Toxicol. Sci. [JOURNAL]
Sun
200 papers
Molecular Dosimetry of DNA Adducts in Mice Exposed to Ethylene Oxide.
Liu CW, Peng J, Feng J … +6 more , Zhao H, Wang X, Gollapudi BB, Li AA, Bus JS, Lu K
Toxicol Sci · 2026 Jul · PMID 42391620 · Publisher ↗
Ethylene oxide (EtO) is a highly reactive industrial chemical and known human carcinogen with a mutagenic mode of action (MOA). Its genotoxicity is primarily mediated through alkylation of DNA, forming the mutagenic addu...
Ethylene oxide (EtO) is a highly reactive industrial chemical and known human carcinogen with a mutagenic mode of action (MOA). Its genotoxicity is primarily mediated through alkylation of DNA, forming the mutagenic adduct O6-(2-hydroxyethyl)-2'-deoxyguanosine (O6-HE-dG), albeit in small quantities, and the more abundant but less- or non-mutagenic N7-(2-hydroxyethyl)guanine (N7-HE-G) adduct. However, dose-response relationships of these DNA adducts, particularly at low inhalation exposure levels (< 3 ppm), remain unknown. These data are necessary to inform the biological plausibility of different statistical dose-response models that have been applied to human or animal data used for cancer risk assessment. In this study, B6C3F1 mice were exposed to EtO (0-200 ppm) for 6 hours/day over 28 consecutive days. DNA adducts in lung, liver, bone marrow, and mammary gland were quantified using highly sensitive mass spectrometry platforms. N7-HE-G was detected in all tissues and exposure groups, showing linear dose-response relationships in the low-dose range (≤ 1 ppm) and increased sharply and exposure-disproportionately in the high-dose range (≥ 50 ppm). Despite high sensitivity, O6-HE-dG was undetectable in any tissue at exposure < 50 ppm, reflecting adduct levels that are below the current quantifiable limit. At higher exposures (≥ 50 ppm), O6-HE-dG exhibited a dose-response pattern of N7-HE-G. Notably the mammary gland, despite being anatomically distant from the site of inhalation, exhibited the second-highest levels of both adducts at higher doses. This study provides the first reliable quantitative dose-response evidence of DNA adducts in tumor target and non-target (liver) tissues across a wide range of EtO exposures. The two DNA adducts differ markedly in their abundance, repairability and mutagenic potential and together provide a molecular MOA dose-response framework to provide the biological foundation for informing quantitative cancer risk assessment and genotoxic hazard characterization.
Exposure timing is a determinant of fine particulate matter (PM2.5) pulmonary, vascular and metabolic toxicity in male mice.
Ribble A, Haberzettl L, Hellmann J … +1 more , Haberzettl P
Toxicol Sci · 2026 Jul · PMID 42384942 · Publisher ↗
Exposure to fine particulate matter (PM2.5) air pollution is associated with an increased cardiometabolic disease risk. However, while exposure timing is recognized as an important toxicity determinant, the chronotoxicit...
Exposure to fine particulate matter (PM2.5) air pollution is associated with an increased cardiometabolic disease risk. However, while exposure timing is recognized as an important toxicity determinant, the chronotoxicity of PM2.5 exposure is less explored. To evaluate whether PM2.5 sensitivity depends on exposure timing, adult male C57/BL6 mice were exposed to concentrated ambient PM2.5 (CAP, 6 h/day, 30 days) either during the inactive (light) phase (Zeitgeber time, ZT1-7) or the active (dark) phase (ZT17-23). Metabolic health was assessed by measuring body weight, fasting blood glucose, and plasma insulin levels. Oxidative stress and inflammatory responses in aortas and lungs were examined by (qRT)-PCR, and pulmonary and circulating redox changes were measured calorimetrically. While CAP exposure during the active phase increased blood glucose levels, inactive phase exposure more profoundly increased antioxidant enzyme and inflammatory mRNA abundance in aortas and lungs. Inactive phase exposure also intensified pulmonary and systemic lipid peroxidation and increased the depletion of circulating nitric oxide and lung glutathione. Examining the ability to protect against CAP-induced pulmonary oxidative stress, we found that the pulmonary antioxidant enzyme mRNA expression showed circadian rhythmicity that peaked during the active phase. These data suggest that a superior pulmonary antioxidant defense potential during the active phase could contribute to the protection against the PM2.5-induced vascular and pulmonary effects, but not its impact on glucose homeostasis. Our study identified that exposure sensitivity depends on the exposure timing, which is of significance as it informs on timely susceptibility windows that could help to mitigate PM2.5 toxicity.
A fond farewell to Jeffrey Peters, editor-in-chief of ToxSci.
Harrill A
Toxicol Sci · 2026 Jul · PMID 42383683 · Publisher ↗
Abstract loading — click title to view on PubMed.
Aryl hydrocarbon Receptor Nuclear Translocator 2: A Forgotten Per-ARNT-Sim Transcription Factor.
Jahan I, Serrano Matos YA, Jayaraman A … +1 more , Joshi AD
Toxicol Sci · 2026 Jun · PMID 42377283 · Publisher ↗
Aryl hydrocarbon receptor nuclear translocator 2 is a member of the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcription factors involved in responding to various environmental, metabolic, and chemical...
Aryl hydrocarbon receptor nuclear translocator 2 is a member of the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcription factors involved in responding to various environmental, metabolic, and chemical signals. Initially known for its involvement in neurodevelopment, ARNT2 is now recognized as an essential binding partner for other transcription factors, including single-minded homologs 1 and 2 (SIM1, SIM2), neuronal PAS domain protein 4 (NPAS4), hypoxia-inducible factor 1 (HIF1), and plausibly Aryl hydrocarbon Receptor (AHR) to regulate stress adaptation, synaptic plasticity, immune signaling, and energy balance pathways. The role of ARNT2 has also been implicated in a plethora of pathologies, including inflammation, cardiovascular diseases, neurological disorders, metabolic diseases, and cancers. This review summarizes the current knowledge of ARNT2's structure, regulation, interacting partners, and its toxicopathological significance. A better understanding of ARNT2 biology may open new avenues for its characterization as a molecular target and designing novel therapeutic strategies across multiple diseases.
ToxMet: a web tool for toxicogenomic data analysis using genome-scale metabolic modeling.
Hari A, Xu Z, Smith Z … +6 more , Hendry JI, Auerbach SS, AbdulHameed MDM, Desai V, Wallqvist A, Pannala VR
Toxicol Sci · 2026 Jun · PMID 42371778 · Publisher ↗
Chemical toxicity assessment commonly includes in vivo rat exposure experiments, with transcriptomic measurements collected at various exposure times and chemical doses. The mechanisms underlying chemical-induced toxicit...
Chemical toxicity assessment commonly includes in vivo rat exposure experiments, with transcriptomic measurements collected at various exposure times and chemical doses. The mechanisms underlying chemical-induced toxicity are then inferred by analyzing changes in gene expression. Recently, genome-scale metabolic models (GSMs), which represent the metabolic network of a cell/organism and contain metabolites, reactions, genes, and the relationship between the genes and reactions, have been used to provide a systems-level understanding of gene expression. However, most of the algorithms that integrate gene expression with GSMs require familiarity with MATLAB or Python programming, making them less accessible for users without computational experience. Here, we introduce ToxMet (https://toxmet.bhsai.org), an open-access, user-friendly web application that provides tabular and graph-based network views to visualize the latest rat GSM (iRno v4.2) and predicts chemical-induced metabolic perturbations in rat tissues by integrating toxicogenomic measurements with the rat GSM. ToxMet uses two well-validated computational algorithms, TIMBR and Pheflux, to predict metabolic perturbations and provides the prediction results as interactive and downloadable tables, scatter plots, and network visualizations. As such, the web tool can process a maximum of 10 conditions for a single job, and the results can be used for dose-response studies to monitor organ metabolism at the subsystem level. We evaluated ToxMet's ability to predict toxicity mechanisms by applying it to publicly available toxicogenomic data for two exemplar toxicants: gentamicin and thioacetamide, which are known to induce kidney and liver injury, respectively. ToxMet predicted known toxicity mechanisms for both chemicals, thus demonstrating its ability to provide novel insights into the metabolic mechanisms of chemical-induced toxicity and aid in the discovery of biomarkers and therapeutics using gene expression data.
T-cell chromatin states reflect individual differences in ex vivo cytokine release and cytotoxicity induced by T-cell engager ERY22 in cynomolgus monkeys.
Iwata Y, Narushima Y, Harada A … +4 more , Sakamoto A, Ikegami H, Mishima M, Suzuki H
Toxicol Sci · 2026 Jun · PMID 42371773 · Publisher ↗
T-cell engager therapies, including CD3-bispecific antibodies, have demonstrated potent antitumor activity but frequently cause cytokine release syndrome (CRS). CRS is a systemic inflammatory response characterized by hi...
T-cell engager therapies, including CD3-bispecific antibodies, have demonstrated potent antitumor activity but frequently cause cytokine release syndrome (CRS). CRS is a systemic inflammatory response characterized by high levels of circulating cytokines and immune-cell hyperactivation, with symptoms ranging from mild features such as fever and fatigue to severe, life-threatening conditions including shock and multiorgan failure. Currently, both prophylactic measures and prompt post-onset treatment are essential for therapy with T-cell engagers. Although CRS mitigation strategies reduce its incidence and severity, marked interindividual variability in CRS remains: Some patients show no symptoms, whereas others develop severe symptoms under identical preventive measures. This study aimed to elucidate the mechanisms underlying the interindividual variability in cytokine release and cytotoxicity following stimulation with a T-cell engager. We used ERY22, a T-cell engager developed as a monkey surrogate of the human therapeutic candidate ERY974, an anti-GPC3/CD3 T-cell engager. ERY22 has been previously reported to induce severe CRS in cynomolgus monkeys following in vivo administration. When PBMCs from 16 cynomolgus monkeys and GPC3-expressing target cells were co-cultured ex vivo with ERY22, there was substantial interindividual variability in cytokine production and cytotoxicity. We hypothesized that epigenetic states in T cells modulate these responses; accordingly, we profiled pretreatment T-cell chromatin accessibility using ATAC-seq. Interindividual variability in cytokine production and cytotoxicity correlated with chromatin accessibility at loci associated with these processes. These findings advance understanding of personalized risk prediction and management of CRS in clinical settings.
DILI-Context: A Dose- and Exposure-Enriched Knowledge Base for Translational Liver Safety Assessment.
Zandie R, Betancort R, Khodaee F
Toxicol Sci · 2026 Jun · PMID 42366670 · Publisher ↗
Drug-induced liver injury (DILI) is a major cause of drug development failure and post-marketing withdrawal. While assessing clinical hepatotoxic risk is critical for decision-making, most benchmark datasets represent DI...
Drug-induced liver injury (DILI) is a major cause of drug development failure and post-marketing withdrawal. While assessing clinical hepatotoxic risk is critical for decision-making, most benchmark datasets represent DILI with categorical hazard labels rather than exposure-dependent risk measures. As a result, the current understanding of DILI risk focuses on hazard rather than context-dependent exposure risk. To address this limitation, we present DILI-Context, a dose- and exposure-enriched knowledge base that integrates hazard annotations with high-content regulatory and toxicological data sources. This framework incorporates therapeutic dose, treatment duration, and preclinical safety thresholds to contextualize hepatotoxic liability. Using this harmonized resource, we observe a consistent monotonic relationship between therapeutic dose and DILI severity, with higher daily dose requirements associated with greater hepatotoxic concern. Our results show that drugs with elevated DILI risk operate within significantly narrower therapeutic windows, demonstrated by systematic declines in both acute Therapeutic Index and chronic Margin of Safety across DILI categories. We also demonstrate that chronic no-effect thresholds (NOAEL-based metrics) more effectively discriminate DILI risk than lowest-effect endpoints (LOAEL). To further capture cumulative burden, we introduce Chronic Load Score that integrates dose magnitude and treatment duration. This metric significantly stratifies DILI concern levels and aligns with independent regulatory signals, including hepatic dose adjustment requirements in prescribing information. Together, these findings demonstrate that hepatotoxic liability is strongly linked to required systemic exposure and constrained safety margins. We further characterize the chemical-property landscape of included small molecules and provide a minimalist benchmark comparing Morgan fingerprint-only classifiers against classifiers enriched with exposure-derived covariates, demonstrating complementary predictive signal beyond structure alone under the cohort constraints of DILIrank 2.0. **DILI-Context** thus provides both a reproducible supplementary feature layer and an explicit resource for advancing exposure-aware DILI modeling.
MEHP exposure damages the basement membrane by suppressing the expression of its constituent proteins in peritubular myoid cells of the rat testis.
Acharya N, Richburg JH
Toxicol Sci · 2026 Jun · PMID 42316782 · Full text
The basement membrane (BM) is a crucial support structure of the seminiferous epithelium, mainly made up of collagens, fibronectin, laminins, and proteoglycans. Along with the collagen fiber network, the peritubular myoi...
The basement membrane (BM) is a crucial support structure of the seminiferous epithelium, mainly made up of collagens, fibronectin, laminins, and proteoglycans. Along with the collagen fiber network, the peritubular myoid cell (PTMC) forms the tunica propria, which acts as a protective barrier for the blood-testis barrier (BTB). Here, we examined how PTMCs respond to mono-2-ethylhexyl phthalate (MEHP) exposure by altering the transcriptomic and proteomic profiles of extracellular matrix proteins, which are essential structural components of the BM. Bulk RNA was used for transcriptomics, and protein lysates were prepared for proteomics from primary PTMC isolates. Interstitial fluid (IF) was utilized to assess the baseline microenvironment of the testis, and the in vivo relevance of the protein changes was confirmed through immunofluorescence of testis cross-sections. Gene Set Enrichment Analysis (GSEA) revealed a suppression of genes in the basement membrane-linked pathway after MEHP exposure. These findings are further supported by proteomics analysis of PTMC lysates. Notably, downregulation of key basement membrane components-such as collagen IV, fibronectin, laminin, and others-was observed alongside the classical complement activation pathway in the testis microenvironment, specifically in the interstitial fluid. The data indicate that MEHP exposure downregulated the expression of BM component proteins in PTMC, underscoring the interconnections among BM degradation, BTB disruption, spermatogenesis, and disorganization of seminiferous tubule architecture during MEHP-induced testicular injury.
Words Matter in Toxicology and Risk Assessment as They Impact Risk Communication.
Klaassen CD
Toxicol Sci · 2026 Jun · PMID 42297737 · Publisher ↗
Clear, consistent language is essential in toxicology and risk assessment because terminology directly affects risk communication and understanding. The original concept of a "No Harm Dose of Reasonable Certainty" (NHDoR...
Clear, consistent language is essential in toxicology and risk assessment because terminology directly affects risk communication and understanding. The original concept of a "No Harm Dose of Reasonable Certainty" (NHDoRC) for an amount of chemical to which people can be exposed without detrimental effects is a plain language expression that clearly describes regulatory intent. However, the subsequent introduction and use of many related technical terms, such as NOAEL, BMD, RP and PoD, with almost the same meaning, can confuse non-experts and even scientists working in different regulatory entities. Similarly, ADI, RfD, TDI, MRL, HBGV and RV are all different abbreviations used in toxicology and risk assessment to describe the "acceptable" human dose in the context of food, water, and environmental chemicals. Likewise, the frequent use of terms such as margin of exposure (MoE) and margin of safety (MoS) interchangeably further complicates communication, as they are mathematically (and toxicologically) quite different. NOAEL and BMD10 are sometimes used interchangeably, but they usually represent two different points on the dose-response curve. Because of the many complications in the terminology used in risk assessment, a committee should be established to harmonize terminology across agencies and the wider risk assessment community, including industry and academia. The recommendations from such a committee would improve clarity, transparency, regulatory efficiency, and public trust in chemical risk assessment.
Tetrabromobisphenol S-induced developmental toxicity in zebrafish embryos: impacts on cytoskeletal proteins during gastrulation.
Serradimigni R, Sabatini HM, Chouinard C … +1 more , Dasgupta S
Toxicol Sci · 2026 Jul · PMID 42286410 · Publisher ↗
3,3',5,5'-Tetrabromobisphenol S (TBBPS) is an emerging brominated flame retardant that is widely detected in the environment, yet its toxic effects remain poorly understood. The objective of this study was to use zebrafi...
3,3',5,5'-Tetrabromobisphenol S (TBBPS) is an emerging brominated flame retardant that is widely detected in the environment, yet its toxic effects remain poorly understood. The objective of this study was to use zebrafish as a model and determine the effects of TBBPS exposure on gastrulation stages of embryogenesis. We initiated TBBPS exposures (0 or 40 µM) at 0.75 h post fertilization (hpf), phenotyped hourly through cleavage, blastula, and gastrula stages, and showed that TBBPS-treated embryos exhibited delay in development beginning at ∼4 hpf, a stage corresponding to early gastrulation, with significant mortality during late gastrulation. To examine the genetic basis of TBBPS-induced effects, we conducted mRNA sequencing on exposures from 0.75 to 7 hpf, revealing downregulation of cytoskeletal organization and tight junction assembly. We then fluorescent-stained for multiple cytoskeletal and tight junction proteins (α-tubulin, β-tubulin, Zonula occludens-1, filamentous actin [F-actin]) following exposures to a wide range of TBBPS concentrations (0, 0.004, 0.04, 0.4, 4, and 40 µM). F-actin expression was consistently upregulated across all exposed TBBPS concentrations. To determine whether activation of p38, a key regulator of F-actin polymerization, plays a role in TBBPS-induced F-actin disruption, we co-exposed embryos with TBBPS (0 or 40 µM) and a known p38 inhibitor (5 µM SB 203580) and assessed developmental phenotypes and F-actin levels. Treatment with p38 inhibitor significantly rescued TBBPS-induced effects, with co-exposure groups exhibiting cell stages and F-actin expression similar to controls. Collectively, these findings demonstrate that TBBPS exposures target gastrulation stages and define a novel mechanism in which TBBPS increases F-actin polymerization through p38/mitogen-activated protein kinase signaling pathways.
Hepatic inflammation after exposure to a mixture of low-dose arsenic and cadmium in a murine model of fatty liver disease.
Subramaniam NK, Gagnon N, Guilbert C … +6 more , Perinpanathan R, Abraham M, Goncalves C, Meliker JR, Rincon SD, Mann KK
Toxicol Sci · 2026 Jun · PMID 42281279 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden and major contributor to chronic liver disease. Evidence suggests arsenic (As) and/or cadmium (Cd) exposure may influence...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden and major contributor to chronic liver disease. Evidence suggests arsenic (As) and/or cadmium (Cd) exposure may influence MASLD development, yet effects of chronic low-dose metal mixtures on hepatic inflammation and immune responses remain unclear. Using the apolipoprotein E-knockout mouse model, we examined low-dose As and Cd exposure in male and female mice. We focused on hepatic steatosis and inflammation. Steatosis-related changes were assessed via lipid metabolism gene expression and PLIN2 levels. No significant changes were observed in males; however, females exposed to the metal mixture showed increased PLIN2 expression. In contrast, males exhibited an inflammatory phenotype following combined exposure. High-plex single-cell imaging (PhenoCycler) in male livers revealed increased Ki67+ hepatocytes, enhanced β-catenin signal, and elevated CD8+ T-cell infiltration, indicating enhanced proliferation and immune activation. These findings suggest sex-dependent responses to low-dose As and Cd, with females showing subtle steatotic changes and males a pronounced inflammatory signature. Collectively, combined metal exposure induces hepatic priming in both sexes; males show an increased inflammatory response with cellular proliferation in the absence of overt steatosis or fibrosis, whereas females demonstrate increased steatosis without inflammation or fibrosis.
Pulmonary vascular remodeling in rats following methamphetamine self-administration: toward a model of methamphetamine-associated pulmonary arterial hypertension.
Charoenpong P, Hall NM, Keller CM … +10 more , Kumar A, Chen L, Gatuz J, Siddiqui N, Yazdi FST, Fels Elliott DR, Dhillon NK, Murnane KS, Goeders NE, Walter RE
Toxicol Sci · 2026 Jun · PMID 42271610 · Full text
Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by pulmonary vascular remodeling. Methamphetamine (MA) exposure is strongly associated with PAH in humans, yet prior animal models rely on...
Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by pulmonary vascular remodeling. Methamphetamine (MA) exposure is strongly associated with PAH in humans, yet prior animal models rely on fixed, non-contingent dosing that does not replicate binge/crash patterns of human MA use. This study introduces an intravenous MA self-administration model to evaluate pulmonary vascular and cardiac consequences of human-like MA exposure. Sixteen male Wistar rats underwent an 8-wk protocol in which 8 rats self-administered MA and 8 yoked-saline controls received volume-matched saline. MA intake, lever-press behavior, and binge/crash dynamics were quantified. Lungs and hearts were harvested for histology, immunofluorescence, medial wall thickness quantification across vessel sizes, ventricular weights, and Fulton index. MA-exposed rats demonstrated escalating intake, with daily self-administered doses increasing from early-week values to a cumulative exposure of 526.7 ± 217.8 mg/kg over 8 wk. Distinct binge-and-crash patterns emerged as intake escalated over the exposure period. Compared with controls, MA-exposed rats exhibited pulmonary vascular remodeling predominantly in distal vessels, including medial hypertrophy, increased muscularization of small arterioles, and focal endothelial proliferation. Additional airway-centered parenchymal changes were observed in a subset of MA rats. No significant differences were found in right or left ventricular weights or Fulton index. Chronic MA self-administration induces early pulmonary vascular remodeling without cardiac hypertrophy, indicating that this behaviorally relevant model captures early pulmonary vascular changes relevant to MA-associated pulmonary vascular disease. This model provides a translational platform for investigating MA-induced pulmonary vascular injury and identifying therapeutic targets.
UVB light activates an S phase-dependent DNA damage response in human keratinocytes independent of oxidative stress.
An Y, Jan YH, Laskin JD
Toxicol Sci · 2026 Jun · PMID 42268659 · Publisher ↗
Ultraviolet B (UVB; 280 to 320 nm) radiation damages DNA in epidermal cells and contributes to the development of skin cancer. In response, keratinocytes activate a DNA damage response (DDR) that regulates DNA repair thr...
Ultraviolet B (UVB; 280 to 320 nm) radiation damages DNA in epidermal cells and contributes to the development of skin cancer. In response, keratinocytes activate a DNA damage response (DDR) that regulates DNA repair through signaling pathways involving the protein kinases ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated), and DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Activation of these kinases promotes recruitment of DNA repair proteins, including phosphorylated H2AX and p53, to sites of DNA damage. Treatment of primary human neonatal foreskin epidermal keratinocytes and HaCaT keratinocytes with UVB (2.5 to 50 mJ/cm2) resulted in dose- and time-dependent activation of DDR proteins. In HaCaT cells, DDR signaling was most pronounced in S phase compared with cells in G0/G1 or G2/M, as determined by flow cytometry and cell cycle synchronization. Confocal microscopy revealed the accumulation of phosphorylated DNA-PKcs and phosphorylated H2AX in discrete subnuclear foci in S-phase cells, consistent with recruitment to sites of DNA double-strand breaks. UVB also induced oxidative stress in HaCaT cells, as reflected by increased intracellular reactive oxygen species (ROS). Depletion of intracellular glutathione using buthionine sulfoximine significantly enhanced UVB-induced ROS production but had little or no effect on activation of DDR signaling. These findings demonstrate that UVB induces cell cycle-dependent DNA damage in human keratinocytes that is independent of oxidative stress. Understanding mechanisms of UVB activation of the DDR in keratinocytes will be important for elucidating molecular pathways contributing to skin carcinogenesis.
Disease-dependent airway epithelial responses to acute electronic cigarette aerosol exposure: a pilot single-cell analysis.
Van C, Mao PH, Nguyen J … +8 more , Jung KJ, Sampath N, Miller RA, Karpurapu M, Wold LE, Chung D, Christman JW, Chung S
Toxicol Sci · 2026 Jun · PMID 42244142 · Full text
Electronic cigarette (e-cig) use is increasingly common among individuals with asthma, yet the cell type-specific airway responses to e-cig exposure remain poorly understood. Because asthma is characterized by altered ep...
Electronic cigarette (e-cig) use is increasingly common among individuals with asthma, yet the cell type-specific airway responses to e-cig exposure remain poorly understood. Because asthma is characterized by altered epithelial composition and heightened inflammatory susceptibility, e-cig exposure could elicit disease-dependent epithelial responses in asthmatic airways. Here, we used single-cell RNA sequencing to define responses to acute e-cig exposure in human primary airway epithelial cells differentiated at the air-liquid interface from healthy and asthmatic donors. Cultures were exposed to e-cig aerosols for 30 min and analyzed 24 h later. Ten epithelial and stromal populations were identified. At baseline, asthma-derived cultures showed descriptive differences in cell-type composition compared with healthy-derived cultures, whereas acute e-cig exposure produced only modest additional changes in relative abundance. In contrast, transcriptional responses were disease dependent. Asthma-derived ATII, basal, goblet, mesenchymal, and mesothelial cells showed distinct inflammatory and immediate-early gene-expression changes, whereas healthy-derived cultures showed defense- and stress-associated responses. Pathway-level analysis showed enrichment of inflammatory signaling, injury/stress-response, and migration/ECM-related pathways in selected asthma-derived populations, whereas healthy-derived ATII and club cells were associated with defense and biotic-response pathways. SenMayo analysis showed cell type-specific patterns of senescence-associated gene set enrichment, with the strongest signal in club cells, together with increased CDKN2A and CDKN1A expression in asthma-derived epithelial populations. These findings suggest that asthma-associated epithelial states shape cell type-specific inflammatory, stress-associated, and senescence-related transcriptional responses to acute e-cig exposure.
Airborne contaminant exposure and bone development: a systematic review and meta-analysis.
Vera-Colón MKM, Meletz RM, Phillipson CN … +1 more , Sparks NRL
Toxicol Sci · 2026 Jun · PMID 42233341 · Full text
Air pollution, including particulate matter (PM10, PM2.5) and airborne metals (Cd, Hg, As, Pb) are a systemic health hazard, but osteotoxic effects remain underrecognized. We systematically synthesized human, animal, and...
Air pollution, including particulate matter (PM10, PM2.5) and airborne metals (Cd, Hg, As, Pb) are a systemic health hazard, but osteotoxic effects remain underrecognized. We systematically synthesized human, animal, and in vitro evidence on airborne contaminants and outcomes to skeletal health. Following Office of Health Assessment and Translation (OHAT) guidance, we searched PubMed and Google Scholar (2014-2024; final search November 24, 2024) for English-language studies relating PM or airborne metals to skeletal outcomes, excluding studies limited to adult occupational exposures, age-related bone disease, or non-peer-reviewed reports. Studies were screened and data extracted in Covidence. Risk of bias was assessed using tools from the Quality Assessment and Risk of Bias Tool Repository, and certainty of evidence was graded with GRADE. We used a random-effects meta-analyses model to estimate relative risks (RRs) interpreted as directional consistency hazards for bone loss, impaired osteoblast differentiation, enhanced osteoclast activity, bone marrow adiposity, epigenetic changes, and altered bone microarchitecture. Fifty-three studies met the inclusion criteria. Across outcomes, meta-analyses showed higher hazard risk in exposed versus control groups, with RRs ranging from 7 to 10; for example, bone loss (RR 7.12, 95% CI 4.20-12.06) and altered bone microarchitecture (RR 10.28, 95% CI 4.67-22.61). Epidemiologic and experimental evidence may implicate oxidative stress, inflammation, and epigenetic dysregulation as key mechanisms. Overall certainty was low to moderate due to residual confounding, exposure misclassification, and heterogeneity. Growing evidence indicates that airborne PM and metals adversely affect bone health, particularly during critical developmental windows, underscoring the need to integrate skeletal endpoints into health assessment and policy.
Artificial intelligence-augmented mixture toxicology: reframing unresolved risk at Camp Lejeune.
Pressman P, Hayes AW
Toxicol Sci · 2026 Jun · PMID 42225985 · Publisher ↗
Persistent uncertainty regarding health risks associated with contaminated drinking water at Camp Lejeune reflects a broader limitation in toxicology: the difficulty of evaluating complex chemical mixtures in genetically...
Persistent uncertainty regarding health risks associated with contaminated drinking water at Camp Lejeune reflects a broader limitation in toxicology: the difficulty of evaluating complex chemical mixtures in genetically heterogeneous populations. Historical assessments have relied on single-chemical paradigms, assumptions of dose additivity, and population-average susceptibility. These approaches are not well aligned with exposures involving multiple volatile organic compounds (VOCs) that share metabolic pathways and generate reactive intermediates. This Forum article advances the position that artificial intelligence (AI)-enabled computational toxicology can strengthen mixture risk assessment by integrating toxicokinetic, toxicodynamic, and toxicogenomic data into mechanistically coherent, testable models. Using the Camp Lejeune VOC mixture-trichloroethylene, tetrachloroethylene, benzene, and vinyl chloride-as a case study, we illustrate how AI-augmented approaches can identify plausible interaction mechanisms, quantify genotype-dependent variability in internal dose, and generate probabilistic estimates of risk. We argue that the principal unresolved issue at Camp Lejeune is whether chronic low-level exposure to interacting mixtures disproportionately affected susceptible subpopulations. AI-driven approaches provide a tractable framework to address this question and to clarify the interface between mechanistic toxicology and public health decision-making.
Do metals in tampons pose a health risk? A toxicological risk assessment study.
Jin Y, Eppihimer M, Alam MS … +3 more , Powell AT, Margerrison E, Nawaby AV
Toxicol Sci · 2026 Jun · PMID 42218823 · Publisher ↗
Recently concern has been raised over metal content in tampons and the possibility of toxicological risk to women. As a result, researchers at the United States Food and Drug Administration (FDA) investigated metals pres...
Recently concern has been raised over metal content in tampons and the possibility of toxicological risk to women. As a result, researchers at the United States Food and Drug Administration (FDA) investigated metals present in tampons and estimated the maximum exposure and toxicological risk associated with tampon use. The levels of metals contained in, and released from 11 tampon products, which are legally marketed in the United States, were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Levels of metals released were determined under exaggerated test conditions (50°C for 24 h in acidified water) considering the recommended use of tampons. The potential for metals to be released from the tampons was used to conduct a toxicological risk assessment (TRA) based on ISO 10993 and FDA guidance. In this investigation, 19 metals were detected including ICH Class I metals-arsenic (As), cadmium (Cd), and lead (Pb) were found at trace levels. Based on the in-depth TRA, all detected metals had margins of safety (MoS) indicating that there is negligible toxicological concern from the presence of metals in tampon materials. This study expands on prior investigations of metal content in tampons.
Zearalenone exposure and the mammalian gut microbiome: a systematic review of the literature.
Juenke A, Longoria CR, Patel A … +4 more , Subrahmanian A, Blaser MJ, Rivera-Núñez Z, Barrett ES
Toxicol Sci · 2026 Jun · PMID 42210027 · Publisher ↗
Mycotoxins are fungal-derived metabolites found in the global food supply, particularly in cereal grains and processed foods. Zearalenone (ZEN), one of the more common mycotoxins, widely contaminates human food supplies...
Mycotoxins are fungal-derived metabolites found in the global food supply, particularly in cereal grains and processed foods. Zearalenone (ZEN), one of the more common mycotoxins, widely contaminates human food supplies at concentrations above established maximum contamination levels. However, the effects of ZEN exposure on human health have only begun to be explored, with most studies on this topic focusing on its endocrine-disrupting effects in the reproductive system. ZEN is readily absorbed following oral administration, making the gastrointestinal (GI) tract and its microbiota primary targets for toxicity. The gut microbiome plays a critical role in nutrient processing and immune function and can be heavily influenced by dietary and chemical exposures. Given widespread human dietary exposure to ZEN, we conducted a comprehensive literature review of ZEN and its metabolites in relation to the mammalian gut microbiome. We identified 19 studies, all conducted in animal models, and each reported alterations in gut microbiome composition in ZEN-treated groups compared with control animals. Several papers reported modified metabolism in ZEN-treated groups, particularly related to short-chain fatty acids. In light of this small but compelling literature and the expected increase in mycotoxin contamination due to the industrialization of the food supply and warmer weather conditions, we identified several priority areas for future study. These include better understanding the mechanisms by which ZEN and its metabolites affect the microbiome and ultimate translation to human health.
Hepatic cellular stress response pathways exhibit species differences in basal and inducible activity.
Coghlan H, Regan S, Chouhan B … +4 more , Williams DP, Sison-Young R, Jones AR, Copple IM
Toxicol Sci · 2026 Jun · PMID 42210022 · Publisher ↗
Cellular stress response pathways such as the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response, endoplasmic reticulum (ER) stress response, and macroautophagy afford protection against many fo...
Cellular stress response pathways such as the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response, endoplasmic reticulum (ER) stress response, and macroautophagy afford protection against many forms of drug toxicity, including the liver toxicity associated with the formation of reactive drug metabolites. In many cases, clinical drug-induced liver injury is poorly predicted by preclinical toxicology studies. To maximize the translatability of preclinical toxicology studies and inform species selection, we have investigated the relative hepatic stress response capacities of humans and preclinical animal species commonly used in toxicology testing. In control liver tissue, the basal gene and protein expression of stress response pathway components was found to be greater in rodents than nonrodent preclinical species and humans. In addition, following in vitro exposure to pharmacological modulators of autophagy and the NRF2 and ER stress responses, rodent hepatocytes generally displayed a greater capacity, relative to those of nonrodent preclinical species and humans, for adaptation to cellular stress. In all, our results indicate that rodent preclinical species possess a greater basal and adaptive hepatic capacity for mitigation of chemical insult than nonrodent preclinical species and humans. This study represents the first to provide a comprehensive comparison of stress response pathway capacity of humans and the animal species most commonly used for preclinical drug safety assessment. Our findings can be used to inform the selection of species for safety testing of drugs with a liability for reactive metabolite-mediated liver toxicity, and to interpret the findings of such studies.
Iodoacetic acid causes developmental toxicity in zebrafish.
Hatlestad S, Wagoner BE, Kim H … +7 more , Xia JS, Shim C, Wang Y, Lua A, Yang J, Flaws JA, Mei W
Toxicol Sci · 2026 Jun · PMID 42210016 · Publisher ↗
Water disinfection can generate disinfection byproducts (DBPs) such as iodoacetic acid (IAA) by reacting with organic matter in water supplies. In vitro studies have shown that IAA is a cytotoxic and genotoxic DBP. In vi...
Water disinfection can generate disinfection byproducts (DBPs) such as iodoacetic acid (IAA) by reacting with organic matter in water supplies. In vitro studies have shown that IAA is a cytotoxic and genotoxic DBP. In vivo studies using animal models further indicate that IAA has toxic effects on reproductive function and the endocrine system. Yet, its developmental toxicity remains unknown. In this study, we show that exposure to IAA at concentrations ranging from 1 to 100 µM induces dose-dependent embryonic mortality, with the greatest sensitivity observed during the first 24 hours of development. Sublethal concentrations cause delayed or failed hatching and disrupt the development of multiple vital organs. Notably, IAA exposure impairs swim bladder inflation, reduces otolith size, and decreases heart rate. Moreover, IAA reduces intestinal mucus production by suppressing genes essential for mucin production. Given the crucial role of intestinal mucus in defending against pathogens and maintaining host and gut microbiota homeostasis, the deleterious effect of IAA on mucus production highlights its potential pathogenic role in driving disorders linked to epithelial barrier dysfunction and microbiome dysfunction. Together, these findings demonstrate that IAA induces pronounced developmental toxicity affecting multiple organ systems in zebrafish. This study provides the first in vivo evidence that IAA disrupts embryonic development and intestinal function.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe