Toxicol. Sci. [JOURNAL]
Sun
200 papers
Short-term electrical stimulation promotes partial functional and morphological maturation of human-induced pluripotent stem cell-derived cardiomyocytes enabling cardiotoxicity risk mitigation at early-stage drug discovery for cardiac contractility modulation.
Miyoshi H, Morimura K, Hara R … +6 more , Hori R, Watanabe E, Mochizuki N, Kamei A, Yamazaki R, Kazusa K
Toxicol Sci · 2026 Mar · PMID 41712753 · Full text
In drug discovery, assessing cardiac contractile force is crucial because of its association with the development of cardiovascular events and heart failure. Human induced pluripotent stem cell-derived cardiomyocytes (hi...
In drug discovery, assessing cardiac contractile force is crucial because of its association with the development of cardiovascular events and heart failure. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a promising in vitro model for drug discovery, particularly for assessing proarrhythmic risk. However, the availability of robust in vitro models to evaluate cardiac contractility has been limited. Here, we demonstrate that subjecting hiPSC-CMs to electrical stimulation for 48 h using a multielectrode array system induces partial functional and morphological maturation, as evidenced by a positive force-frequency relationship, increased conduction velocity of depolarization signals and improved sarcomere orientation with distinct Z-bands compared to unstimulated controls. We confirmed that electrical stimulation enables the evaluation of the positive inotropic effects of drug compounds with diverse pharmacological actions. The functional maturation induced by the electrical stimulation was observed across different facilities. The method also effectively detected prolonged QT intervals. These findings demonstrate the utility of the electrical stimulation for 48 h for hiPSC-CMs using the multielectrode array assay system to assess drug-induced contractile function and detect prolonged QT intervals in a single experiment, thereby enhancing the early-stage assessment of cardiotoxicity in drug discovery.
Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants.
Crombie TA, Mckeown R, Widmayer SJ … +12 more , Shaver AO, Moya ND, Collins JB, Wit J, Tanny RE, Braendle C, Stevens L, Van Sluijs L, Rockman MV, Sterken MG, Félix MA, Andersen EC
Toxicol Sci · 2026 Mar · PMID 41706139 · Publisher ↗
Genetic differences among individuals shape how they respond to environmental toxicants, but the identification and validation of the genes responsible for this variation is difficult, particularly in humans. Consequentl...
Genetic differences among individuals shape how they respond to environmental toxicants, but the identification and validation of the genes responsible for this variation is difficult, particularly in humans. Consequently, our limited knowledge of the genes that influence susceptibility constrains our ability to accurately predict the risks posed by environmental toxicants. To identify genes underlying natural differences in toxicant susceptibilities, we measured the effects of 23 environmental toxicants on larval development across 195 genetically diverse Caenorhabditis elegans strains using a high-throughput imaging platform. We then combined these response data with whole-genome sequences to perform genome-wide association mappings, identifying 40 genomic regions where genetic variants are correlated with susceptibility differences. Many of these regions are enriched for genes involved in biological processes previously linked with toxicant responses, supporting the potential contributions of these genes to natural variation in susceptibility. Using biologically informed heuristics based on genomic context and functional annotation, we prioritized genes for follow-up experimentation and identified 94 candidate susceptibility genes, offering feasible targets for experimental validation that could ultimately inform toxicant risk prediction and regulatory assessment by linking genetic variation to differences in susceptibility. Analysis of natural genetic variation among 195 wild C. elegans strains identified 94 candidate genes putatively linked to differences in susceptibility to 23 environmental toxicants. These findings can inform the discovery of conserved susceptibility genes and the development of biomarkers that improve chemical risk assessment by accounting for genetic differences among humans.
Application of in vitro to in vivo extrapolation (IVIVE) to inform chemical health guidance value derivation-sample case studies comparing neuro-, hepato-, and developmental toxicities.
Chang X, Allen DG, Kleinstreuer NC … +1 more , Mumtaz MM
Toxicol Sci · 2026 Mar · PMID 41703654 · Full text
Traditional chemical risk assessment is often based on published mammalian in vivo toxicity data, which are used to identify a point-of-departure (PoD) to derive the minimal risk level (MRL) and similar health guidance v...
Traditional chemical risk assessment is often based on published mammalian in vivo toxicity data, which are used to identify a point-of-departure (PoD) to derive the minimal risk level (MRL) and similar health guidance values. However, time and resource requirements prohibit efficient multi-target-organ toxicity assessments for a large number of environmental chemical pollutants. In vitro high-throughput screening assays and other new approach methodologies could address this problem by using reverse dosimetry to contextualize activity concentrations obtained from the in vitro assays to in vivo settings. In this study, we selected sample priority of diverse chemicals for which both curated high-throughput screening (cHTS) assay data and acute oral MRLs were available for neurotoxicity, hepatotoxicity, and developmental toxicity. We obtained in vitro activity concentrations for these chemicals and conducted in vitro to in vivo extrapolation (IVIVE) to estimate the daily equivalent administered dose (EAD) that would result in rat or human plasma concentrations equivalent to the in vitro activity concentrations. The range of EAD values across various cHTS assays was then compared with in vivo PoDs, MRLs, and predicted human exposure levels. Although variations existed depending on toxicity endpoints evaluated, our results showed that PoDs for a majority of chemicals can be predicted using such data. Our results also demonstrated that a majority of MRL and EAD values fall well below predicted human exposure levels. In summary, our findings demonstrate the usefulness and limitations of using cHTS data and IVIVE approaches for the derivation of health guidance values.
ToxPoint: the case study for respiratory sensitization assessment of methyl methacrylate using new approach methodologies.
Faulhammer F, Kolle SN, Wiench K
Toxicol Sci · 2026 Mar · PMID 41678712 · Publisher ↗
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Progeny effects of rotenone exposure depend on parental toxicity.
Bergemann CM, Mello DF, Chitrakar R … +10 more , Fisher K, Bijwadia SR, Huayta J, Ryde IT, Presman R, Huang Z, Herring AH, Murphy SK, Baugh LR, Meyer JN
Toxicol Sci · 2026 Mar · PMID 41678270 · Full text
Parental exposure to toxicants can affect progeny health. However, laboratory studies often employ exposures that result in loading of pollutants to gametes or toxic effects to parents, which could indirectly affect germ...
Parental exposure to toxicants can affect progeny health. However, laboratory studies often employ exposures that result in loading of pollutants to gametes or toxic effects to parents, which could indirectly affect germ cell or gamete health. Here, we took advantage of the biology of Caenorhabditis elegans to carry out a study in which we minimized the potential for maternal loading of toxicants, and used an exposure paradigm that either did (high concentration) or did not (low concentration) significantly impact the health of the P0 generation. We hypothesized that parental exposure to mitochondrial toxicants during germ cell and gamete development, at levels not causing P0 toxicity, would result in altered mitochondria and organismal health in offspring. In the P0 generation, a high rotenone concentration altered growth, mitochondrial respiration, gene expression, induction of the mitochondrial unfolded protein response, and susceptibility to dopaminergic neurodegeneration induced by a chemical rechallenge later in life. However, we observed minor or no effects in P0 at a low concentration. In high-exposure F1 offspring, we observed altered embryo size, larval developmental stage distribution, spare respiratory capacity, heat shock protein expression, and dopaminergic neurodegeneration after a secondary rotenone challenge. The only effects observed in the F1 offspring of the low exposure were a 1.7% decrease in egg size (size later in development was normal), and moderate evidence of a slightly increased sensitivity to heat shock protein expression and dopaminergic neurodegeneration caused by a secondary later-in-life rotenone exposure. We recommend that parental toxicity be carefully assessed to contextualize offspring outcomes.
Detection and characterization of alterations in miRNA in urine of firefighters.
Sachs PC, Bjerring JS, Blando J … +1 more , Bruno RD
Toxicol Sci · 2026 Mar · PMID 41678268 · Publisher ↗
Firefighters are exposed to high levels of toxic chemicals while fighting fires, and previous studies have established these men and women have a significantly elevated risk for various cancers. Improved risk management...
Firefighters are exposed to high levels of toxic chemicals while fighting fires, and previous studies have established these men and women have a significantly elevated risk for various cancers. Improved risk management for firefighters requires the identification of biomarkers indicative of physiological response. Micro-RNAs (miRNAs) have emerged as promising noninvasive prognostic and diagnostic biomarkers for various diseases. Here, we isolated miRNA from the urine of a large dataset of firefighters, collected pre- and post-fire exposure, as well as from healthy non-firefighter controls. miRNA was analyzed by microarray using the Affymetrix GeneChip miRNA 4.0 array. Analysis revealed 23 human miRNAs were significantly up-regulated and 25 significantly down-regulated in firefighters compared with control samples (analysis 1). Gene targets of these miRNAs were analyzed using the Online Database for Annotation, Visualization, and Integrated Discovery (DAVID) and found to cluster in several pathways and disease associations with smoking, cancer, and inflammatory diseases. Furthermore, we performed a longitudinal analysis of samples from firefighters that provided a sample prior to a fire exposure and immediately after a fire (analysis 2). This analysis found 20 miRNAs that were significantly up-regulated post-fire exposure. Of these, 5 were also up-regulated in firefighters vs control samples (hsa-miR-1268b, hsa-miR-4433b-3p, hsa-miR-4253, hsa-miR-6824-5p, and hsa-miR-3188). Again, analysis of gene targets of these miRNAs found association of mostly the same pathways and disease processes found in analysis 1. These findings are consistent with epidemiological evidence for increased risks associated with firefighting and offer a proof of concept and framework for the use of miRNA in urine as biomarkers for health risk assessment associated with firefighting.
Removal of volatile organic compounds by chemical filters significantly inhibited the development of atopic dermatitis symptoms in mice: potential implications for air-conditioning systems in healthcare environments.
Ohira C, Tomita K, Ota Y … +9 more , Yano K, Amano M, Kaneki M, Yamada A, Usui R, Nagai Y, Nagane M, Takagi S, Fukuyama T
Toxicol Sci · 2026 Mar · PMID 41678259 · Full text
Volatile organic compounds (VOCs) are increasingly implicated in systemic diseases, but their contribution to skin disorders such as atopic dermatitis (AD) remains unclear. This study assessed VOC concentrations in medic...
Volatile organic compounds (VOCs) are increasingly implicated in systemic diseases, but their contribution to skin disorders such as atopic dermatitis (AD) remains unclear. This study assessed VOC concentrations in medical environments, their effects on AD development, and the efficacy of VOC removal using chemical filters. Total VOC levels were monitored in 3 types of veterinary hospitals. AD-like lesions were induced in female NC/Nga mice by repeated dermal application of toluene diisocyanate or house dust mite ointment, with or without topical exposure to a VOC mixture (10 μg/ml). Clinical parameters, including dermatitis scores, transepidermal water loss, and skin thickness, were measured weekly, and immunological and histological analyses were performed. VOC monitoring revealed that 1 hospital exhibited concentrations exceeding 400 μg/m³. In the mouse model, direct VOC exposure significantly aggravated keratinocyte inflammation and worsened AD symptoms. Application of chemical filtering systems effectively reduced VOC levels in real clinical settings, and their use in the experimental model suppressed AD development. However, therapeutic application of VOC removal showed only limited effects on systemic immunological markers. These findings suggest that VOCs present in healthcare environments may contribute to the onset and progression of AD. Incorporating VOC-removing filters into air-conditioning systems could serve as a preventive strategy to improve the management of allergic skin diseases.
Deciphering the mechanisms of Cupferron reproductive toxicity: insights from in vitro assays, network toxicology, and molecular docking.
Daşman M, Qaoud MT, Abudayyak M
Toxicol Sci · 2026 Mar · PMID 41668288 · Publisher ↗
Cupferron, widely used in industrial and analytical contexts, has been proposed as a potential nitric oxide (NO) donor; however, its effects on the male reproductive system remain unclear. We assessed toxicity in TM3 (Le...
Cupferron, widely used in industrial and analytical contexts, has been proposed as a potential nitric oxide (NO) donor; however, its effects on the male reproductive system remain unclear. We assessed toxicity in TM3 (Leydig) and TM4 (Sertoli) mouse cells. Cytotoxicity (6 to 0.0035 mg/ml) was measured by MTT/NRU; genotoxicity by comet assay; oxidative stress markers (MDA, 8-OHdG, GSH, SOD) and testosterone by ELISA; cell death and ROS by flow cytometry; and gene expression by RT-qPCR. MTT IC50 values were 0.131 mg/ml (TM3) and 0.219 mg/ml (TM4). At 0.125 mg/ml, comet assay revealed markedly increased DNA damage, ≥ 16-fold (P ≤ 0.05) in both TM3 and TM4 cells. In TM4, MDA and 8-OHdG rose ≥ 1.3-fold, while SOD activity increased in both TM3 (1.2-fold) and TM4 (1.5-fold) cells (P ≤ 0.05). Annexin V/PI analysis indicated increased necrosis without significant changes in apoptosis. Testosterone levels were unaffected at all doses. RT-qPCR showed upregulation of SOD1, HMOX1, GSTA1, GPX1 antioxidant genes in both TM3 and TM4 (P ≤ 0.05). Network toxicology highlighted NOS1, NOS3, and PTGS2 as putative targets, supported by docking indicating high affinity and substrate-like poses, implicating modulation of oxidative/inflammatory pathways. ADMETLab 3.0 predicted genotoxic, hepatotoxic, and carcinogenic risks. Overall, Cupferron induces oxidative stress, DNA damage, necrosis, and antioxidant gene activation in Leydig and Sertoli cells, supporting potential male reproductive toxicity and the need for comprehensive in vivo and mechanistic in vitro studies.
Suppression of haptoglobin and loss of striatal neurons in mice chronically exposed to chlorpyrifos-contaminated drinking water.
Fikse E, Anderson F, Cho S … +8 more , Landry J, Carloni E, Biggs K, Paul K, Daley T, Chang TY, Kettenbach A, Havrda MC
Toxicol Sci · 2026 Mar · PMID 41668286 · Full text
Exposure to agricultural chemicals is a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Chlorpyrifos (CPF) is an organophosphate insecticide widely used in agr...
Exposure to agricultural chemicals is a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Chlorpyrifos (CPF) is an organophosphate insecticide widely used in agricultural and occupational settings. Epidemiological studies have associated CPF exposure with developmental impairments and an increased risk of AD and PD. Experimental characterization of the impact of chronic, systemic CPF exposure is essential for understanding how organophosphates actually influence disease risk. Multiple studies have assessed the effects of gestational exposure to CPF in preclinical models. To model exposure faced by adults, we administered CPF-contaminated drinking water to mice from 6 to 22 mo of age. This chronic exposure led to systemic effects, including reduced levels of the acute-phase protein haptoglobin (HTP) in both plasma and liver. Notably, the combination of aging and CPF exposure resulted in astrogliosis in the hippocampus and striatum, as well as neuronal loss in the striatum, primarily due to the loss of GAD65/67-immunoreactive interneurons. Having identified CPF-driven suppression of HPT in peripheral tissues, we examined HPT expression in brain tissues. We readily detected HPT expression in brain microglia. We then cultivated primary microglia and found that CPF exposure decreased HPT secretion in vitro. These findings indicate systemic and neurotoxic effects resulting from adult exposure to CPF-contaminated water.
Characterization of an anti-STEAP1 T-cell dependent bispecific antibody for the treatment of prostate cancer and associated toxicity in cynomolgus monkeys.
Tonkin EG, Lepherd M, Davies J … +11 more , Gampa G, Hötzel I, Koeppen H, Liu W, Melnikov F, Niu X, Nickles D, Romero-Lopez M, Shao L, Totpal K, Schaefer G
Toxicol Sci · 2026 Mar · PMID 41668284 · Publisher ↗
BSTP0204A is a T-cell dependent-bispecific (TCB) antibody targeting 6-transmembrane epithelial antigen of the prostate 1 (STEAP1) that induces T-cell mediated killing of STEAP1 expressing cancer cells. STEAP1 is consider...
BSTP0204A is a T-cell dependent-bispecific (TCB) antibody targeting 6-transmembrane epithelial antigen of the prostate 1 (STEAP1) that induces T-cell mediated killing of STEAP1 expressing cancer cells. STEAP1 is considered an attractive target for prostate cancer due to its high expression in the prostate and prostate cancer. Characterization of BSTP0204A showed potent T-cell-mediated killing in vitro and anti-tumor activity in mouse xenograft models against prostate cancer cell lines with both moderate and high STEAP1 expression. Analysis of STEAP1 protein expression in human and monkey tissues confirmed low STEAP1 expression outside of the prostate, suggesting a low potential for on-target/off-tumor toxicity. However, administration of BSTP0204A in a repeat-dose toxicity study in cynomolgus monkeys revealed adverse vascular inflammation that was inconsistent with STEAP1 expression observed in normal tissues. Additional assessments of STEAP1 expression in the vascular lesions from the toxicity study in monkeys and in human inflammatory disease conditions showed increased STEAP1 expression associated with inflammation and/or injury in both species. Furthermore, upregulation of STEAP1 was observed in both human and monkey primary cells in the presence of inflammatory stimuli. These findings suggest that systemic inflammation induced by T-cell activation following BSTP0204A treatment may have resulted in increased STEAP1 expression, inducing additional inflammation and tissue damage. This work demonstrated the need to understand not only baseline target expression for T-cell-engaging therapies, but also expression under conditions such as inflammation, injury, or disease.
Zonal hepatocellular responses to acute ethanol consumption: impacts on mitochondrial function and liver metabolism.
Savoca MT, Takemoto K, Hu J … +3 more , Li L, Zhong Z, Lemasters JJ
Toxicol Sci · 2026 Mar · PMID 41668283 · Full text
Hepatocellular mitochondrial depolarization (mtDepo) after ethanol (EtOH) increases respiration to stimulate EtOH detoxification. mtDepo also triggers mitophagy, which may contribute to alcohol-associated liver disease....
Hepatocellular mitochondrial depolarization (mtDepo) after ethanol (EtOH) increases respiration to stimulate EtOH detoxification. mtDepo also triggers mitophagy, which may contribute to alcohol-associated liver disease. This study characterized sublobular respiration and distribution of mtDepo and mitophagy after acute EtOH. C57BL/6J and GFP-LC3 transgenic mice were gavaged with 6 g/kg EtOH or vehicle and administered MitoTracker Red (MTR). Hepatocytes were zonally sorted by MTR fluorescence for assessment of oxygen consumption rates (OCRs). Cytochrome P4502E1 (CYP2E1) immunolabeling identified central halves of liver lobules. After vehicle, MTR localized to mitochondria throughout lobules, indicating polarization, with higher OCRs in periportal (PP) hepatocytes compared with pericentral (PC). After EtOH, MTR fluorescence became diffuse in CYP2E1-positive central halves of lobules, signifying mtDepo, whereas portal halves remained polarized. GFP-LC3 puncta marking mitophagy also increased predominantly in central halves. Surface hepatocytes accessible by multiphoton microscopy were CYP2E1-positive and developed mtDepo and GFP-LC3 puncta after EtOH. After hepatocyte isolation, mtDepo reversed shown by rhodamine 123 uptake. At 6 h post-EtOH, OCRs approximately doubled in both PP and PC hepatocytes, returning to baseline by 24 h, but PC displayed greater proportional increases. Acute EtOH induces mtDepo and mitophagy predominantly in central halves of lobules, including within <50 μm of the liver surface. Although mtDepo reverses after isolation, elevated respiratory capacity persists. Due to central half mtDepo, PP and PC hepatocytes contribute about equally to the respiratory burst after EtOH.
A systematic review of nervous system effects of ethylbenzene exposure in animal models.
Dishaw LV, Taylor MM, Segal D … +1 more , Carlson LM
Toxicol Sci · 2026 Mar · PMID 41668282 · Publisher ↗
Ethylbenzene is a high-production-volume chemical. Exposure occurs in the general population, but there is potential for additional exposure in certain groups, such as workers in petrochemical industries or individuals l...
Ethylbenzene is a high-production-volume chemical. Exposure occurs in the general population, but there is potential for additional exposure in certain groups, such as workers in petrochemical industries or individuals living near contaminated areas. This paper presents a systematic review of currently available evidence in animals focused on potential nervous system-related effects of ethylbenzene exposure. A broad literature search was conducted. A total of 9,679 studies were screened for inclusion based on Populations, Exposures, Comparators, and Outcomes (PECO) criteria. Included studies were evaluated for potential concerns related to risk of bias and sensitivity, and informative studies moved forward for data extraction and evidence synthesis. Twenty-one animal toxicology studies were identified that evaluated nervous system effects, including auditory effects, neurotransmitters, neurobehavior, brain weight, and histopathology. Six studies rated medium or low confidence showed consistent concentration- and exposure duration-related effects on cochlear hair cells and hearing thresholds. The evidence for the other nervous system outcomes is inconclusive. Although some studies showed effects on neurotransmitters and neurobehavior, they were rated low confidence, and findings were inconsistent. Relative brain weight changes were observed, but the direction of the effect was inconsistent. No changes were observed in absolute brain weights, which is considered the more reliable measure for evaluating effects on brain weight. No changes in brain histopathology were reported.
CYP1B1 modulates stress and repair pathways in airway cells challenged by wood smoke particles.
Sun L, Almestica-Roberts M, Nguyen ND … +8 more , Cowley J, Romero EG, Serna SN, Zhang P, Niu C, Memon TA, Deering-Rice CE, Reilly CA
Toxicol Sci · 2026 Feb · PMID 41581139 · Publisher ↗
Environmental pollution negatively impacts respiratory health by damaging and reprogramming airway epithelial cells (AECs). CYP1B1 is one of the most highly induced genes in AECs exposed to combustion-derived air polluta...
Environmental pollution negatively impacts respiratory health by damaging and reprogramming airway epithelial cells (AECs). CYP1B1 is one of the most highly induced genes in AECs exposed to combustion-derived air pollutants such as wood smoke particulate matter (WSPM) and plays dual roles in generating toxic reactive intermediates and in the detoxification of xenobiotics of diverse nature. However, the significance of CYP1B1 induction by AECs challenged with pollutants remains unclear. A comparison of BEAS-2B and CYP1B1-overexpressing BEAS-2B cells revealed that CYP1B1 overexpression reduced acute cytotoxicity and enhanced proliferation and migration following WSPM-induced injury in vitro. Conversely, inhibition of CYP1B1 in HBEC3-KT cells increased cytotoxicity and decreased proliferation. CYP1B1 inhibition in HBEC3-KT cells exacerbated endoplasmic reticulum stress (ERS), which promotes cell cycle arrest and cytotoxicity, while overexpression of CYP1B1 attenuated ERS. CYP1B1 Inhibition also enhanced the expression of mRNA for the NRF2 target genes NQO1 and HMOX1, and the proinflammatory cytokine IL8, whereas CYP1B1 overexpression downregulated mRNA expression for NQO1 and HMOX1. In vivo, Cyp1b1-deficient mice exhibited greater basal lung inflammation, but limited response to WSPM-treatment compared with wild-type mice. However, Cyp1b1-/- derived mouse tracheal epithelial cells treated with WSPM showed a more pronounced inflammatory response, characterized by exacerbated Cxcl1, Cxcl2, and Trpa1 mRNA expression compared with wild-type cells. In conclusion, CYP1B1 mitigates WSPM-induced damage to AECs by squelching ERS, oxidative stress, NRF2, and inflammatory signaling, thereby supporting cellular defense and repair. Additional interactions with CYP1A1 and TRP channels also suggest a broader role in AEC physiology.
Chronic exposure to low levels of glyphosate and metals induces kidney dysfunction.
Merutka IR, Ettinger KM, Chernick M … +4 more , Kolli RT, De Silva MCS, Drummond IA, Jayasundara N
Toxicol Sci · 2026 Feb · PMID 41580968 · Full text
Chronic kidney disease (CKD) affects ∼15% of US adults and over 840 million people worldwide. Environmental contaminants, including pesticides and metals, are increasingly recognized as disease contributors, yet mechanis...
Chronic kidney disease (CKD) affects ∼15% of US adults and over 840 million people worldwide. Environmental contaminants, including pesticides and metals, are increasingly recognized as disease contributors, yet mechanisms and consequences of long-term, low-level mixture exposures remain poorly defined. Our prior work identified glyphosate and metals (cadmium, arsenic, lead, and vanadium) in drinking water from agricultural regions with high CKD prevalence and showed that early-life co-exposures disrupt kidney development. Here, using adult zebrafish as a mechanistic model, we tested whether chronic, low-level exposure to glyphosate, metals, and their combination impairs kidney function and structure. We exposed zebrafish for 10 and 60 days to glyphosate (10 ppb), metals (2 ppb Cd, 4 ppb As, 5 ppb Pb, 15 V), or glyphosate + metals and evaluated low-molecular-weight proteinuria, histopathology, metabolomics, mitochondrial function, mitochondrial copy number, and mitophagy in the kidney. Chronic exposure to glyphosate and metals produced distinct yet overlapping kidney toxicity signatures, including tubular injury, altered metabolism, and impaired mitochondrial function. Co-exposures generated the most severe effects, with mitochondrial beta oxidation, respiration, and mitophagy as sensitive targets. These findings demonstrate that glyphosate and metals at levels found in drinking water damage kidney function over time, with co-exposure worsening outcomes compared with individual chemicals. Our study identifies mitochondria-rich proximal tubules as critical targets of chronic glyphosate-metal exposure, providing mechanistic insight into how environmental contaminants contribute to CKD risk. This work advances understanding of disease etiology in environmental nephropathies and highlights environmental factors as important drivers of kidney health.
Transcriptomic profiling reveals thyroid hormone-mediated and compound-specific effects of methimazole and amitrole on testis development.
Strand IW, Draskau MK, Rising SF … +5 more , Evrard B, Ramhøj L, Axelstad M, Chalmel F, Svingen T
Toxicol Sci · 2026 Feb · PMID 41580965 · Publisher ↗
Thyroid hormones (THs) influence testis development, with early life hypothyroidism resulting in smaller testes. Developmental exposure to thyroperoxidase (TPO)-inhibiting drugs such as propylthiouracil (PTU) and methima...
Thyroid hormones (THs) influence testis development, with early life hypothyroidism resulting in smaller testes. Developmental exposure to thyroperoxidase (TPO)-inhibiting drugs such as propylthiouracil (PTU) and methimazole (MMI) also impair testis development in rodents by reducing TH levels, leading to smaller testes in pups due to, for instance, disrupted Sertoli cell proliferation and maturation. Comparable effects are seen following exposure to the TPO-inhibiting pesticide amitrole, one of many environmental chemicals with TH-disrupting properties. Despite this phenotype, the molecular underpinnings of hypothyroid-induced testis effects are less clear, complicating mechanism-based chemical toxicity testing relying on alternative test methods and omics approaches. Here, we report on transcriptomics profiling of testes from hypothyroid rats induced by chemical exposures. Pregnant Sprague-Dawley rat dams were exposed by oral gavage to 2 doses of MMI (8 or 16 mg/kg body weight/day) or amitrole (25 or 50 mg/kg bw/day) from gestational day (GD) 7 to pup day (PD) 16, with BRB-seq performed for both life stages, specifically GD21 and PD16. Both MMI and amitrole caused significant changes to the testis transcriptome, seen particularly at PD16, with 313 differentially expressed genes (DEGs) defining a shared TH-mediated profile. Additionally, amitrole exposure resulted in a distinct profile of 1,517 DEGs, suggesting compound-specific effects beyond TH disruption. This study underscores the potential sensitivity of transcriptomic profiling in detecting early tissue disruption under toxicological conditions, in this case, testis disruption under hypothyroid state, offering critical insights for chemical risk assessment beyond histopathological endpoints.
Aryl hydrocarbon receptor activation alters emergency hematopoiesis during influenza A virus infection.
Fenner KN, Healey AM, Franchini AM … +2 more , Morrell CN, Lawrence BP
Toxicol Sci · 2026 Feb · PMID 41580964 · Publisher ↗
Hematopoietic stem and progenitor cells (HSPC) produce all cells of the blood and immune system in a process known as hematopoiesis. During infection, there is an increased demand for immune cells which causes HSPC to ra...
Hematopoietic stem and progenitor cells (HSPC) produce all cells of the blood and immune system in a process known as hematopoiesis. During infection, there is an increased demand for immune cells which causes HSPC to rapidly and transiently modify cellular output, a response described as emergency hematopoiesis. Small molecules from the host environment may contribute to signals that regulate emergency hematopoiesis, providing a means to influence important processes during infection. Environmental exposures have long been associated with altered immune responses in human population and experimental studies. Specifically, chemicals that bind the aryl hydrocarbon receptor (AHR) modulate immune responses in a broad range of contexts, including during viral infection. Separate studies have shown that AHR signaling also influences steady-state hematopoiesis. Using two different AHR ligands, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2-(1H-indol-3-ylcarbonyl)-4-thiazole-carboxylic acid methyl ester (ITE), we characterized the impact of AHR activation on the proportion of HSPC and lineage-committed progenitor cells over the course of an influenza A virus infection in mice. AHR activation via these two ligands had a distinct impact on HSPC yet affected monocytes in the blood and lung similarly. For example, AHR activation with TCDD, but not ITE, increased myeloid-biasing among HSPC. However, the frequency of monocytes in the lung was reduced by either TCDD or ITE treatment. Using Vav1CreAhrfxfx mice, we showed that these effects depend on AHR expression in hematopoietic cells. Collectively, these findings highlight the differential effects of AHR ligands and their role in regulating emergency hematopoiesis in response to a common respiratory pathogen.
Maternal exposure to air pollution alters the postnatal metabolic response to ozone in peri-adolescent offspring.
Dye JA, Stewart EJ, Nguyen HH … +8 more , Schladweiler MC, Richards JH, Williams WC, Grindstaff RD, Padgett WT, Hill D, Fisher AA, Miller CN
Toxicol Sci · 2026 Feb · PMID 41580963 · Publisher ↗
Exposure to environmental pollutants during key stages of development increases the risk of disease later in life. One such toxicant with growing evidence of this response is the air pollutant, ozone (O3). Exposure to O3...
Exposure to environmental pollutants during key stages of development increases the risk of disease later in life. One such toxicant with growing evidence of this response is the air pollutant, ozone (O3). Exposure to O3 during the implantation receptivity period in rats affects the metabolic status of offspring at adolescence, which may increase their susceptibility to subsequent environmental exposures. Herein, we studied the impacts of maternal O3 exposure on postnatal systemic responses to O3 in male and female offspring. Following peri-implantation O3 exposure (0.8 ppm for 4 h/d on gestation days 5 and 6), offspring were exposed to O3 for 1 d/wk on postnatal weeks 5 to 7. After the final exposure, metabolic effects were analyzed by circulating hormones and clinical chemistries, as well as hepatic lipid status and transcriptomic alterations. By and large, male offspring from O3-exposed dams were more greatly impacted than those from air-exposed dams. This included increased hepatic lipid mobilization, increased circulating glucose, and a robust number of differentially expressed genes (2,348). Interestingly, many of these transcriptomic differences were attributed to maternal O3 exposure, with 1,741 of these genes sharing directional similarity with postnatally exposed air littermates. Females, on the other hand, reported minimal baseline effects of maternal O3 exposure (108). However, postnatal O3 exposure in female offspring substantially increased these differences to 947 genes. Collectively, this work supports the growing evidence that early pregnancy exposure to O3 alters the metabolic development of the offspring. Furthermore, postnatal exposure to environmental stressors reveals hepatic susceptibilities that are sexually dimorphic.
The International Collaborative Animal Study of the carcinogenicity and genotoxicity of mobile phone radiofrequency radiation: the Korean study.
Kim HS, Han KH, Kim YB … +10 more , Jeon SB, Lee AK, Moon JI, Choi HD, Imaida K, Yokohira M, Kawabe M, Imai N, Wang J, Ahn YH
Toxicol Sci · 2026 Mar · PMID 41546387 · Full text
A chronic bioassay investigating radiofrequency (RF) carcinogenicity, intentionally designed to be conducted simultaneously in Korea and Japan, using the same research protocol and experimental environment. The study aim...
A chronic bioassay investigating radiofrequency (RF) carcinogenicity, intentionally designed to be conducted simultaneously in Korea and Japan, using the same research protocol and experimental environment. The study aimed to assess the potential carcinogenicity of Code Division Multiple Access (CDMA)-modulated 900 MHz RF signals at a whole-body specific absorption rate (SAR) of 4 W/kg, which is the reference level of the international human safety guideline, and to verify the key findings from the National Toxicology Program (NTP) study at that SAR level. Two reverberation chamber systems were used for RF exposures, and the same study protocols were followed. Male Harlan Sprague-Dawley (Hsd:Sprague Dawley SD) rats were randomly assigned to cage-control, sham-exposed, or RF-exposed groups. The exposure started on gestational day 5 and lasted for 18 h and 20 min each day, with 10-min on/off cycles. The project included a 28-d toxicity study, a 2-yr carcinogenicity study, and a 14-wk genotoxicity test. Histopathological evaluations were conducted in a partially blinded manner. The results were independently analyzed and submitted separately based on each country's research findings. In the Korean study, no statistically significant changes in tumor incidence or survival rates were observed. No significant RF-related effects were detected in the heart, brain, or adrenal glands. No changes in body temperature. Genotoxicity tests showed no evidence of DNA damage or mutation. In conclusion, the Korean part found that long-term exposure to CDMA-modulated 900 MHz RF was neither carcinogenic nor genotoxic at a SAR of 4 W/kg in male rats. An international animal study was jointly conducted as a chronic bioassay in Japan and Korea to evaluate the carcinogenicity of mobile phone RF signals and to verify key findings from the NTP study using identical protocols and exposure systems.
The International Collaborative Animal Study of mobile phone radiofrequency radiation carcinogenicity and genotoxicity: the Japanese study.
Imaida K, Kawabe M, Wang J … +7 more , Yokohira M, Imai N, Han KH, Kim YB, Jeon SB, Kim HS, Ahn YH
Toxicol Sci · 2026 Jan · PMID 41527296 · Full text
The potential carcinogenic and genotoxic effects of radiofrequency electromagnetic fields, particularly those emitted by mobile communication systems, have raised public health concerns. A previous study by the U.S. Nati...
The potential carcinogenic and genotoxic effects of radiofrequency electromagnetic fields, particularly those emitted by mobile communication systems, have raised public health concerns. A previous study by the U.S. National Toxicology Program suggested increased incidences of gliomas and cardiac schwannomas in rats exposed to high levels of RF radiation. To evaluate these findings, an international collaborative study was initiated between Japan and Korea. Male Hsd:Sprague Dawley SD rats were exposed to 900 MHz CDMA-modulated RF-EMFs at a whole-body specific absorption rate of 4 W/kg for 18 h and 20 min daily over 2 yr. The study included a 28-d preliminary toxicity study, genotoxicity assays (alkaline comet and micronucleus tests), and a 2-yr carcinogenicity assessment. All procedures followed OECD guidelines and Good Laboratory Practice. No statistically significant increases in the incidences of neoplastic or non-neoplastic lesions were found in any major organ, including the brain, heart, and adrenal glands. Genotoxicity assays revealed no evidence of DNA damage or chromosomal aberrations in RF-exposed rats. A higher survival rate in the RF-exposed group, likely due to lower body weight and food consumption, was observed. This study, performed in Japan, jointly planned and executed by Japan and Korea, provides strong evidence that long-term exposure to 900 MHz RF-EMFs did not produce reproducible carcinogenic or genotoxic effects in male rats. Combined with data from the Korean counterpart study, these results are expected to contribute to future international assessments of the carcinogenic potential of electromagnetic radiation.
Quantitative adverse outcome pathway modeling of cisplatin-induced nephrotoxicity: developing in vitro and in vivo models for predictive extrapolation.
Di Tillio F, Wijaya LS, Kunnen SJ … +9 more , Eugenio CJ, Buzzanca G, Bruns IB, Martens M, Kramer NI, Kers J, Callegaro G, van de Water B, Beltman JB
Toxicol Sci · 2026 Feb · PMID 41514178 · Publisher ↗
Nephrotoxicity is a major concern in the safety assessment of chemicals and drugs. Computational modeling, particularly the use of quantitative adverse outcome pathways (qAOPs), offers a promising strategy to improve the...
Nephrotoxicity is a major concern in the safety assessment of chemicals and drugs. Computational modeling, particularly the use of quantitative adverse outcome pathways (qAOPs), offers a promising strategy to improve the translation from in vitro to in vivo, thereby facilitating reliable predictions of in vivo adverse outcomes and potentially reducing the need for animal testing. Platinum-based drugs are widely used in chemotherapy, yet their clinical application is frequently constrained by nephrotoxic effects. Here, we focus on the development of ordinary differential equation (ODE)-based qAOPs for platinum-induced nephrotoxicity by defining both an in vitro and an in vivo data-driven model. The in vitro model incorporates newly generated, time-course gene expression and propidium iodide (PI) staining data from RPTEC/TERT1 cells exposed to cisplatin. The in vivo model employs published rat data, including dose-response platinum kinetics as well as single-dose time-course platinum kinetics, gene expression, and histopathology data. Our quantitative approach shows that key processes in the AOP related to immune system activity are nonlinear. Specifically, clearance of necrotic kidney cells by immune system activity counters damage accumulation on a timescale of days, yet low-level inflammation still cumulatively affects kidney failure in the long run. Moreover, we perform quantitative in vitro to in vivo extrapolation (QIVIVE) to link the 2 models. With this approach, in vivo adverse outcome predictions can be made in the future not only for platinum-based compounds but also for the safety assessment of other chemicals and drugs, reducing the need for animal testing.
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