Toxicology letters最新文献

{"title":"Pre-clinical safety assessments of gadobutrol in diabetes-induced neuropathy: In vivo, in vitro and in silico studies","authors":"Batuhan Bilgin ,&nbsp;Munevver Gizem Hekim ,&nbsp;Muhammed Adam ,&nbsp;Ferah Bulut ,&nbsp;Seval Ulku Orhan ,&nbsp;Suat Tekin ,&nbsp;Mehmet Tahir Husunet ,&nbsp;Mete Ozcan","doi":"10.1016/j.toxlet.2025.111733","DOIUrl":"10.1016/j.toxlet.2025.111733","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111733"},"PeriodicalIF":2.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual and mixed effects of PFAS on osteoporosis: Insights from epidemiological and bioinformatic approaches","authors":"Wei Wei ,&nbsp;Hongjin Huo ,&nbsp;Xinxi Song ,&nbsp;Dongxuan Wang ,&nbsp;Hongyu Huang ,&nbsp;Fei Jiang","doi":"10.1016/j.toxlet.2025.111731","DOIUrl":"10.1016/j.toxlet.2025.111731","url":null,"abstract":"<div><div>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 &gt; 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 _Ln-PFOA = 1.963, 95 %CI: 1.433, 2.687, OR _Ln-PFOS = 1.422, 95 %CI: 1.061, 1.907, OR _Ln-PFHxS = 1.530, 95 %CI: 1.141, 2.052, OR _Ln-PFNA = 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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111731"},"PeriodicalIF":2.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics as vectors for environmental contaminants in the food chain: Assessing the combined toxicological effects and bioavailability","authors":"Jia Du,&nbsp;Linlin Qiu,&nbsp;Qingwei Zhou,&nbsp;Meiqing Jin,&nbsp;Weihong Wu","doi":"10.1016/j.toxlet.2025.111734","DOIUrl":"10.1016/j.toxlet.2025.111734","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111734"},"PeriodicalIF":2.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of immune checkpoint LAG3 in mice exposed to silica","authors":"Meixiu Duan ,&nbsp;Youliang Zhao ,&nbsp;Yaqian Qu ,&nbsp;Changfu Hao ,&nbsp;Wu Yao","doi":"10.1016/j.toxlet.2025.111729","DOIUrl":"10.1016/j.toxlet.2025.111729","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111729"},"PeriodicalIF":2.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive androstane receptor activation modulates YAP expression and activity through ubiquitination and sumoylation","authors":"Fengting Liang ,&nbsp;Shuaishuai Zhang ,&nbsp;Wenhong Zhou ,&nbsp;Guofang Bi ,&nbsp;Xiao Yang ,&nbsp;Peng Wang ,&nbsp;Shicheng Fan ,&nbsp;Shuang Hu ,&nbsp;Chenghua Wu ,&nbsp;Xiaowen Jiang ,&nbsp;Dan Li ,&nbsp;Hui Ouyang ,&nbsp;Jian-Hong Fang ,&nbsp;Huichang Bi","doi":"10.1016/j.toxlet.2025.111728","DOIUrl":"10.1016/j.toxlet.2025.111728","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111728"},"PeriodicalIF":2.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Studying APAP metabolism in a cohort of intoxicated patients using HRMS-based profiling: Detection of catechol and delayed thiomethyl metabolites","authors":"Thomas Gicquel ,&nbsp;Romain Pelletier ,&nbsp;Eva Gorrochategui ,&nbsp;Margaux Heurté ,&nbsp;Diane Le Bouedec ,&nbsp;Jade Chaker ,&nbsp;Isabelle Morel ,&nbsp;Brendan Le Daré ,&nbsp;Arthur David","doi":"10.1016/j.toxlet.2025.111727","DOIUrl":"10.1016/j.toxlet.2025.111727","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111727"},"PeriodicalIF":2.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Follicular and neural toxic effect of prolonged exposure of synthetic dye fast green FCF (E143)–Insights from zebrafish model","authors":"Gokul Sudhakaran ,&nbsp;P. Snega Priya ,&nbsp;Raghul Murugan ,&nbsp;B. Haridevamuthu ,&nbsp;Jagan Kannan ,&nbsp;Saeedah Musaed Almutairi ,&nbsp;Dina S. Hussein ,&nbsp;Yasmine Hamdy Eisa ,&nbsp;Kathiravan Muthu Kumaradoss ,&nbsp;S. Karthick Raja Namasivayam ,&nbsp;Jesu Arockiaraj","doi":"10.1016/j.toxlet.2025.111726","DOIUrl":"10.1016/j.toxlet.2025.111726","url":null,"abstract":"<div><div>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&amp;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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111726"},"PeriodicalIF":2.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically based toxicokinetic models in aggregate exposure: A review","authors":"L. Lamon ,&nbsp;A. Paini ,&nbsp;M. Siccardi ,&nbsp;J. Doyle ,&nbsp;C. McNamara ,&nbsp;K.S. Galea ,&nbsp;M. Ghosh ,&nbsp;H. Louro ,&nbsp;M.J. Silva ,&nbsp;N. El Yamani ,&nbsp;M. Dusinska ,&nbsp;R. Moeller ,&nbsp;R.C. Duca ,&nbsp;F. Cubadda ,&nbsp;S. Viegas ,&nbsp;C. Martins ,&nbsp;P. Price","doi":"10.1016/j.toxlet.2025.111725","DOIUrl":"10.1016/j.toxlet.2025.111725","url":null,"abstract":"<div><div>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).</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111725"},"PeriodicalIF":2.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct responses of the constitutive androstane receptor NR1I3 to indole-containing metabolites of bacterial origin","authors":"Ryuya Narita ,&nbsp;Misaki Kaito ,&nbsp;Takashi Kondo ,&nbsp;Keiko Abe ,&nbsp;Akihito Yasuoka","doi":"10.1016/j.toxlet.2025.111724","DOIUrl":"10.1016/j.toxlet.2025.111724","url":null,"abstract":"<div><div>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 EC₅₀ 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 <em>Ruminococcus gnavus</em> and skatole by <em>Lactobacillus spp</em>. Our findings suggest that the CAR can be positively or negatively regulated by indole-containing metabolites, depending on the composition of the gut microbiota.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111724"},"PeriodicalIF":2.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between urinary levels of organic phosphorus insecticide exposure and subclinical thyroid disorders","authors":"Gaohui Wei ,&nbsp;Yi Shen ,&nbsp;Xian Wang ,&nbsp;Dandan Xiong ,&nbsp;Lingli Zhang ,&nbsp;Tianliang Zhao ,&nbsp;Xinjie Li ,&nbsp;Mengmeng Sun ,&nbsp;Sihui Yu ,&nbsp;Xueqi Huang ,&nbsp;Shengkang Cao ,&nbsp;Ning Liao ,&nbsp;Tao Chen ,&nbsp;Xiangzhi Li","doi":"10.1016/j.toxlet.2025.111723","DOIUrl":"10.1016/j.toxlet.2025.111723","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 &lt; $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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"413 ","pages":"Article 111723"},"PeriodicalIF":2.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}