS exposure and provides guidance for future work that may strengthen links between PFAS exposure and their proposed effects on human health.
Leveraging toxicogenomics in a weight of evidence approach to demonstrate a CAR-mediated mode of action for cyclobutrifluram-related mouse liver tumors.
Zhang F, Lord CC, Kende A … +5 more , Cowie DE, Doonan LB, Bailey KA, McInnes EF, Hofstra A
Toxicol Sci · 2025 Sep · PMID 40504036 · Publisher ↗
Toxicogenomics-based approaches are powerful tools for investigating the mode of action and human relevance of chemical-induced effects in animal toxicity studies, thus supporting human risk assessment and regulatory dec...
Toxicogenomics-based approaches are powerful tools for investigating the mode of action and human relevance of chemical-induced effects in animal toxicity studies, thus supporting human risk assessment and regulatory decisions. Here, we incorporated transcriptomics and metabolomics into a mode of action assessment of male mouse liver tumors observed following 80-week dietary exposure to cyclobutrifluram, a novel complex II succinate dehydrogenase inhibitor agrochemical. The assessment was conducted using the framework developed by the International Programme on Chemical Safety (IPCS) and the International Life Sciences Institute (ILSI), based on activation of the nuclear constitutive androstane receptor (CAR) and subsequent downstream events that have been established as human non-relevant. Cyclobutrifluram was shown to activate rat, mouse, and human CAR in in vitro transactivation assays. Dietary administration of cyclobutrifluram in male mice was associated with time- and/or dose-dependent liver weight increases, centrilobular hepatocellular hypertrophy, induction of CAR-related liver enzyme activity, specifically CYP2B and CYP3A, and hepatocellular proliferation. Transcriptomics analysis of mouse liver identified cyclobutrifluram-induced gene expression profiles consistent with CAR activation, based on published signatures and similarity to the reference CAR inducer phenobarbital. Metabolomics analysis of mouse plasma and liver further indicated that cyclobutrifluram induced similar biochemical changes as phenobarbital, with no evidence of any additional activity. Overall, this work demonstrates how toxicogenomics can provide valuable weight of evidence to identify the mode of action for chemical-induced rodent liver tumors and to exclude alternative modes of action.
Dermal absorption and metabolism of [14C]-C12 alkyl benzoate in Finsolv TN in human skin in vitro.
Dawick J, Kavanagh L, Roper C … +5 more , Paris K, Toner F, Cubberley R, Dent M, Pendlington R
Toxicol Sci · 2025 Sep · PMID 40504031 · Publisher ↗
C12 alkyl benzoate is present in the commercial emollient cosmetic ingredient C12-15 alkyl benzoate (Finsolv TN). Finsolv TN is a mixture of linear and branched esters of benzoic acid and aliphatic alcohols where linear...
C12 alkyl benzoate is present in the commercial emollient cosmetic ingredient C12-15 alkyl benzoate (Finsolv TN). Finsolv TN is a mixture of linear and branched esters of benzoic acid and aliphatic alcohols where linear C12 alkyl benzoate is a representative homolog with the shortest alkyl C-chain and lowest molecular weight. A preliminary non-GLP in vitro skin penetration study which monitored dermal bioavailability of all C12-15 alkyl benzoate constituents using GC-MS was carried out which demonstrated C12 alkyl benzoate could be considered a worst-case representative constituent to determine dermal absorption of the overall substance. Subsequently, [14C]-C12 alkyl benzoate was mixed into Finsolv TN, and applied, neat (10 µl/cm2), to dermatomed human skin mounted in a flow-through diffusion cell system. Receptor fluid was collected up to 24 h postdose and the skin was decontaminated at 8 h postdose. The absorbed dose, dermal delivery, potentially absorbable dose and dermally absorbed value of [14C]-C12 alkyl benzoate were 0.41%, 0.97%, 2.20%, and 2.97%, respectively. Metabolism during absorption was assessed in skin from the same donors, with no C12 alkyl benzoate detected in the receptor fluid, although the primary metabolite, [14C]-benzoic acid (>93%), was detected. A phenyl acetate esterase assay confirmed the presence of esterase activity in the donor skins used. Therefore, this study confirmed that dermal exposure of C12-15 alkyl benzoate (Finsolv TN) results in an absorbed dose of 2.97% completely metabolized to benzoic acid and aliphatic alcohol(s) in human skin. These findings indicate that a more in-depth investigation and assessment of toxicokinetic behavior (specifically for occupational exposures via the skin) provide opportunities to develop exposure-led strategies to avoid unnecessary animal testing allowing registrants to fulfill obligations to adhere to the "last resort" principle under REACH.
Chemical-induced heart defects using a transgenic zebrafish model.
Liu S, Kawanishi T, Shimada A … +4 more , Nukada Y, Miyazawa M, Takeda H, Tasaki J
Toxicol Sci · 2025 Sep · PMID 40504024 · Full text
Congenital heart defects (CHDs) are common birth defects attributed to genetic and environmental factors, such as pharmaceuticals and chemicals. Identifying modifiable environmental factors and understanding their impact...
Congenital heart defects (CHDs) are common birth defects attributed to genetic and environmental factors, such as pharmaceuticals and chemicals. Identifying modifiable environmental factors and understanding their impact on heart development is crucial for mitigating chemical-induced CHDs. Given the increasing number of chemical agents, efficient high-throughput systems are essential to evaluate their teratogenic potential during cardiovascular development, which is a major concern for chemical safety. In this study, we developed 3 transgenic zebrafish reporter lines, myl7:EGFP, kdrl:mRFP, and gata1:mKate2, which enable real-time visualization of myocardial and endocardial development and cardiac function based on blood flow. These transgenic embryos were used to investigate the teratogenic effects of chemicals well known to induce heart defects in mammals, including humans. Our real-time imaging revealed that the teratogens induced significant malformations in cardiac morphogenesis, including abnormal heart tube formation, incomplete cardiac looping, and reduced heart chamber size. These teratogens also disrupted the expression of cardiac progenitor markers, suggesting impaired cardiac progenitor development. These defects were detected at the early stages (4-48 h post-fertilization), suggesting that the stages of progenitor development to heart looping were most susceptible to teratogen exposure, i.e. the critical period for teratogen-induced heart defects. Functional defects, such as impaired blood flow, were observed using real-time imaging of the gata1-reporter line. This study demonstrates the utilization of transgenic zebrafish embryo models for high-throughput teratogenicity testing, which also allows us to analyze the mechanisms underlying chemical-induced heart defects. Therefore, our zebrafish models would contribute to the identification and reduction of risks associated with CHDs.
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