Toxicology Letters[JOURNAL]
Sun
200 papers
Human serum albumin-adduct biomarkers to prove human poisoning with methanethiol.
Zhang C, Yang R, Liu S … +2 more , Li P, Guo F
Toxicol Lett · 2025 Nov · PMID 41061905 · Publisher ↗
Exposure to methanethiol (MT) presents a significant challenge in public healthcare and could be a concern in the context of terrorist attacks. Therefore, reliable verification procedures for MT intoxication are essentia...
Exposure to methanethiol (MT) presents a significant challenge in public healthcare and could be a concern in the context of terrorist attacks. Therefore, reliable verification procedures for MT intoxication are essential for forensic, toxicological, and clinical purposes. We developed and validated a bioanalytical method for the simultaneous detection and identification of biomarkers indicative of MT exposure. Neat human serum albumin (HSA) and human plasma were incubated with MT to form adducts, which served as references. Subsequently, HSA and human plasma were subjected to proteolysis using two proteases, resulting in the formation of disulfide adducts detected as adducts of the single amino acid cysteine (MT-Cys), the dipeptide cysteine-proline (MT-CysPro), and the tripeptides aspartic acid-isoleucine-cysteine (AspIleCys-MT) and cysteine-proline-phenylalanine (MT-CysProPhe). The adducts were analyzed using a sensitive ultra-performance liquid chromatography-quadrupole exactive orbitrap-high resolution mass spectrometry (UPLC-Q Exactive Orbitrap-HRMS) method operating in full scan mass spectrometry (Full MS) and parallel reaction monitoring (PRM) mode. Time- and concentration-dependent adduct formation during exposure was investigated. The limits of detection (LODs) for the adducts ranged from 20 ng/mL to 2 μg/mL, corresponding to the MT concentrations in plasma. Adducts at Cys exhibited the lowest LOD (20 ng/mL MT in plasma), the fastest adduct formation (20 min), and superior stability in plasma at 37 °C. The applicability of the method was demonstrated by the successful detection of adducts in sample from MT-poisoned patient, establishing the method as a reliable bioanalytical procedure for forensic and toxicological analysis.
Geniposide induces hepatotoxicity via the bile acid-induced activation of NLRP3 inflammasome and regulation of the FXR/PERK/TXNIP pathway.
Jin Z, Cheng S, Liu B … +4 more , Liu Y, Wei Y, Hao X, Li H
Toxicol Lett · 2025 Nov · PMID 41043658 · Publisher ↗
Gardenia jasminoides, as a widely used traditional Chinese medicine, excessive consumption of it may lead to severe liver injury. As the main hepatotoxic component in Gardenia jasminoides, the specific mechanism by which...
Gardenia jasminoides, as a widely used traditional Chinese medicine, excessive consumption of it may lead to severe liver injury. As the main hepatotoxic component in Gardenia jasminoides, the specific mechanism by which geniposide (GE) causes liver injury remains elusive. In this study, we conducted a systematic investigation of the effects of GE on bile acid (BA) metabolism and related signal transduction and inflammatory pathways in healthy Sprague-Dawley (SD) rats after oral administration of a 13-fold clinical equivalent dose (450 mg/kg) for 5 days. It is noteworthy that GE administration altered the content and composition of BAs and disrupted BA metabolism. At the same time, the expressions of farnesoid X receptor (FXR) and its downstream proteins bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP) are significantly inhibited. In addition, the inhibition of FXR will increase the signal transduction of the protein kinase R-like endoplasmic reticulum kinase (PERK)-thioredoxin-interacting protein (TXNIP)-nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome axis, thereby triggering cysteine protease-1 (caspase-1), leading to the release of inflammatory factors and worsening liver injury. The addition of the FXR agonist obeticholic acid (OCA) effectively reversed the expressions of the above proteins and mRNA, and alleviated the liver injury caused by GE by restoring BAs homeostasis and regulating the inflammatory pathway. Conclusion: GE causes severe liver injury by affecting bile acid metabolism and inflammatory pathways, and the inhibition of FXR is a crucial factor.
Challenges and solutions in measuring commonly used biomarkers for drug-induced liver injury in a liver-on-a-chip platform.
Shi Q, Schnackenberg LK, Ren L … +12 more , Papineau KS, Oliphant JJH, Avigan MI, Ewart L, Sauld JF, Dai E, Brown PC, Davis Bruno KL, Moulin F, da Costa GG, Patterson TA, Sadrieh N
Toxicol Lett · 2025 Nov · PMID 41043657 · Publisher ↗
Liver-on-a-chip (liver-chip) is designed to better maintain in vitro-cultured hepatic cells and improve the prediction of drug-induced liver injury (DILI). Albumin, urea, alanine aminotransferase (ALT), aspartate aminotr...
Liver-on-a-chip (liver-chip) is designed to better maintain in vitro-cultured hepatic cells and improve the prediction of drug-induced liver injury (DILI). Albumin, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) are proposed translational biomarkers for the prediction of DILI using liver microphysiological systems (MPS), including liver-chip. However, the performance of commonly-used assays for these biomarkers in liver MPS may vary. While using the Emulate® liver-chip, we observed that the activity of ALT, but not AST, measured using the extensively validated International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Reference Procedure, spontaneously and remarkably decreased in the perfusing medium after 24 h. Furthermore, ALT and AST activity remained largely below the detection limit (5 U/L) after acetaminophen treatment when their protein concentrations were increased by approximately 20-fold, as determined by an enzyme-linked immunosorbent assay (ELISA). The protein concentrations of ALT and AST, but not activity, showed good correlation with LDH activity, which was nearly eliminated after a freeze-thaw cycle. For viability of non-parenchymal cells, an unusually high background signal, largely attributable to CultureBoost and fetal bovine serum in the perfusion medium, prevented the use of LDH activity assays; however, LDH ELISA appeared to be a useful alternative. Of two widely used urea assays, the enzymatic approach was profoundly affected by medium supplements, wherein sample dilution increased the limit of detection, making it impossible to observe drug-induced urea inhibition. By contrast, the chemical assay offered adequate and improved specificity and sensitivity. For albumin, an ELISA had to be adopted, since routinely used dye-binding methods were not sensitive enough. These findings provide a plausible explanation for some controversies in the literature and highlight the significance of establishing reliable and reproducible assays for translational DILI biomarkers in liver MPS.
Toxicity of humectants propylene glycol and vegetable glycerin in electronic nicotine delivery systems.
Sun Y, Lin K, Effah F … +5 more , Cartujano Barrera F, Li D, McIntosh S, McGraw MD, Rahman I
Toxicol Lett · 2025 Nov · PMID 41043656 · Full text
BACKGROUND: E-cigarettes and other electronic nicotine delivery systems (ENDs) remain a significant public health risk. Although deployed as tobacco smoking cessation tools, e-cigarettes have gained greater popularity am...
BACKGROUND: E-cigarettes and other electronic nicotine delivery systems (ENDs) remain a significant public health risk. Although deployed as tobacco smoking cessation tools, e-cigarettes have gained greater popularity among non-smokers, specifically adolescents and young adults. Previous research has focused primarily on the toxicities associated with nicotine, flavorings, and other chemicals generated from e-cigarette liquid aerosolization; however, little attention has been given to the two primary and most abundant chemicals found in most e-cigarette liquids - propylene glycol (PG) and vegetable glycerin (VG). PURPOSE: The purpose of this review is to assess the toxicity associated with PG/VG in e-cigarettes to inform future ENDS regulations. METHODS: Database searches were performed using PubMed for relevant literature published from 1/1/2014-9/1/2025. Cited articles about the prevalence, toxicities, and public perceptions of PG/VG. RESULTS: Toxicity associated with PG/VG inhalation is primarily due to thermal degradation byproducts (TDBs) generated by PG/VG-containing e-liquids. More specifically, high-power ENDS devices with sub-ohm power capabilities generate aerosols with larger mass and higher concentrations of TDBs. The most common TDBs identified in e-cigarette aerosols include formaldehyde, acetaldehyde, acrolein, acetone, acetoin/diacetyl, as well as benzene. These TDBs, along with other chemical adducts, contribute significantly to the e-cigarette aerosols' potential to cause oxidative stress, airway inflammation, and increase risks for cancer. Mechanistically, the toxicity associated with e-cigarette aerosols is mediated through the activation of the NF-κB and MAPK pathways, as well as the dysfunction of ion channels responsible for mucus hydration. These effects of e-cigarette aerosol exposures, whether induced by TDBs or other chemicals, can be affected by factors involved in the aerosolization process, including the ratio of PG/VG, the device power, and the resistance of the coil. CONCLUSIONS: E-cigarettes are often considered a harm-reduction alternative to combustible cigarettes due to PG and VG's FDA designation as "Generally Recognized as Safe" (GRAS) for consumption. However, when heated and inhaled, mixtures of PG/VG in e-cigarette liquids have their toxicities independent of the other constituents of e-liquids. Future regulations that focus on the PG/VG ratios, set limits on thermal degradation byproducts, and establish exposure thresholds for e-cigarette aerosols will help reduce toxic exposures associated with PG/VG inhalation. As such, further research is needed on PG/VG alone to understand its long-term health effects better and to inform evidence-based public health policies.
Application of an in vitro reconstructed human skin coculture with THP-1 on cosmetics in skin sensitization.
Wang B, Ma H, Cheng Y … +2 more , Cheng D, Wang F
Toxicol Lett · 2025 Nov · PMID 41038497 · Publisher ↗
BACKGROUND: Sensitivity testing for cosmetic formulations mainly involves human patch tests. Cell models, including KeratinoSens, ARE-Nrf2 luciferase LuSens and h-CLAT, can predict chemical sensitization according to the...
BACKGROUND: Sensitivity testing for cosmetic formulations mainly involves human patch tests. Cell models, including KeratinoSens, ARE-Nrf2 luciferase LuSens and h-CLAT, can predict chemical sensitization according to the OECD 442E standard. OBJECTIVE: The aim of this study was to identify a potential approach for the assessment of the sensitization potential of cosmetics using skin models cocultured with THP-1 cells. METHODS: We identified the surface markers CD54 and CD86 in THP-1 cells using flow cytometry and enzyme-linked immunosorbent assays (ELISAs); detected the relative secretion of IL-18, MTT and 7AAD; and evaluated tissue and cell viability. Adverse reactions were analysed using the human patch test. RESULTS: The relative level of IL-18 secretion after exposure to cinnamyl aldehyde, 2,4-dinitrochlorobenzene, propyl gallate and coumarin was less than 0.79. The relative fluorescence intensity of CD54 was greater than 150, and that for CD86 was greater than 200. Using RFI CD54 ≥ 150, RFI CD86 ≥ 200 or RS IL-18 ≤ 0.79 as the potential sensitization standard, an 18-item cosmetic formulation caused sensitization. Moreover, a 23-item cosmetic formulation caused sensitization in the human patch test. The sensitivity to the products in the in vitro test reached 56.52 %, compared with 75 % for the cleaning products. CONCLUSION: RFI CD54/CD86 and IL-18 may serve as a new approach to evaluate potential sensitization to cosmetics. In vitro SkinEthic and THP-1 cell coculture combined with the human patch test may better predict potential sensitization to cosmetics.
Association between volatile organic compound exposure and elevated total immunoglobulin E: Risk factor screening in mixed exposure scenarios and potential biological mechanisms.
Wang X, Wang X, Yan R … +8 more , Ma T, Wang X, Shi F, Zhao Z, Kong L, Zhou J, Li D, Yuan Y
Toxicol Lett · 2025 Nov · PMID 41033587 · Publisher ↗
Environmental pollutants are increasingly recognized as important modulators of immune function, yet the influence of volatile organic compound (VOC) exposure on immunoglobulin E (IgE) levels remains poorly characterized...
Environmental pollutants are increasingly recognized as important modulators of immune function, yet the influence of volatile organic compound (VOC) exposure on immunoglobulin E (IgE) levels remains poorly characterized. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2006, we systematically evaluated the association between VOC metabolites and total IgE levels through five statistical approaches combined with machine learning algorithms. Mediation analyses were conducted to examine the role of inflammatory markers in these associations. Finally, functional enrichment analyses were employed to identify potential pathways and key molecular targets. Our analyses consistently demonstrated significant positive associations between VOC exposure and elevated total IgE levels. 2-aminothiazoline-4-carboxylic acid (ATCA), N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA), and N-Acetyl-S- (3-hydroxypropyl)-L-cysteine (HPMA) emerged as robust risk factors. Mediation analysis revealed that eosinophil (EOS) counts accounted for 15.89-29.03 % of the observed associations between VOC metabolites and total IgE levels. TNF and IL-17 signaling pathways were significantly enriched. Integrated analyses confirmed VOC exposure as a significant environmental risk factor for elevated total IgE levels, primarily driven by ATCA, CYMA, and HPMA, with inflammatory responses as a plausible mechanism.
Bisphenol A exposure associates with colorectal cancer metastasis and immunosuppression: A five-year cohort study.
Shen X, Bao C
Toxicol Lett · 2025 Nov · PMID 41033586 · Publisher ↗
BACKGROUND: Bisphenol A (BPA) is a widespread endocrine-disrupting chemical found in consumer products. While BPA exposure has been associated with various health risks, its specific impact on colorectal cancer (CRC) pro...
BACKGROUND: Bisphenol A (BPA) is a widespread endocrine-disrupting chemical found in consumer products. While BPA exposure has been associated with various health risks, its specific impact on colorectal cancer (CRC) progression and underlying mechanisms remain poorly understood. METHODS: In this five-year retrospective cohort study, we analyzed 63 CRC patients selected from an initial cohort of 574. Urinary BPA was quantified using HPLC-MS/MS, and patients were stratified into normal (n = 15), low (n = 30), and high (n = 18) BPA exposure groups. Flow cytometry and immunohistochemistry profiled immune cell populations in blood and tumor tissues. Multivariate regression analyses identified relationships between BPA exposure, metabolic parameters, and clinical outcomes. RESULTS: BPA levels showed significant inverse correlations with HDL/LDL ratio (p = 0.010) and positive correlations with BMI (p = 0.028). Patients with high BPA exposure demonstrated significantly higher rates of metastasis (61.1 % vs. 10 % in low exposure and 0 % in normal exposure groups, p < 0.001) and shorter overall survival (median 20 months vs. 51 months in low exposure group, p = 0.034). Flow cytometric analysis revealed dose-dependent reductions in circulating CD8 + T cells, CD4 + T cells, and NK cells with increasing BPA exposure. Immunohistochemical analysis showed pronounced decreases in tumor-infiltrating CD8 + T lymphocytes correlating with BPA exposure levels (p = 0.0027). High BPA exposure was also significantly associated with increased post-surgical infection rates (OR=1.9, 95 % CI: 1.1-3.1). CONCLUSION: These preliminary findings suggest BPA exposure represents a potential risk factor for CRC progression, likely mediated through metabolic alterations and immunosuppression within the tumor microenvironment. Environmental exposures may significantly influence cancer outcomes through immune-metabolic pathways, though further validation in larger cohorts is warranted.
PFOA exposure causes kidney injury via disruption of lipid metabolism mediated by PPARα signaling pathway: An integrated analysis.
Wu Y, Jiang Y, Fan Z … +4 more , Liu X, Sun W, Wang L, Liu H
Toxicol Lett · 2025 Nov · PMID 41027542 · Publisher ↗
Perfluorooctanoic acid (PFOA) is a persistent organic pollutant (POP) that can accumulate in living organisms and cause damage to multiple organs and systems in the human body. The kidney is viewed as a key organ affecte...
Perfluorooctanoic acid (PFOA) is a persistent organic pollutant (POP) that can accumulate in living organisms and cause damage to multiple organs and systems in the human body. The kidney is viewed as a key organ affected by PFOA, but the exact mechanism by which PFOA exposure causes kidney damage remains unclear. We selected data from 13,804 participants aged > 12 years old from the National Health and Nutrition Examination Survey (NHANES) database from 2003 to 2018 to analyze the relationship between PFOA and kidney injury. In addition, in the animal experiment, twenty adult male SD rats were divided into four groups randomly: one control group and three PFOA-treated groups. The experiment lasted 28 days, during which time water consumption and urine output were recorded daily. Kidney tissue samples were collected at the end of the experiment. Biochemical assays, RT-qPCR and Western blotting techniques were used to investigate the toxic effects of PFOA exposure on the kidney. Analysis of NHANES data shows a positive correlation between serum PFOA and uric acid (UA) with a β-value of 0.23 (95 % CI: 0.18-0.27) in Model 2. In animal studies, PFOA significantly affected rats' water intake (increased at 5 mg/kg/d, decreased at 20 mg/kg/d) and urine output (5 > 1.25 > 20 mg/kg/d > control). Renal biochemical analyses revealed significantly lower total cholesterol (TC) (1.25, 20 mg/kg/d groups) and triglyceride (TG) (1.25, 5 mg/kg/d groups) in PFOA-exposed rats. The peroxisome proliferator-activated receptors (PPAR) pathway-related gene/protein levels were significantly altered, such as 900 differentially expressed genes (DEGs) in the 20 mg/kg/d group and upregulated ACOT1 in all PFOA groups. In conclusion, the present study confirms that exposure to PFOA leads to increased oxidative catabolism of fatty acids and impaired renal lipid metabolism. These findings provide an important basis for elucidating the potential health hazards of PFOA.
Role of inflammatory response in benzo[a]pyrene-induced noradrenergic axon degeneration in mouse brain.
Reda Y, Zong C, Ikoma A … +5 more , Fergany A, Ahmed S, Abd El Naby WSH, Ichihara S, Ichihara G
Toxicol Lett · 2025 Nov · PMID 41022340 · Publisher ↗
Environmental pollution is a major contributor to neurotoxicity and could explain various nervous system dysfunctions. The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) is widely present in the environment...
Environmental pollution is a major contributor to neurotoxicity and could explain various nervous system dysfunctions. The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) is widely present in the environment, including air polluted with combustion or cigarette smoke, and considered to be involved in the development of neurodegenerative disorders. Our previous study demonstrated that B[a]P decreased noradrenergic axon density and upregulated proinflammatory cytokines in the mouse brain. The aim of this study was to explore the hypothesis that B[a]P induced neurodegeneration through signals related to inflammatory response in the brain and that sulforaphane (SFN), a naturally present antioxidant and anti-inflammatory compound, can protect against B[a]P-induced neurotoxicity. Adult male mice (C57Bl/6JJcl) were exposed to B[a]P at 0, 0.87, 2.74 or 8.67 µg which is approximately equivalent to (0.037,0.117 and 0.37 mg/kg) by pharyngeal aspiration once a week, with subcutaneous injection of SFN at 0 or 25 mg/kg body weight daily for 4 weeks. Neurotoxicity was evaluated by morphological examination of noradrenergic axon density and the positive stained Iba-1 microglia in the hippocampal areas CA1 and CA3. Moreover, we also analyzed the expression of various genes in the same tissues. At 8.67 µg, B[a]P significantly increased brain weight. Sulforaphane protected against B[a]P-induced neurotoxicity, including brain weight gain, decreased noradrenergic axon density, and microglial activation in the hippocampus. Sulforaphane also suppressed B[a]P-induced upregulation of Nf-κB and Il-6. These findings demonstrate that SFN effectively protected against B[a]P-induced neuroinflammation and axonal degeneration and suggest that B[a]P-induced neurodegeneration is mediated through brain inflammatory response.
Pre-clinical safety assessments of gadobutrol in diabetes-induced neuropathy: In vivo, in vitro and in silico studies.
Bilgin B, Hekim MG, Adam M … +5 more , Bulut F, Orhan SU, Tekin S, Husunet MT, Ozcan M
Toxicol Lett · 2025 Nov · PMID 41022339 · Publisher ↗
Due to its vascular complications, patients with diabetes mellitus (DM) are exposed to gadobutrol in imaging. However, the safety concerns of gadobutrol to diabetes-induced neuropathy, a common complication of DM, remain...
Due to its vascular complications, patients with diabetes mellitus (DM) are exposed to gadobutrol in imaging. However, the safety concerns of gadobutrol to diabetes-induced neuropathy, a common complication of DM, remain unclear as a scientific gap. This study aimed to investigate the effects of gadobutrol on hypersensitivity in a streptozotocin (STZ)-induced diabetic neuropathy model in mice and its effects on cytotoxicity and genotoxicity in high glucose (HG)-induced neuropathy in dorsal root ganglion (DRG) neurons. Adult (6-8 weeks old) BALB/c male mice were intraperitoneally administered STZ (150 mg/kg) and hot plate, cold plate, von Frey, and rota rod tests were performed 21 days after blood glucose levels rose above 250 mg/dL (N = 40). Gadobutrol was administered intravenously. DRG neurons were isolated from neonatal Sprague-Dawley rats and HG (45 mmol/L) was administered. Subsequently, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and comet assay were performed on gadobutrol-treated and HG-exposed DRG neurons. Furthermore, molecular docking analysis was performed between gadobutrol and catalase (CAT). STZ + gadobutrol showed a statistically significant increase in sensitivity in hot plate, cold plate and von Frey assays compared to STZ (p = 0.0013, p = 0.0019 and p = 0.0189, respectively). HG + gadobutrol showed statistically significant increases in cytotoxicity and genotoxicity compared to HG. The binding affinity of gadobutrol to CAT was determined as - 8.59 kcal/mol. The results of this study suggest for the first time that gadobutrol can exacerbate diabetes-induced neuropathy. Further clinical studies are needed to elucidate these results, which may pose a new safety concern for patients with diabetic neuropathy.
Individual and mixed effects of PFAS on osteoporosis: Insights from epidemiological and bioinformatic approaches.
Wei W, Huo H, Song X … +3 more , Wang D, Huang H, Jiang F
Toxicol Lett · 2025 Nov · PMID 41022338 · Publisher ↗
This cross-sectional study investigated the associations between individual and mixed exposure to per- and polyfluoroalkyl substances (PFAS) and osteoporosis, and explored potential biological mechanisms in 2764 U.S. adu...
This cross-sectional study investigated the associations between individual and mixed exposure to per- and polyfluoroalkyl substances (PFAS) and osteoporosis, and explored potential biological mechanisms in 2764 U.S. adults. Multivariable logistic regression and weighted quantile sum (WQS) regression were applied to examine associations between individual and mixed PFAS exposure and osteoporosis. Restricted cubic spline (RCS) was used to assess dose-response relationships. Mediation analysis was used to evaluate the mediated effects of neutrophil-to-lymphocyte ratio (NLR). Five PFAS compounds (PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonic acid; PFHxS, perfluorohexane sulfonic acid; PFDeA, perfluorodecanoic acid; PFNA, perfluorononanoic acid) with > 80 % detection rates were selected for investigation in this study. Individual exposure to PFOA, PFOS, PFHxS and PFNA were associated with increased lumbar osteoporosis risk (OR = 1.963, 95 %CI: 1.433, 2.687, OR = 1.422, 95 %CI: 1.061, 1.907, OR = 1.530, 95 %CI: 1.141, 2.052, OR = 1.597, 95 %CI: 1.218, 2.094). Dose-response relationships were observed for PFOA and PFHxS, particularly in women and young adults. WQS regression demonstrated that mixed PFAS exposure increased osteoporosis risk (OR = 1.198, 1.077-1.318) and decreased bone mineral density (BMD, β = -0.017, -0.026 to -0.008), with PFOA contributing most significantly (41-48 % weight). NLR partially mediated these associations. Bioinformatic analyses further identified osteoporosis-related targets and pathways, with inflammation emerging as a key mechanistic link in these associations. Our findings demonstrated a significant association between PFAS exposure and osteoporosis risk, underscoring the importance of reducing PFAS exposure in mitigating bone disease burden.
Microplastics as vectors for environmental contaminants in the food chain: Assessing the combined toxicological effects and bioavailability.
Du J, Qiu L, Zhou Q … +2 more , Jin M, Wu W
Toxicol Lett · 2025 Nov · PMID 41016659 · Publisher ↗
The global proliferation of microplastics (MPs) and nanoplastics (NPs) has raised concerns not only for their persistence in ecosystems but also for their role as transport agents of environmental contaminants through fo...
The global proliferation of microplastics (MPs) and nanoplastics (NPs) has raised concerns not only for their persistence in ecosystems but also for their role as transport agents of environmental contaminants through food chains. This review provides a comprehensive analysis of the mechanisms driving the sorption and desorption of diverse pollutants-including hydrophobic organics, metals, additives, and microbial agents-onto plastic particles, emphasizing how polymer composition, particle size, environmental aging, and eco-corona formation influence these interactions. Particular attention is paid to the transfer of MPs/NPs across trophic levels and their documented presence in various food items consumed by humans. The paper evaluates how ingestion may lead to desorption of contaminants in gastrointestinal environments, with in vitro studies demonstrating variable bioaccessibility depending on physicochemical and digestive conditions. Furthermore, the review synthesizes findings on cellular and systemic toxicity, highlighting how exposure to MPs/NPs-alone or in combination with other contaminants-can disrupt oxidative balance, immune responses, metabolic regulation, and reproductive health. Notably, combined exposures often result in synergistic or antagonistic effects, contingent on concentration, particle properties, and biological context. The potential for translocation of smaller particles and their associated chemicals across epithelial barriers introduces an additional vector of concern for internal exposure. Methodological variability in contamination assessment, limited real-world exposure data, and unresolved questions regarding long-term health consequences underscore the need for standardization and further investigation. This review aims to inform future risk assessments by integrating current knowledge of contaminant transport, bioavailability, and co-toxicological effects related to MPs/NPs in environmental and food systems.
Dysregulation of immune checkpoint LAG3 in mice exposed to silica.
Duan M, Zhao Y, Qu Y … +2 more , Hao C, Yao W
Toxicol Lett · 2025 Nov · PMID 40975466 · Publisher ↗
Silica exposure can cause silicosis, and its pathogenesis is not fully understood. This study investigates the role of immune checkpoint lymphocyte activation gene 3 (LAG3) in silicosis. Mice were intratracheally exposed...
Silica exposure can cause silicosis, and its pathogenesis is not fully understood. This study investigates the role of immune checkpoint lymphocyte activation gene 3 (LAG3) in silicosis. Mice were intratracheally exposed to silica, and tissues were collected and analyzed after 7 and 28 days. Additionally, peripheral blood samples were also collected from silicosis patients. The mRNA and protein expression levels of LAG3 in various tissues were quantified using qRT-PCR and western blot techniques. The localization of LAG3 in the lung, spleen, thymus and hilar lymph nodes was visualized by immunochemistry. Our data showed that silica exposure induced systemic changes in LAG3 expression in an organ-specific manner. In mouse lungs, LAG3 levels were significantly upregulated after silica exposure. In mouse spleen, LAG3 expression changed only during early stage of silica exposure. In mouse thymus, the level of LAG3 decreased during early stage of silica exposure but reversed to increase during late stage. In mouse hilar lymph nodes, expression of LAG3 increased significantly. A marked increase in the concentration of soluble LAG3 was observed in the plasma of mice exposed to silica. Plasma soluble LAG3 levels in silicosis patients were found to be significantly higher than healthy controls. These findings suggest that LAG3 may be involved in the pathogenesis of silicosis and that immune disorders in lung tissue may further affect systemic immune homeostasis.
Constitutive androstane receptor activation modulates YAP expression and activity through ubiquitination and sumoylation.
Liang F, Zhang S, Zhou W … +11 more , Bi G, Yang X, Wang P, Fan S, Hu S, Wu C, Jiang X, Li D, Ouyang H, Fang JH, Bi H
Toxicol Lett · 2025 Nov · PMID 40975465 · Publisher ↗
Constitutive Androstane Receptor (CAR) is a member of the nuclear receptor superfamily that significantly contributes to the metabolism of endogenous and exogenous substances and the homeostatic regulation of the body. Y...
Constitutive Androstane Receptor (CAR) is a member of the nuclear receptor superfamily that significantly contributes to the metabolism of endogenous and exogenous substances and the homeostatic regulation of the body. Yes-associated protein (YAP) is a core component of the Hippo signaling pathway. We have previously demonstrated that CAR activation interacts with YAP and induces the nuclear translocation of YAP, although the specific binding site and regulatory mechanism remain unclear. In this study, we identified the ligand-binding domain (LBD) of CAR as essential for its interaction with YAP, while the WW domain (Tryptophan- Tryptophan domain) of YAP was found to be crucial for CAR binding. We further explored the impact of CAR activation on YAP post-translational modifications. CAR agonism inhibited YAP ubiquitination but promoted its SUMO1 modification, and had no effect on acetylation, glycosylation, and methylation. Notably, CAR activation enhanced the K63-linked ubiquitination of YAP, facilitating its nuclear translocation, and this effect was dependent on the E3 ligase TRAF6. Furthermore, PIAS4 was identified as a key SUMO E3 ligase, promoting YAP SUMO1 modification upon CAR activation. These findings provide new insights into how CAR regulates YAP activity through post-translational modifications, contributing to the understanding of CAR's role in liver regeneration.
Follicular and neural toxic effect of prolonged exposure of synthetic dye fast green FCF (E143)-Insights from zebrafish model.
Sudhakaran G, Priya PS, Murugan R … +8 more , Haridevamuthu B, Kannan J, Almutairi SM, Hussein DS, Eisa YH, Kumaradoss KM, Namasivayam SKR, Arockiaraj J
Toxicol Lett · 2025 Nov · PMID 40962213 · Publisher ↗
This study highlights the toxic effects of prolonged exposure of synthetic food dye fast green FCF (E143) in zebrafish and the cumulative consequences of such exposure on multiple biological systems mainly neural and rep...
This study highlights the toxic effects of prolonged exposure of synthetic food dye fast green FCF (E143) in zebrafish and the cumulative consequences of such exposure on multiple biological systems mainly neural and reproductive. Chronic exposure to FCF at concentrations of 0.1 %, 0.3 %, and 0.5 % led to a reduction in acetylcholinesterase (AChE) activity and an increase in malondialdehyde (MDA) levels, indicating impaired neuronal function. The disruption in the production of key antioxidant enzymes, including catalase (CAT), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and nitric oxide (NO), further supported the link between elevated reactive oxygen species (ROS) levels and increased oxidative stress and lipid peroxidation (LPO). Histopathological analysis using H&E, MTS, Toluidine blue, and PAS staining revealed significant changes in the brain, liver, and ovaries of FCF-exposed zebrafish, suggesting potential neurological damage, hepatotoxicity, and reproductive disturbances, particularly arrest of follicular maturation. High-performance liquid chromatography (HPLC) analysis confirmed bioaccumulation of FCF in the ovaries. Gene expression analysis of SOD1, CAT, NF-κB, TNF-α, IL-1β, BCL2, BAX, MBP, and Syn2a provided molecular evidence of disrupted antioxidant defenses, impaired myelin formation, altered synaptic function in the brain, inflammatory responses, and increased apoptosis in the ovaries. This study is crucial for understanding the potential risks to zebrafish and provides insights into the broader implications for consumer health when exposed to similar food dyes in the environment.
Studying APAP metabolism in a cohort of intoxicated patients using HRMS-based profiling: Detection of catechol and delayed thiomethyl metabolites.
Gicquel T, Pelletier R, Gorrochategui E … +6 more , Heurté M, Le Bouedec D, Chaker J, Morel I, Le Daré B, David A
Toxicol Lett · 2025 Nov · PMID 40962212 · Publisher ↗
Acetaminophen (APAP) overdose is one of the most important causes of drug-induced liver injury worldwide. Hepatotoxicity induced by APAP is mainly caused by the production of N-acetyl-p-benzoquinone imine (NAPQI), a high...
Acetaminophen (APAP) overdose is one of the most important causes of drug-induced liver injury worldwide. Hepatotoxicity induced by APAP is mainly caused by the production of N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive intermediate. Although, the medical management of APAP intoxication is well known, research is still ongoing to identify markers that could help to predict adverse issues after APAP intoxication. In this study, we aimed to study APAP biotransformation pathways in a cohort of patients with proven acute APAP intoxication to identify new biomarkers using state-of-the-art high-resolution mass spectrometry (HRMS) methodologies that could help improve the diagnosis of intoxication as well as patient follow-up. We used a cohort of 37 patients whom blood plasma samples were stratified according to the collection time after APAP intoxication. Our results showed that direct phase II metabolites from glucuronidation and sulfation pathways remain the main markers of APAP consumption. Our study also revealed that several oxidative pathways produce significant metabolites (including catechol ones) that could also help to monitor the intoxication and the elimination of the hepatotoxic NAPQI. In particular, significant levels of thiomethyl metabolites derived from the glutathione-NAPQI conjugates could be detected with a delay in their kinetics of appearance.
Physiologically based toxicokinetic models in aggregate exposure: A review.
Lamon L, Paini A, Siccardi M … +14 more , Doyle J, McNamara C, Galea KS, Ghosh M, Louro H, Silva MJ, El Yamani N, Dusinska M, Moeller R, Duca RC, Cubadda F, Viegas S, Martins C, Price P
Toxicol Lett · 2025 Nov · PMID 40953653 · Publisher ↗
This literature review explores the application of Physiologically Based Kinetic (PBK) models in aggregate exposure (AE) assessment across different chemical classes. It builds on the screening of 1119 publications and t...
This literature review explores the application of Physiologically Based Kinetic (PBK) models in aggregate exposure (AE) assessment across different chemical classes. It builds on the screening of 1119 publications and the identification of 40 relevant articles. The most frequently studied chemicals include volatile organic compounds and plant protection products, with metals, personal care products, persistent organic pollutants and plasticisers also represented. Most studies reported in this review are applied to human populations and build on human biomonitoring (HBM) data to enhance model reliability. However, some studies use animal models (primarily rat models) and apply cross-species extrapolation to the human AE scenario. Occupational exposure is taken into consideration as part of the AE scenario in a few studies. Many of the reviewed studies are designed in support of chemical risk assessment (CRA), illustrating the wide applicability of PBK models. The review discusses the joint role of HBM data and PBK model in AE scenarios, highlighting its importance for a reliable risk assessments. The studies identified and discussed in this review suggest a broad interpretation of AE. The diversity across case reported studies is attributed to varying interpretations and existing definitions of AE. Finally, the roles of forward and reverse dosimetry in refining AE assessments are discussed, highlighting their importance for future research. This scoping review provides a comprehensive overview of PBK model applications in addressing AE, serving as a valuable foundation for future research and development aimed at advancing human health protection towards the Next-Generation Risk Assessment (NGRA).
Distinct responses of the constitutive androstane receptor NR1I3 to indole-containing metabolites of bacterial origin.
Narita R, Kaito M, Kondo T … +2 more , Abe K, Yasuoka A
Toxicol Lett · 2025 Nov · PMID 40947077 · Publisher ↗
The constitutive androstane receptor (CAR, NR1I3) has been recognised as a nuclear receptor for various xenobiotics, such as barbiturates and dietary polyphenols. In this study, the CAR responded to internal metabolites...
The constitutive androstane receptor (CAR, NR1I3) has been recognised as a nuclear receptor for various xenobiotics, such as barbiturates and dietary polyphenols. In this study, the CAR responded to internal metabolites produced by intestinal bacteria from the dietary amino acid tryptophan. We screened 15 indole-containing compounds in HepG2 cells using a luciferase reporter assay and found that three of them, tryptamine, indole-3-pyruvic acid, and indole-3-ethanol, significantly increased transcriptional activity of both mouse and human CAR. The estimated EC values of these compounds at the micromolar concentration order, which were close to those found in the host sera and tissues. Importantly, 3-methyl indole (skatole) inhibited mouse CAR activity to a lesser extent than androstanol, an inverse agonist of mouse CAR. Considering this, we investigated the transactivation mechanisms of these compounds in terms of their nuclear translocation. Indole-3-pyruvic acid and diindolylmethane slightly but not significantly increased the nuclear translocation of mouse CAR, whereas skatole significantly increased nuclear translocation. This is in contrast to the observation that androstanol does not induce nuclear translocation. Tryptamine is produced by Ruminococcus gnavus and skatole by Lactobacillus spp. Our findings suggest that the CAR can be positively or negatively regulated by indole-containing metabolites, depending on the composition of the gut microbiota.
The association between urinary levels of organic phosphorus insecticide exposure and subclinical thyroid disorders.
Wei G, Shen Y, Wang X … +11 more , Xiong D, Zhang L, Zhao T, Li X, Sun M, Yu S, Huang X, Cao S, Liao N, Chen T, Li X
Toxicol Lett · 2025 Nov · PMID 40935209 · Publisher ↗
OBJECTIVE: Studies have shown that exposure to organophosphorus pesticides (OPPs) may disrupt thyroid endocrine function in animal models and in agroforestry practitioners, leading to subclinical hyperthyroidism (SHyper)...
OBJECTIVE: Studies have shown that exposure to organophosphorus pesticides (OPPs) may disrupt thyroid endocrine function in animal models and in agroforestry practitioners, leading to subclinical hyperthyroidism (SHyper). However, the relationship between exposure to OPPs and SHyper in the general population remains unclear. This research aims to investigate the relationship between OPPs exposure and SHyper in the general population. METHODS: This was a retrospective cross-sectional study based on data collected from three cycles of the National Health and Nutrition Examination Survey (NHANES, 2001-2010), which ultimately analyzed 3425 participants who met the inclusion criteria. The study period is particularly relevant because it reflects the era of widespread chlorpyrifos (CPF) use in the United States before its subsequent ban, thereby providing important historical context for understanding OPP exposure levels. OPPs exposure was estimated by measuring urinary composition of two OPPs metabolites (3,5,6-trichloropyridinol and paranitrophenol). Logistic regression models were employed to assess the correlation between OPPs metabolites and SHyper. Subgroup analyses were conducted based on gender, age, body mass index (BMI), and household income, and interactions with OPPs were investigated. The two metabolites were categorized into quartiles, and trend analysis was performed. Restrictive cubic spline models were used to fit the relationship between the two metabolites and the risk of SHyper. Sensitivity analyses were conducted by excluding participants who consumed alcohol and those with iodine deficiency to validate the model's stability. RESULTS: Adjusted logistic regression analyses revealed significant positive associations between both para-nitrophenol (PNP) and 3,5,6-trichloropyridinol (TCPy) with subclinical hyperthyroidism (SHyper). Participants in the second, third, and highest quartiles of PNP exposure exhibited a progressively increased risk of SHyper compared to those in the lowest quartile.Stratified analyses demonstrated that TCPy's association with SHyper was particularly pronounced in specific subgroups: individuals aged 12-64 years, males, those with household incomes < $20,000/year, and participants with obesity (BMI ≥30 kg/m²). Similarly, PNP was consistently associated with elevated SHyper risk across all stratified populations. Sensitivity analyses confirmed the robustness of these associations, as the relationships between PNP/TCPy and SHyper persisted even after excluding alcohol consumers or iodine-deficient individuals. CONCLUSIONS: Our study suggests that exposure to OPPs is associated with an increased risk of SHyper, an association reflected by the observed correlations between urinary metabolites (PNP and TCPy) and SHyper.
A core physiologically based toxicokinetic (PBTK) model for exposure assessment of multiple environmental phenols.
Choi JW, Lee S, Lee J … +2 more , Shin MY, Kim S
Toxicol Lett · 2025 Nov · PMID 40930470 · Publisher ↗
Environmental phenols are widely used in consumer products and are of increasing concern due to their potential endocrine-disrupting effects. Physiologically based toxicokinetic (PBTK) models offer a powerful tool for es...
Environmental phenols are widely used in consumer products and are of increasing concern due to their potential endocrine-disrupting effects. Physiologically based toxicokinetic (PBTK) models offer a powerful tool for estimating human exposure by translating biomonitoring data into external intake values. However, conventional PBTK models are typically chemical-specific and resource-intensive. In this study, we developed a core human PBTK model capable of describing the absorption, distribution, metabolism, and excretion (ADME) of four groups of environmental phenols-parabens (MeP, EtP, PrP), bisphenols (BPA, BPS), triclosan (TCS), and benzophenone-3 (BP-3)-based on shared toxicokinetic characteristics. The model was calibrated and validated using human volunteer data and applied to urinary biomonitoring data from 3787 Korean adults in the Korean National Environmental Health Survey (KoNEHS 2015-2017). Estimated daily intakes (EDIs) for MeP, EtP, PrP, and BPA were estimated via reverse dosimetry and compared with values derived from the conventional fractional urinary excretion (F) method. Median EDIs derived from the PBTK model were 3.7, 4.8, 0.4, and 0.02 μg/kg-bw/day for MeP, EtP, PrP, and BPA, respectively, and showed good agreement with F based estimates. The core model successfully captured blood and urinary concentration profiles across multiple phenols, demonstrating its potential as a practical and scalable framework for exposure assessment. Furthermore, the model was used in a reverse dosimetry framework to estimate human exposure levels from urinary biomonitoring data. This approach can be particularly valuable when chemical-specific models are unavailable, offering an efficient alternative for interpreting biomonitoring data in environmental health risk assessment.
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