Toxicology Letters[JOURNAL]
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200 papers
Occupational lead exposure induces oxidative stress, pulmonary dysfunction, and reduced exercise capacity: A cross-sectional study.
Sirayder U, Acik C
Toxicol Lett · 2026 Feb · PMID 41539630 · Publisher ↗
AIM: This study aimed to evaluate the effects of occupational lead exposure on exercise capacity, oxidative stress, and pulmonary function using a multisystemic approach. METHODS: A total of 48 lead-exposed and 51 contro...
AIM: This study aimed to evaluate the effects of occupational lead exposure on exercise capacity, oxidative stress, and pulmonary function using a multisystemic approach. METHODS: A total of 48 lead-exposed and 51 control male workers participated in this cross-sectional study. Incremental Shuttle Walk Test (ISWT), spirometry, blood lead levels (ICP-MS), and oxidative stress markers (MDA, FRAP) were assessed. Correlation and stepwise linear regression analyses were performed. RESULTS: The exposed group showed significantly lower ISWT distances (p < 0.001, Cohen's d = 0.93), higher dyspnea and fatigue scores (p < 0.01), elevated MDA (d = 2.99), and reduced FRAP levels (d = 0.64). FVC (%) was significantly lower (p < 0.001, d = 1.48), while FEV₁/FVC ratio was higher (p < 0.001, d = 1.46). Regression analyses revealed that lead exposure duration significantly predicted reduced ISWT distance (β = -0.299, p = 0.039), increased dyspnea (β = 0.591, p < 0.001), general fatigue (β = 0.476, p = 0.001), and lower FVC (β = -0.353, p = 0.014). CONCLUSION: Occupational lead exposure is associated with impaired exercise performance and pulmonary function. While oxidative stress contributes to this impairment, cumulative exposure duration emerged as the most consistent predictor. This is the first study to integratively evaluate the impact of lead on maximal exercise capacity alongside biochemical and respiratory parameters, offering novel insights into its systemic physiological burden.
Cadmium interferes with the antiproliferative effect of fulvestrant in endocrine therapy-resistant estrogen receptor α-positive breast cancer cells.
Kanameda K, Hirao-Suzuki M, Takeda S
Toxicol Lett · 2026 Feb · PMID 41525851 · Publisher ↗
Fulvestrant (FUL), an estrogen receptor α (ERα)-degradative anti-estrogen, is used alone or in combination with cyclin-dependent kinase 4/6 inhibitors for the treatment of advanced ERα-positive breast cancer (BC) in post...
Fulvestrant (FUL), an estrogen receptor α (ERα)-degradative anti-estrogen, is used alone or in combination with cyclin-dependent kinase 4/6 inhibitors for the treatment of advanced ERα-positive breast cancer (BC) in postmenopausal women. Cadmium (Cd), an environmental pollutant and metalloestrogen, binds to ERα as a ligand. Patients with BC may experience disease progression despite FUL treatment, suggesting potential interactions between FUL and Cd in long-term estrogen-deprived (LTED) cells. Therefore, the effect of FUL and Cd interaction in LTED cells, a model of postmenopausal BC, was investigated. LTED cells were treated with FUL and Cd at therapeutically or physiologically relevant concentrations, both simultaneously and sequentially (either with FUL treatment followed by Cd or Cd pre-treatment followed by FUL). FUL treatment alone decreased LTED cell viability; however, Cd pre/post-treatment attenuated the antiproliferative effect of FUL. Western blotting showed that Cd pre/post-treatment did not affect FUL-induced ERα degradation. Hence, Cd could suppress the antiproliferative effect of FUL in LTED cells.
Piecing together the puzzles: Aryl hydrocarbon receptor-mediated genetic and epigenetic signatures in dioxin-induced carcinogenicity- A systematic review and meta-analysis.
A HA, Mohamed S, Alkhaldi MY … +6 more , Asiri HA, Ali AM, Shaher FA, Al-Shahrani MS, Al-Qarni MA, El-Hawary HM
Toxicol Lett · 2026 Feb · PMID 41525850 · Publisher ↗
BACKGROUND: Dioxins, are highly potent environmental carcinogens. Their toxic effects are mediated primarily by the Aryl Hydrocarbon Receptor (AhR). A comprehensive understanding of how AhR-induced genetic and epigenetic...
BACKGROUND: Dioxins, are highly potent environmental carcinogens. Their toxic effects are mediated primarily by the Aryl Hydrocarbon Receptor (AhR). A comprehensive understanding of how AhR-induced genetic and epigenetic alterations drive carcinogenesis, especially through effects on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and transgenerational inheritance, remains imperative. OBJECTIVES: This study investigated the interplay between AhR signaling and some molecular modifications in dioxin-induced carcinogenicity. We aimed to characterize resultant gene expression signatures, cell-specific responses, identify novel AhR targets and susceptible organs, and develop a molecular profile for biomarker and therapeutic development. METHODS: We searched databases for peer-reviewed experimental and epidemiological studies on AhR activation by dioxins and its effects on genetic/epigenetic mechanisms, cancer pathways, EMT/CSCs, or transgenerational impacts. Two reviewers performed selection, data extraction, and bias assessment. RESULTS: From 7510 records, 39 studies were incorporated in the qualitative synthesis including 19 in the meta-analyses. Dioxin/AhR significantly increased the expression of certain DNA methylating enzymes. AhR upregulates Gadd45b and LAT1/SLC7A5, induces IL-6, promotes cell cycle progression and interacts with key cancer pathways. AhR signaling alters DNA methylation at promoters, modulates histone modifications, dysregulates ncRNAs, facilitates EMT, influences CSCs, and elicits cell-specific liver responses. Evidence for transgenerational epigenetic inheritance of disease susceptibility was identified. CONCLUSION: Dioxin-induced carcinogenicity involves intricate AhR-mediated genetic damage and profound epigenetic reprogramming. These alterations, which are often cell-type and species-specific, disrupt critical cellular processes, including EMT and CSC biology, and are susceptible to transgenerational inheritance. The identified molecular signatures offer a foundation for improved biomarkers and targeted therapeutic interventions.
Rubber-derived contaminants N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone alter intergenerational cholesterol metabolism in F1 offspring of exposed mice.
Fang L, Fang C, Di S … +2 more , Wang X, Jin Y
Toxicol Lett · 2026 Feb · PMID 41513114 · Publisher ↗
This study examined the hepatic effects of parous exposure to the rubber-derived contaminant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidation product, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylen...
This study examined the hepatic effects of parous exposure to the rubber-derived contaminant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidation product, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPDQ), in C57BL/6 mice during gestation and lactation. Both compounds exhibited dose-dependent bioaccumulation in the liver of the F0 generation and lactated F1 offspring, with 6PPDQ accumulating more due to its greater stability. Lactational transmission of both compounds was observed, and the accumulation declined with age, disappearing by 8 weeks. Notably, 6PPDQ exposure resulted in reduced body weight in mature F1 female mice, which was associated with altered cholesterol metabolism and disrupted expression of the estrogen receptor gene. In these mice, molecular analysis revealed dysregulation of key cholesterol-related genes, such as HMGCR and PCSK9. In contrast, male offspring showed less pronounced effects. These results indicate that the toxicity of 6PPD and 6PPDQ can be transmitted through placental and lactational pathways, with 6PPDQ presenting a greater risk, particularly to female mice, through its impact on cholesterol metabolism and endocrine signalling. These findings offer valuable insights for assessing the environmental and health risks associated with these compounds.
An integrated in vitro and in silico testing strategy applied to PFAS inhibition of antibody production to define a tolerable daily intake.
Iulini M, Janssen AWF, Beekmann K … +5 more , Russo G, Pappalardo F, Fragki S, Paini A, Corsini E
Toxicol Lett · 2026 Feb · PMID 41490601 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals known for their persistence, bioaccumulation, and adverse health effects, particularly on the immune system. Epidemiological studies link PFAS exposure...
Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals known for their persistence, bioaccumulation, and adverse health effects, particularly on the immune system. Epidemiological studies link PFAS exposure to immunosuppression, with increased infection susceptibility and reduced vaccine efficacy. In this paper, we describe the workflow we used to establish an integrated testing strategy (ITS) combining in vitro and in silico methods to model PFAS inhibition of antibody production and to define a tolerable daily intake. This strategy was based on data generated within an EFSA-sponsored project. Using human peripheral blood mononuclear cells, the effects of PFAS on antibody production were assessed. Mathematical models were then applied to determine PFAS free concentrations in vitro, while Physiologically Based Kinetics (PBK) modeling enabled quantitative in vitro to in vivo extrapolation (QIVIVE) to translate in vitro effects into external doses. In addition, the Universal Immune System Simulator was used to predict immune-related outcomes and threshold doses for sensitive populations. Following this strategy, we were able to demonstrate that the oral equivalent effect doses derived through QIVIVE were similar to, or lower than, the tolerable weekly intake established by EFSA for PFAS, indicating that our approach is conservative. We demonstrate the possibility of using alternative methods for studying PFAS toxicity, offering insights into their dynamics and kinetics without animal testing. The strategy provides a promising framework for assessing other chemicals, advancing toxicology toward more human-relevant and ethical practices.
Mechanisms, pathological features, and intervention strategies for nitrogen mustard-induced skin toxicity.
Zhu B, Mao G, Meng Q … +10 more , Li A, Jin C, Wang Y, Wang X, Xue W, Hou F, Yang J, Xu Q, Xue C, Wu M
Toxicol Lett · 2026 Feb · PMID 41490600 · Publisher ↗
Nitrogen mustard (NM) is a representative alkylating vesicant that produces severe and long-lasting damage to the skin. This review summarizes current understanding of its pathological features, molecular mechanisms, and...
Nitrogen mustard (NM) is a representative alkylating vesicant that produces severe and long-lasting damage to the skin. This review summarizes current understanding of its pathological features, molecular mechanisms, and therapeutic approaches, with emphasis on how key signaling pathways interact with one another. Evidence suggests that NM-induced toxicity develops as a cascade of interconnected processes, where genotoxic stress, oxidative imbalance, and innate immune activation mutually reinforce each other. Based on this framework, we outline available intervention strategies and discuss promising directions for future studies.
Predicting acute developmental toxicity of chemicals in embryos of the African clawed frog (Xenopus laevis): Calibration and validation of regression-based quantitative structure activity relationship models for hazard assessment of chemicals in anuran amphibians.
Novello C, Di Nicola MR, Cm Dorne JL … +10 more , Colombo E, Viganò EL, Ortiz-Santaliestra ME, Kramer N, Carnesecchi E, Steinbach AM, Eberini I, Williams A, Benfenati E, Roncaglioni A
Toxicol Lett · 2026 Feb · PMID 41483836 · Publisher ↗
Global decline of amphibian populations has been correlated with a range of endogenous and exogenous variables including their unique physiology and ecology, exposure to chemicals, habitat reduction, climate change, as w...
Global decline of amphibian populations has been correlated with a range of endogenous and exogenous variables including their unique physiology and ecology, exposure to chemicals, habitat reduction, climate change, as well as biological hazards such as emerging infectious diseases. The African clawed frog (Xenopus laevis) is an OECD test species used in toxicity testing as a specific proxy for humans and environmentally relevant species, for which acute toxicity data for a range of chemicals have been generated historically by industry, a number of public health agencies and academia. Of particular relevance are mechanistic effects of endocrine-active substances on metamorphosis and the thyroid axis, resulting in developmental toxicity. From such toxicity data, no open-source quantitative structure-activity relationships (QSARs) have been developed as in silico tools to predict such toxicity for data-poor chemicals in X. laevis. Such QSAR models can provide a quantitative starting point for the hazard assessment of chemicals in other anuran amphibians. This manuscript provides a description of the data collection and curation from the largest historical databases including the US EPA ECOTOX knowledgebase and the Ortiz-Santaliestra databases available for Xenopus embryos as acute median lethal concentrations (LC-12 h) for a total of 349 unique structures and 1978 individual entries. After data curation, the database contained 359 individual entries for a total of 175 compounds, and were computed using the negative logarithm of molar concentrations expressed as 12 h log 1/LC50 mmol/L. Subsequently, the database was then split into training set, test set and prediction set with 120, 40 and 13 compounds, respectively. These datasets were then used for the development and validation of two different QSAR models: 1. A k-Nearest Neighbours (k-NN) models using istKNN (in silico tools - KNN). 2. A multiple linear regression model (MLR) using the QSARINS (QSAR-INSUBRIA) software version 2.2.4. Overall, the QSAR models performed well for predicting acute toxicity of chemicals in Xenopus embryos and the MLR model performed slightly better than the k-NN model with correlation coefficients of 0.76 and 0.75 and root mean square errors of 0.63 and 0.67, respectively. However, underestimation of predictions for highly toxic compounds were observed and these limitations are discussed for both the k-NN and multiple linear regression model in the light of mechanistic interpretation and expert knowledge. Variability in the experimental datasets as well as under-representation of the most toxic compounds in the database are highlighted as major drivers influencing such underpredictions. Future directions from the present work include the modelling of other endpoints and developmental stages as well as other amphibian species using the available, although limited, data. Overall, it can be foreseen in the near future that such databases and models will be important to develop more performant in silico models, and ultimately to develop NAMs for ecotoxicity assessment of chemicals in anuran amphibians while reducing animal testing.
Effects of cannabidiol on the viability and neuronal differentiation of human iPS cells.
Sogawa K, Funada M
Toxicol Lett · 2026 Feb · PMID 41482016 · Publisher ↗
Cannabidiol (CBD) is a non-psychoactive cannabinoid with increasing global use, yet safety data during pregnancy remain limited. Preclinical studies suggest possible developmental neurotoxicity. Here, we examined the eff...
Cannabidiol (CBD) is a non-psychoactive cannabinoid with increasing global use, yet safety data during pregnancy remain limited. Preclinical studies suggest possible developmental neurotoxicity. Here, we examined the effects of CBD (0.001-100 μM) on human induced pluripotent stem cells (hiPSCs) using cell counting, morphology, flow cytometry, and qRT-PCR. Acute exposure to CBD (≥10 μM) markedly reduced hiPSC viability, accompanied by morphological disruptions and upregulation of caspase-3 and -7 within 3-5 h. These effects were significantly attenuated by the pan-caspase inhibitor Z-VAD-FMK, indicating caspase-dependent apoptosis as a key mechanism. Chronic exposure to CBD (0.001-1 μM) for 7 days did not alter transcriptional profiles of Nanog, Pax6, or Map2 during neural ectodermal induction, and immunocytochemical analyses further confirmed that early neuroectodermal morphology was preserved, with comparable PAX6- and NESTIN-positive populations in CBD-treated and control cultures. However, higher CBD concentrations caused marked cytotoxicity and impaired colony formation. These findings define a narrow concentration window between safe and toxic levels, highlighting stage-specific vulnerability to CBD during early development. Use of CBD in pregnancy should therefore be approached cautiously, considering potential risks to fetal neural development.
Organic matter of PM induces cardiomyocyte toxicity by driving oxidative potential and impairing AMPK/PGC-1α-dependent mitochondrial biogenesis.
Chen S, Chen W, Geng H … +3 more , Li Z, Yue J, Li R
Toxicol Lett · 2026 Feb · PMID 41478367 · Publisher ↗
INTRODUCTION: While fine particulate matter (PM) is an established risk factor for cardiovascular disease (CVD), the relative contribution of its specific chemical components to cardiotoxicity remains unclear. This study...
INTRODUCTION: While fine particulate matter (PM) is an established risk factor for cardiovascular disease (CVD), the relative contribution of its specific chemical components to cardiotoxicity remains unclear. This study aimed to systematically compare the cytotoxicity driven by the oxidative potential (OP) of different PM components and elucidate the underlying mechanisms. METHODS: We conducted a comparative assessment of the water-soluble particle (WSP), non-water-soluble particle (NWSP), and organic matter (OM) of PM collected in winter in Taiyuan, China, in H9c2 cardiomyocytes, focusing on OP, cytotoxicity, and mitochondrial biogenesis. OP was measured by the dithiothreitol (DTT) assay, a non-cellular method. The mitochondrial biogenesis-related gene expressions (AMPKα, PGC-1α, Nrf1, Nrf2, TFAM) were quantified by RT-qPCR and western blot. The mitochondrial DNA (mtDNA) copy number was detected. The correlation between the PM composition (water-soluble ions, metals, and PAHs, etc.) and OP was analyzed. RESULTS: Among the three components, OM exhibited the highest OP values. Cellular experiments consistently demonstrated that the OM was the most potent inducer of ROS, LDH release, and ATP depletion, and displayed the lowest LD. Mechanistically, it most severely suppressed mtDNA copy number and the expression of key regulators of mitochondrial biogenesis, including AMPKα, PGC-1α, and its downstream targets Nrf1, Nrf2, and TFAM. Critically, correlation analysis revealed that the OP was strongly associated with the content of PM-bound PAHs. CONCLUSION: The OM fraction, particularly the PAHs, is the primary driver of PM-induced cardiomyocyte toxicity. This effect is mediated through a mechanism involving high oxidative potential, which triggers severe oxidative stress and disrupts mitochondrial biogenesis. This study provides crucial experimental evidence for the increased CVD risk associated with PM.
Research on the therapeutic effects of recombinant protein PON1 intervention on mice poisoned by different categories of organophosphorus compounds.
Zhou S, Cui Y, Li L … +4 more , Zhang P, Zhu Z, Yuan L, Zhao M
Toxicol Lett · 2026 Feb · PMID 41478366 · Publisher ↗
Organophosphorus compounds are widely used in agriculture, but their poisoning poses a great threat. This study focuses on exploring the therapeutic effects of rePON1 and rePON1 on mice poisoned with different types of o...
Organophosphorus compounds are widely used in agriculture, but their poisoning poses a great threat. This study focuses on exploring the therapeutic effects of rePON1 and rePON1 on mice poisoned with different types of organophosphorus compounds. These two recombinant proteins are prepared via gene synthesis into the pET - 32a vector and expression in E. coli BL21.Organophosphorus compounds are divided into two groups by structure: one group contained a pyrimidine ring (similar in structure to diazinon), and the other group contained multiple chlorine atoms (similar in structure to chlorpyrifos). Each group included a control group, a rePON1 control group, a poisoned group, and a rePON1 treatment group. Kaplan-Meier survival analysis assessed the 12-h survival proportion of mice per group. Use ELISA to detect IL - 6 expression, HE staining to assess lung and brain injuries, TUNEL staining to observe apoptosis in brain and lung tissues, and electron microscopy to examine mitochondrial structural changes in brain tissues and alterations in lung tissues of each group. The results showed that rePON1 could improve the clinical manifestations of mice with organophosphorus poisoning, increase the survival proportion, reduce the release of the inflammatory factor IL - 6, alleviate the pathological damage of brain and lung tissues, as well as mitochondrial damage. The number of apoptotic cells in the brain and lung tissues of mice in the rePON1 treatment group was significantly reduced. In animal experiments, the therapeutic effects vary: rePON1 is better for diazinon poisoning, while rePON1 is better for chlorpyrifos-like poisoning. Thus, the therapeutic effects of rePON1 and rePON1 vary depending on the type of organophosphorus poison, likely due to differences in their molecular structures.
Comparative transcriptomic analysis reveals STAT3 as a candidate gene involved in aristolochic acid I-induced hepatorenal toxicity.
Zhu G, Wang F, Wang S … +5 more , Huang K, Chen G, Liu C, Peng Y, Tao Y
Toxicol Lett · 2026 Feb · PMID 41478365 · Publisher ↗
Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to ind...
Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to induce hepatorenal toxicity, the precise underlying mechanism remains unclear. The objective of this research is to investigate the mechanisms by which AAI induces hepatorenal toxicity. Both in vivo and in vitro studies were conducted, involving the administration of AAI to C57BL/6 mice and the exposure of human hepatocytes (HL-7702/L-02) and proximal kidney tubular epithelial cell (HK-2) to AAI. RNA sequencing analysis of liver and kidney was conducted to ascertain hepatorenal toxicity mechanism, with follow-up experiments for validation. Upon identifying the common target, STAT3, for AAI induced hepatorenal toxicity, we further employed STAT3 inhibitor, Stattic for in vitro validation. The results revealed that elevated expressions of STAT3 caused hepatorenal toxicity, leading to impaired liver and kidney functions, as well as tissue damage. Western Blot demonstrated that AAI increased STAT3 phosphorylation. Furthermore, the application of the STAT3 inhibitor reduced damage to hepatocytes and kidney tubular epithelial cell, confirming the effectiveness of Stattic against AAI-induced harm. These findings provide evidence of the significant hepatorenal toxicity of AAI and indicate that STAT3 may serve as a potential common target.
Advances in understanding the neurotoxicity of lead, cadmium, arsenic, and therapeutic strategies.
Li YL, Huang ZX, Peng JC … +4 more , Ho TT, Huang H, Aschner M, Jiang YM
Toxicol Lett · 2026 Jan · PMID 41453694 · Publisher ↗
The rapid progression of industrialization and urbanization has intensified the public health threat posed by heavy metal pollution. Among these, lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxi...
The rapid progression of industrialization and urbanization has intensified the public health threat posed by heavy metal pollution. Among these, lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects. Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases. This review aims to summarize the neurotoxicity mechanisms of Pb, Cd, and As. Additionally, it focuses on the latest advancements in therapeutic strategies for their neurotoxicity. Particular emphasis is placed on evaluating research progress of nanoparticle-assisted therapeutic approaches. It is expected that this review will offer theoretical and empirical support and research insights for the development of more efficient therapeutic methods in the future.
Association between polycyclic aromatic hydrocarbons (PAHs) and insulin resistance: A comprehensive study utilizing NHANES data and network toxicology.
Xu L, Cheng L, Wu H … +8 more , Pan Z, Li G, Zhao Y, Li Z, Ren Y, Gao M, Ma Y, Pan F
Toxicol Lett · 2026 Jan · PMID 41453693 · Publisher ↗
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants with potential endocrine-disrupting effects, yet prior epidemiological research on their association with insulin resistance has yielded inc...
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants with potential endocrine-disrupting effects, yet prior epidemiological research on their association with insulin resistance has yielded inconsistent results. Using data from 3294 participants in the National Health and Nutrition Examination Survey (NHANES) cycles from 2005 to 2016, we applied multivariable linear regression, restricted cubic spline models, weighted quantile sum (WQS) regression, and the g-computation model to examine the relationships between individual and mixed PAH exposures and insulin resistance, with subgroup analyses stratified by sex and age. The analyses revealed that 2-hydroxyfluorene (2-FLU) and 1-hydroxyphenanthrene (1-PHE) were significantly positively associated with the triglyceride-glucose index (TyG), metabolic score for insulin resistance (METS-IR), and triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) (P < 0.05). Consistently, both weighted quantile sum regression and quantile g-computation demonstrated significant positive associations between PAH mixture exposure and TyG, MEST-IR, triglyceride-glucose-body mass index (TyG-BMI), and TG/HDL-C (P < 0.05), with 2-FLU and 1-PHE identified as dominant contributors. Stratified analyses suggested that women and non-elderly individuals may represent susceptible subpopulations. Network toxicology and molecular docking further indicated that PAHs may disrupt glucose homeostasis by inducing inflammation, promoting oxidative stress, and interfering with insulin signaling pathways. Together, these findings provide both epidemiological and mechanistic evidence for the impact of PAHs on insulin resistance, underscoring the importance of considering PAHs as potential environmental correlates of insulin resistance and related metabolic disorders.
Effects of gestational prednisone exposure on long bone development in fetal mice: Role of Sost/Wnt/β-catenin signaling pathways.
Tu M, He H, Chen L … +2 more , Wen Y, Wang H
Toxicol Lett · 2026 Jan · PMID 41421716 · Publisher ↗
Prednisone, a synthetic glucocorticoid, is widely used in the treatment of various maternal diseases during pregnancy, such as autoimmune disorders. However, epidemiological studies suggest that prenatal prednisone treat...
Prednisone, a synthetic glucocorticoid, is widely used in the treatment of various maternal diseases during pregnancy, such as autoimmune disorders. However, epidemiological studies suggest that prenatal prednisone treatment may lead to fetal growth restriction. Preclinical research has shown that gestational prednisone exposure (PPE) exerts developmental toxicity on multiple organs in offspring. Nevertheless, the impacts of PPE at different doses and time windows on long bone development in offspring remain unclear. This study examined the effects of prednisone (PPE) on fetal long bone development using clinically relevant dosing regimens. pregnant mice received PPE at different doses (0.25, 0.5, or 1.0 mg/kg·d) throughout gestation or at 1.0 mg/kg·d during specific gestational periods: entire gestation (GD0-18), early pregnancy (GD0-9), or mid-to-late pregnancy (GD10-18). Results demonstrated that PPE induced femoral dysplasia in both male and female fetal mice, manifested as reduced femoral length, delayed growth plate differentiation, and impaired primary ossification center formation. These abnormalities were concurrent with suppressed development of osteoblasts, osteoclasts, and endothelial cells. Furthermore, PPE inhibited long bone development in a dose-dependent manner, with the most pronounced effects observed during mid-to-late gestation. In vitro experiments confirmed that prednisone, converted to prednisolone, suppresses the Sost/Wnt/β-catenin signaling pathway. In conclusion, PPE inhibits long bone development in male and female fetal mice, predominantly at high doses and during mid-late pregnancy, without significant sexual dimorphism. Mechanistically, suppression of the Sost/Wnt/β-catenin signaling pathway may mediate the long bone developmental toxicity of PPE. This study enhances our understanding of the risks associated with gestational prednisone exposure and provides theoretical and experimental evidence for guiding rational medication and effectively evaluating the long bone developmental toxicity of prednisone.
PUMA upregulation promotes the necroptosis of hepatocytes in trichloroethylene-sensitized mice via mtDNA-mediated ZBP1 pathway.
Peng X, Zhu L, Wan C … +5 more , Dong L, Yang W, Zhu Q, Xie H, Zhang J
Toxicol Lett · 2026 Jan · PMID 41421715 · Publisher ↗
Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) caused by trichloroethylene (TCE) is a systemic allergic disease mainly manifested by acute inflammatory reactions in the skin and mucosa. In add...
Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) caused by trichloroethylene (TCE) is a systemic allergic disease mainly manifested by acute inflammatory reactions in the skin and mucosa. In addition to fever, skin and mucosal damage, superficial lymph node enlargement and tenderness, OMDT patients often have severe multi-organ damage, with liver function damage being the most common. The degree of liver function injury can seriously affect the cure rate of OMDT, but the mechanism of injury has not been fully elucidated. The aim of our study was to explore the mechanism of mitochondrial DNA (mtDNA) release and the role of mtDNA in trichloroethylene-sensitized liver injury. Previous studies found amounts of tumor necrosis factor TNF- α in the liver of mice sensitized to TCE. Moreover, we found a leakage of mtDNA during TCE sensitization. Mitochondrial DNA Exposure to cytosol can activate innate immune responses and play a key role in immune liver injury induced by TCE, but the mechanism by which mtDNA is released to the cellular cytoplasm is unknown. In this study, we found that TNF-α promotes the upregulation of PUMA (p53 upregulated modulator of apoptosis) pro-apoptotic proteins in the liver of TCE-sensitized mice, and then PUMA promotes mtDNA release by regulating the mitochondrial BAX / BAK apoptotic pore, and subsequently activates the DNA sensor ZBP1 (Z-DNA Binding Protein 1), which ultimately leads to RIPK3 / MLKL-dependent necroptosis in hepatocytes.
Evaluation of interspecies differences in DS-2087b-induced gastrointestinal toxicity using mouse and monkey intestinal organoids.
Shirai Y, Iguchi T, Fujimoto K … +3 more , Imaoka M, Hasegawa Y, Chiba K
Toxicol Lett · 2026 Jan · PMID 41419071 · Publisher ↗
Gastrointestinal (GI) toxicity is a common adverse event induced by anti-cancer drugs; however, the information of the correlations in vitro to in vivo regarding GI toxicity is limited. The objective of this study was el...
Gastrointestinal (GI) toxicity is a common adverse event induced by anti-cancer drugs; however, the information of the correlations in vitro to in vivo regarding GI toxicity is limited. The objective of this study was elucidating the usefulness of animal small intestinal organoids using DS-2087b, a novel epidermal growth factor receptor/human epidermal growth factor receptor 2 exon 20 insertion inhibitor. Mice showed no DS-2087b-related GI toxicities up to 100 mg/kg in 28-day repeated oral toxicity studies, while monkeys exhibited diarrhea at 10 mg/kg, along with histopathological changes including intestinal atrophy/erosion at 30 and 100 mg/kg. To clarify the mechanisms involved in interspecies differences, cell viability and transcriptomic analysis were performed using mouse and monkey small intestinal organoids generated from adult stem cells treated with DS-2087b at 0-10,000 nM for 3 days. Cell viability in monkey small intestinal organoids treated with DS-2087b at 1000 and 10,000 nM was significantly decreased compared to that of mice. In the transcriptomic analysis, expression of stem- and Paneth-cell marker genes was markedly decreased in the monkey small intestinal organoids. In conclusion, the intestinal organoids are valuable in vivo-in vitro translation of drug-induced GI toxicity and the changes in specific cell-type composition induced by DS-2087b may be important factors for contributing the interspecies differences.
Diverse impacts of cadmium exposure on adolescent liver health: Suppression of steatosis and promotion of fibrosis.
Hong SJ, Hong LW, He XQ … +3 more , Yang XQ, Zhong XH, Wu JZ
Toxicol Lett · 2026 Jan · PMID 41412331 · Publisher ↗
OBJECTIVES: Cadmium exposure's impact on adolescent liver health is of concern. This study aimed to explore the association between cadmium exposure and liver health in adolescents. METHODS: A cross-sectional study was c...
OBJECTIVES: Cadmium exposure's impact on adolescent liver health is of concern. This study aimed to explore the association between cadmium exposure and liver health in adolescents. METHODS: A cross-sectional study was conducted using data from NHANES 2017-2020.3. Urinary cadmium concentration was used as an indicator of exposure. Liver ultrasound parameters, controlled attenuation parameter (CAP) and stiffness (E) (STF), were employed to assess the degree of liver steatosis and fibrosis in adolescents. Multivariate linear and logistic regression analyses were performed to examine the correlations between cadmium exposure and liver health. Mediation analysis was utilized to explore the roles of alkaline phosphatase, creatine phosphokinase, cholesterol, triglycerides, C-reactive protein, and creatinine. Additionally, a restricted cubic spline (RCS) analysis was conducted to evaluate the impact of nutritional intake on liver health in high-cadmium exposure groups. RESULTS: Cadmium exposure levels were associated with ethnicity and family income. Regression analysis showed a negative correlation with CAP and a positive correlation with STF. Mediation analysis demonstrated that creatinine and triglycerides partially mediated cadmium's effect on CAP, while only creatinine mediated the effect on STF. Dietary intake, including eicosadienoic acid and theobromine, significantly impacts liver health in adolescents with high cadmium exposure. CONCLUSIONS: Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes.
RANKL/OPG axis as a therapeutic target for microplastic-induced bone loss: Mechanistic insights from transcriptomic and functional validation.
Zhang W, Liu K, Zhou B … +11 more , Feng D, Li Z, Dai Z, Huang S, Liang J, Chen S, Wang Z, Guo W, Mao C, Wei Y, Wei J
Toxicol Lett · 2026 Jan · PMID 41412330 · Publisher ↗
Although plastic products have offered substantial benefits to modern society and daily life, their degradation into microplastics (MPs) has raised significant concerns owing to their adverse effects on ecosystems and hu...
Although plastic products have offered substantial benefits to modern society and daily life, their degradation into microplastics (MPs) has raised significant concerns owing to their adverse effects on ecosystems and human health. This study investigated MP deposition in human skeletal tissues and elucidated their effects on bone metabolism. Comprehensive analysis of human bone tissue using Nile red staining, Raman spectroscopy, and infrared microspectroscopy identified MP particles in 33 out of 40 samples (covering the cervical, thoracic, and lumbar vertebrae, as well as the upper and lower limb bones). These detected MPs exhibited a granular morphology, with particle sizes ranging from 10 to 20 μm, predominantly composed of polyethylene and polypropylene, with 2-3 MPs/2 g bone tissues in each sample. To explore the underlying mechanisms, transcriptomic profiling of femoral tissues from MP-PE-fed mice revealed 870 up-regulated and 930 down-regulated genes, which were enriched in the hematopoietic cell lineage, NF-κB, PPAR, PI3K-Akt, and HIF-1 signaling pathways, and metabolic pathways. In vitro validation further demonstrated that MPs enhanced osteoclast differentiation by modulating the RANKL/OPG axis in bone marrow stromal cells, thereby activating the RANK-NFATc1 signaling pathway in Raw264.7 cells. These findings provide experimental and theoretical evidence of the detrimental impact of MPs on skeletal health, underscoring the urgent need for environmental and public health interventions.
Developing a novel in vitro toxicity assay for predicting inhalation toxicity in rats.
Vachiraarunwong A, Fujioka M, Alexander DB … +13 more , Suzuki S, Guo R, Qiu G, Kawamura Y, Shibano K, Noura I, Praseatsook K, Akane H, Takasu S, Tsuda H, Ogawa K, Wanibuchi H, Gi M
Toxicol Lett · 2026 Jan · PMID 41386503 · Publisher ↗
The development of alternative in vitro methods for assessing acute inhalation toxicity is essential to reduce animal testing and aligns with the 3Rs principles (replacement, reduction, refinement). In this study, we dev...
The development of alternative in vitro methods for assessing acute inhalation toxicity is essential to reduce animal testing and aligns with the 3Rs principles (replacement, reduction, refinement). In this study, we developed a neutral red uptake (NRU) assay using human lung adenocarcinoma cells (A549) as a predictive model (A549-NRU) for acute inhalation toxicity. The assay incorporates two key features: a 15-minute incubation time to simulate the transient contact of inhaled chemicals with the airway surface under acute inhalation conditions, and the use of both polystyrene plates and glass plates for chemicals reactive with polystyrene. LC values were determined for 49 chemicals and compared with reported LC values from 4-hour rat inhalation studies. A significant positive correlation was observed between A549-NRU-derived LC values and in vivo LC values for water-soluble compounds (r = 0.4632, p = 0.0197) as well as chemicals containing aldehyde and ketone (r = 0.9339, p = 0.0007), and alcohol, ether, and epoxide (r = 0.7668, p = 0.0159) functional groups, suggesting that in vivo LC values may be predictable using the A549-NRU assay. Importantly, the A549-NRU assay (r = 0.8879, p = 0.1121) demonstrated a stronger correlation with in vivo LC values than the conventional NRU assay using mouse 3T3 fibroblast cells (r = 0.4524, p = 0.5476). These findings support the A549-NRU assay as an alternative for predicting acute inhalation toxicity and for estimating starting doses for confirmatory in vivo studies.
Multi-omics analysis reveals the mechanism of indirect hepatotoxicity of triptolide upon LPS stimulation.
Shen T, Fan L, Luo H … +3 more , Zha Y, Zhang Y, Ren H
Toxicol Lett · 2026 Jan · PMID 41381020 · Publisher ↗
PURPOSE: Triptolide (TP), an active compound derived from the traditional Chinese herb Tripterygium wilfordii Hook F, is notable for its therapeutic properties. However, hepatotoxicity remains its primary adverse effect....
PURPOSE: Triptolide (TP), an active compound derived from the traditional Chinese herb Tripterygium wilfordii Hook F, is notable for its therapeutic properties. However, hepatotoxicity remains its primary adverse effect. There is a new perspective about TP hepatotoxicity: hepatic hypersensitivity triggered by lipopolysaccharide (LPS) stimulation. However, the global molecular alterations underlying this synergistic effect remain poorly defined. METHODS: We employed an integrated proteomics and metabolomics approach to systematically characterize the molecular landscape in the livers of mice treated with TP and LPS. Liver injury was assessed by serum biochemistry and histopathology. RESULTS: The TP+LPS combination induced severe liver damage, based upon histopathological and biochemical analyses, which was not observed with either agent alone. Proteomic analysis revealed that TP+LPS co-treatment induced aberrant expression of fatty acid/cholesterol metabolizing enzymes and dysregulation of cytoskeletal proteins, which collectively contributed to hepatocyte steatosis, structural disruption, and impaired regeneration. Metabolomics results showed that TP+LPS co-treatment significantly inhibited glucose metabolic pathways compared to LPS treatment alone, leading to a reduction of critical metabolic intermediates. This inhibition significantly impaired ATP production and triggered energy depletion. Integrated analysis showed that the suppression of these enzymes in the TP+LPS group impaired mitochondria integrity and the electron transport chain, contributing to ROS-mediated oxidative stress and consequent aggravation of inflammatory response. The inflammatory environment further inhibits mitochondrial function, worsening metabolic disorders and promoting ROS accumulation, thereby forming a self-perpetuating cycle of "metabolism-oxidation-inflammation". CONCLUSION: Our multi-omics data provide a comprehensive resource and novel insights into the mechanism of TP-potentiated, LPS-induced hepatotoxicity. TP might amplify hepatotoxicity by influencing energy metabolism, activating oxidative stress and inflammation in the context of LPS-induced inflammation.
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