Journal of Applied Toxicology最新文献

{"title":"Biochar-nZVI Mediated Immobilization of Soil As and Cd Reduces Their Gastrointestinal Bioaccessibility and Cytotoxic Potential in Caco-2/HL-7702 Cells.","authors":"Maria Aziz, Muhammad Tariq Rafiq, Ying Feng, Xiaoe Yang, Muhammad Arshad, Rukhsanda Aziz, Niaz Muhammad","doi":"10.1002/jat.70472","DOIUrl":"https://doi.org/10.1002/jat.70472","url":null,"abstract":"<p><p>Soil-bound arsenic (As) and cadmium (Cd) reach the human body through accidental ingestion, yet most risk assessments rely on total soil metal content rather than the fraction that is actually released and absorbed. The present study linked these steps directly by coupling simulated gastrointestinal digestion with human intestinal (Caco-2) and hepatic (HL-7702) cell models and evaluated whether biochar supported nano-zero-valent iron (BC-nZVI) could interrupt the pathway from contaminated soil to cellular injury. SEM-EDS and XRD confirmed the successful doping of crystalline Fe⁰ nanoparticles on biochar surface. Linear regression revealed strong correlation between DTPA-extractable and total soil As (R² = 0.9963) and Cd (R² = 0.9984), confirming DTPA-extraction as a reliable proxy for extractable metal pool. Bioaccessibility increased with increase in co-contamination levels reaching 72.0% for As and 62.2% for Cd at the highest co-contamination level (T3). BC-nZVI significantly reduced bioaccessibility to 27.3% (As) and 17.3% (Cd) at 3% application rate. This immobilization translated to biological protection, where HL-7702 viability (MTT) reduced to 15.8% and membrane damage (LDH release) reached 85.2% at highest co-contamination. BC-nZVI enhanced the cell viability to 94.5% and reduced membrane damage to 49.2% with 3% dose. Multivariate modeling identified bioavailable As as a significant predictor of cytotoxicity (each 1% increase in bioavailable As predicted ≈1.1% reduction in cell viability), while Cd toxicity followed a pH-mediated pathway decoupled from its bioavailable fraction. This study traces the full exposure chain from soil chemistry through gut-liver response to remediation outcomes within co-contaminated system. Therefore, it provides a mechanistic framework for contaminated soil and highlights the potential of BC-nZVI for reducing dietary exposure in co-contaminated agricultural lands.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mixture Effects of Lead and Chromium in Zebrafish (Danio rerio) Brain: Involvement of Nrf2-Keap1-ARE Pathway.","authors":"Olivia Sarkar, Sunanda Mukherjee, Tanmoy Das, Ansuman Chattopadhyay","doi":"10.1002/jat.70476","DOIUrl":"https://doi.org/10.1002/jat.70476","url":null,"abstract":"<p><p>Lead (Pb) and chromium (Cr) are prevalent aquatic contaminants capable of inducing oxidative and neurological disturbances; however, the consequences of their combined exposure on brain oxidative homeostasis remain poorly understood. The present study examined the progressive oxidative, molecular, and histopathological effects of chronic Pb and Cr exposure, individually and in combination, in zebrafish (Danio rerio), with particular emphasis on modulation of the Nrf2-Keap1-ARE pathway. Adult male zebrafish were exposed to environmentally relevant concentrations of Pb (2.5, 5, and 10 ppb), Cr (0.5, 1, and 2 ppm), and corresponding mixed exposures for 15, 30, and 60 days. Prolonged exposure caused progressive reductions in the brain somatic index, accompanied by marked oxidative imbalance characterized by increased reactive oxygen species generation, elevated lipid peroxidation, enhanced catalase activity, and reduced glutathione. Cr exposure elicited comparatively greater oxidative and molecular responses than Pb, while co-exposure consistently produced the most severe alterations. Histopathological analysis revealed vacuolar degeneration, edema, tectal disorganization, meningeal deformation, and increased mononuclear cells with surrounding clear spaces within the optic tectum. Molecular analysis demonstrated significant upregulation of nrf2, nqo1, ho1, hsp70, cyp1a, gst, gpx, cat, mnsod, cu/znsod, and ache, along with suppression of keap1 and ucp2, indicating activation of antioxidant defense and stress-responsive pathways. Enhanced Nrf2 immunoreactivity further confirmed activation of the Nrf2-mediated protective response in exposed brain tissue. Together, these results exhibited that prolonged co-exposure to environmentally relevant Pb and Cr concentrations promoted progressive oxidative, molecular, and histopathological alterations in the zebrafish brain, accompanied by activation of the Nrf2-Keap1-ARE signaling pathway.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Europium Oxide Disrupts Metabolic Homeostasis and Antioxidant Defenses in African Catfish (Clarias gariepinus): Integrated Physiological and Molecular Docking Approaches.","authors":"Abdallah Tageldein Mansour, Ahmed Saud Alsaqufi, Fatma Mahsoub, Sameh A Abdelnour","doi":"10.1002/jat.70470","DOIUrl":"https://doi.org/10.1002/jat.70470","url":null,"abstract":"<p><p>Chemical pollution from rare earth elements (REEs) has emerged as a significant threat to the stability of freshwater ecosystems. Among these elements, europium oxide (Eu₂O₃) is widely used across various industrial sectors; however, its specific impacts on fish physiology, health, and immune function remain poorly understood. This study aimed to evaluate the effects of Eu₂O₃ on growth, hepatic markers, intestinal enzyme, systemic immune response, and cytokine expression in African catfish (Clarias gariepinus). Fish were divided into four experimental groups and exposed to Eu₂O₃ concentrations of 0 (Eu0), 5 (Eu5), 10 (Eu10), and 50 (Eu50) μg/L of water for 28 days. The results revealed a lower doses (Eu5) appeared to stimulate growth, whereas higher doses (Eu10 and Eu50) significantly impaired growth performance, digestive enzymes, and hepatic damage (p < 0.01). High doses of europium (Eu10 and Eu50) significantly suppressed immune function, as shown by lower IgM, IgG, lysozyme activity, and C3 levels (linear effect, p < 0.05). High concentration exposure induced severe oxidative stress levels (ACE, myeloperoxidase, cortisol, glucose, MDA, and nitric oxide), along with a depletion of antioxidant status (TAC, GSH, and SOD) (linear effect, p < 0.05). Compared to the control, the Eu10 and Eu50 groups showed significantly higher levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and significantly lower activities of mitochondrial metabolic enzymes (citrate synthase and malate dehydrogenase) (linear effect, p < 0.05). Histological examination revealed severe tissue damage in the kidneys and intestines of catfish exposed to high concentrations of Eu₂O₃. Molecular docking analyses suggested that Eu₂O₃ potentially binds to ATP, cytochrome P450 aromatase, and HSP70, proposing that it potential triggers mitochondrial dysfunction and disrupts metabolic homeostasis. Overall, exposure to elevated concentrations of Eu₂O₃ causes marked immune dysfunction, impairs antioxidant defenses, damages mitochondrial pathways, and provokes systemic inflammation, ultimately compromising the physiological integrity of C. gariepinus.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Exposure to Effect: Oxidative Stress Biomarkers as Chemical-Biological Indicators of Heavy Metal Toxicity in Freshwater Fish.","authors":"Adnan Ahmad Qazi","doi":"10.1002/jat.70467","DOIUrl":"https://doi.org/10.1002/jat.70467","url":null,"abstract":"<p><p>Heavy metal-induced toxicity in freshwater fish is driven at the cellular level by reactive oxygen species (ROS) generated through Fenton chemistry, mitochondrial electron transport chain disruption, and competitive displacement of essential metals at sulfhydryl-bearing antioxidant molecules and enzymes. The enzymatic antioxidant battery (superoxide dismutase, catalase, glutathione peroxidase) together with the lipid peroxidation end-product malondialdehyde has been shown in this review to provide a mechanistically grounded and temporally sensitive measure of toxic effect that tracks the Keap1-Nrf2-ARE adaptive cascade far more directly than conventional tissue concentration endpoints can. Subcellular metal partitioning and metallothionein-mediated sequestration, rather than total tissue burden, are demonstrated to govern which fraction of the internal metal pool is biologically reactive; antioxidant responses integrate this bioavailability information automatically. The biphasic dose-response of enzymatic antioxidants, reflecting early Nrf2-driven induction followed by direct metal inactivation at higher exposures, is examined as the mechanistic signature that distinguishes adaptive from damage phases at the individual level. Complementary pro-inflammatory and immunological readouts, including IL-6, TNF-α, NF-κB activation, and altered cytokine balance, are reviewed as second-tier effect markers that broaden the diagnostic envelope beyond pure redox endpoints. Drawing on evidence from industrially impacted river systems, with Pakistan's Indus Basin serving as a representative developing-country case, the Adverse Outcome Pathway paradigm is integrated with classical biomarker science, and a three-stage Bioavailability-Effect Monitoring Framework (BEMF) is proposed as a practical, transferable pathway from exposure measurement to effect-based environmental assessment. The transition from exposure metrics to effect indicators is argued to constitute a necessary conceptual advance for applied toxicology in the protection of aquatic ecosystems under Anthropocene multistressor conditions.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Heavy Metal Contamination in Scratch-Off Coatings of Prepaid Mobile Phone Cards in Saudi Arabia: Analytical Determination, Exposure Pathways, and Human Health Risk Evaluation.","authors":"Ahmed H Bakheit, Eram Eltahir, Badraddin M H Al-Hadiya","doi":"10.1002/jat.70465","DOIUrl":"https://doi.org/10.1002/jat.70465","url":null,"abstract":"<p><p>Prepaid mobile phone recharge cards remain widely used consumer products in many low- and middle-income settings, yet the scratch-off coatings that conceal personal identification numbers (PINs) have received little attention as potential sources of trace-metal exposure. The present study quantified lead (Pb), cadmium (Cd), and copper (Cu) in scratch-off coatings collected from three major telecommunications brands marketed in Saudi Arabia and evaluated potential health risks using conservative and realistic exposure models. Thirty cards from each brand were purchased from retail outlets in Taif city. Scratch-off coatings were mechanically removed, homogenized, and digested using nitric/perchloric acid prior to analysis by flame atomic absorption spectrometry (AAS). Quality assurance procedures included blank correction, triplicate analysis, calibration verification, and recovery assessment (> 90% for all analytes). Measured concentrations ranged from 16.12 to 17.62 mg/kg for Pb, 0.26 to 0.52 mg/kg for Cd, and 9.69 to 13.13 mg/kg for Cu, with Pb consistently representing the dominant contaminant. Exposure was assessed by the daily intake of metals (DIM), average daily intake (ADI), and dermal absorbed dose (DAD) approaches. Under the conservative DIM scenario, Pb yielded values of 0.0248-0.0271 mg/kg/day and corresponding Health Risk Index (HRI) values of 6.20-6.78, exceeding the safety threshold. In contrast, ingestion-based ADI estimates (10^-6 mg/kg/day) and DAD estimates (10^-8-10^-9 mg/kg/day) were markedly lower, indicating that realistic exposure is substantially less than the upper-bound scenario. Target hazard quotient (THQ) values exceeded unity for Pb but not for Cd or Cu; however, the cumulative Hazard Index (HI) ranged from 7.08 to 7.76, indicating possible noncarcinogenic concern dominated by Pb. Target cancer risk (TCR) values for Cd (1.52 × 10^-6-3.04 × 10^-6) fell within the generally acceptable regulatory range but still indicate a measurable lifetime cancer risk. Overall, the findings identify scratch-off coatings as a previously underrecognized consumer-product exposure pathway and support the need for improved quality control, regulatory oversight, and safer coating formulations.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Glyphosate and Glyphosate-Based Herbicides on the Mammalian Gut Microbiome: A Critical Review.","authors":"Robin Mesnage","doi":"10.1002/jat.70475","DOIUrl":"https://doi.org/10.1002/jat.70475","url":null,"abstract":"<p><p>Glyphosate has long been considered to pose negligible direct risk to mammals on the grounds that its molecular target, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), of the shikimate pathway, is absent from animal cells. This rationale is inaccurate as a complete toxicological argument, because the shikimate pathway is present in some commensal bacteria in the mammalian gut. This review appraises the evidence that glyphosate and glyphosate-based herbicides (GBHs) perturb the gut microbiome of mammals. Controlled rodent studies provide the most consistent evidence, with several reporting shifts in community composition, including a depletion of lactobacilli, sometimes accompanied by intestinal inflammation, altered microbial metabolism and increased intestinal permeability. Experimental evidence indicates that luminal aromatic amino acid availability attenuates the antibacterial effect. Formulated products are frequently more disruptive than the active ingredient alone. Some studies suggest that the gut mycobiome is also affected. Neurobehavioural and reproductive outcomes have also been reported, although microbiome-mediated causality is not established in most studies. Glyphosate-induced effects are strongly influenced by dose, by whether the active ingredient or a formulated product is tested, by sex and by a developmental window of exposure. Available human data, confined to in vitro systems and small biomonitoring cohorts, are limited. In conclusion, glyphosate and some GBHs can perturb the rodent gut microbiome under defined experimental conditions. These animal findings are relevant to hazard assessment and support inclusion of microbiome endpoints in regulatory toxicology, although the magnitude and health relevance of comparable effects at realistic human exposures remain uncertain.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adverse Effects of Unsaturated Organic Compounds on Kinetic States During Locomotion Uncovered by Comprehensive Analysis of Behavioral Toxicities in C. elegans.","authors":"Masahiro Tomioka","doi":"10.1002/jat.70471","DOIUrl":"https://doi.org/10.1002/jat.70471","url":null,"abstract":"<p><p>Organisms in human living spaces are surrounded by a variety of engineered substances. These chemical compounds have unexpected effects on the environment and human health. In particular, workers in industries face the risk of a health hazard caused by high-dose or long-term exposure to chemicals in the workplace. Thus, understanding chemical toxicities in a multifaceted manner is necessary to save the environment and human health from engineered chemicals. In this study, the behavioral toxicities of workplace chemicals with various functional groups are assessed using Caenorhabditis elegans. I compared the acute effects of 68 chemical compounds on locomotion speed with a lethal dose of 50% (LD₅₀) in mammals, and a significant correlation was found between them. Allyl alcohol is toxic to the internal organs, such as the liver and stomach, dependent on acrolein, an α,β-unsaturated aldehyde metabolized by alcohol dehydrogenase in mammals. Allyl alcohol caused various abnormalities in C. elegans locomotion dependent on ADH-1, an ortholog of alcohol dehydrogenase, indicating the adverse effects of acrolein on behavior. Further locomotion tests revealed that chemicals with unsaturated carbon adjacent to electron-withdrawing functional groups, such as carbonyl, nitrile, and sulfonyl groups, caused a common effect on locomotion, which is a substantial increase in the frequency of backward movement during random locomotion. Accordingly, this study proposes the usefulness of locomotion tests in C. elegans for estimating the acute toxicities of chemicals across species and understanding the common features of chemical groups that cause adverse effects on behavior.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rotenone-Induced Cytotoxicity in Human Umbilical Vein Endothelial Cells (HUVECs): Involvement of Oxidative Stress, Mitochondrial Dysfunction, and Intrinsic Apoptosis.","authors":"Maqsood A Siddiqui, Nida N Farshori","doi":"10.1002/jat.70473","DOIUrl":"https://doi.org/10.1002/jat.70473","url":null,"abstract":"<p><p>Rotenone is a well-defined inhibitor of Mitochondrial Complex I, which induces oxidative stress and apoptosis in various cell types. However, its cytotoxicity and molecular mechanisms in human umbilical vein endothelial cells (HUVECs) remain unexplored. Therefore, the purpose of this study was to examine the effects of rotenone on HUVECs. Cells were exposed to rotenone at concentrations of 5-100 μM for 24 h. Cell viability and cytotoxicity were assessed using MTT and LDH assays, respectively. Morphological alterations were examined using light microscopy. Further, using cytotoxic doses of rotenone, glutathione (GSH) levels, lipid peroxidation (LPO), catalase activity, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Apoptosis was assessed by measuring caspase-3 and caspase-9 activities, and the mRNA expression of apoptosis-related genes (caspase-3, caspase-9, Bax, Bcl-2, p53, and p21) was analyzed using quantitative real-time PCR. Our results showed that rotenone induced concentration-dependent cytotoxicity in HUVECs. Morphological studies showed cell shrinkage, membrane damage, and cell detachment after rotenone treatment. Rotenone exposure caused oxidative stress in HUVECs, as evidenced by a significant increase in ROS and LPO levels and depletion of GSH and catalase activity. The loss of MMP observed upon rotenone treatment suggests mitochondrial dysfunction. Moreover, rotenone significantly increased the activities of caspase-3 and caspase-9; enhanced the mRNA expression of caspase-3, caspase-9, Bax, p53, and p21; and reduced the expression of Bcl-2, which further confirmed the induction of apoptosis through mitochondrial signaling. Overall, rotenone caused substantial cytotoxicity in HUVECs through oxidative stress, mitochondrial dysfunction, and activation of the intrinsic apoptotic pathway.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Analysis of Buccal-Cell microRNAs Reveals Molecular Signatures Associated With Chronic Pesticide Exposure in Agricultural Workers.","authors":"Fábio Morato de Oliveira, Raquel Alves Dos Santos, Mario Fernando Estorino Moreno, Fermino Lizarte Sanches Neto","doi":"10.1002/jat.70450","DOIUrl":"https://doi.org/10.1002/jat.70450","url":null,"abstract":"<p><p>Chronic pesticide exposure has been associated with oxidative stress, inflammation, and genomic instability, and microRNAs (miRNAs) may reflect regulatory responses occurring between exposure and adverse outcomes. This cross-sectional biomonitoring study evaluated selected miRNAs as molecular response indicators associated with chronic pesticide exposure and genomic instability in 137 participants classified as putatively non-exposed (n = 34), indirectly exposed (n = 41), or directly exposed agricultural workers (n = 62). Buccal epithelial cells were analyzed for micronucleus frequency and expression of miR-21-5p, miR-34a-5p, miR-146a-5p, miR-155-5p, miR-126-3p, and miR-222-3p by RT-qPCR. Hierarchical clustering, principal component analysis (PCA), logistic regression, ROC analysis, and repeated 10-fold cross-validation were performed. Directly exposed workers showed significantly increased expression of miR-21-5p, miR-34a-5p, miR-146a-5p, miR-155-5p, and miR-222-3p, whereas miR-126-3p was significantly reduced (all p < 0.001). Micronucleus frequency increased progressively across the three groups (2.1 ± 0.4, 4.6 ± 0.7, and 7.8 ± 1.2 MN/2000 cells; p < 0.001). PCA explained 78.1% of the total variance and distinguished the exposure groups. The integrated six-miRNA signature achieved an AUC of 0.92 (95% CI: 0.88-0.97) and an optimism-corrected AUC of 0.89 after internal validation. These findings indicate that chronic pesticide exposure is associated with coordinated miRNA dysregulation and increased genomic instability. The six-miRNA signature may complement established occupational biomonitoring approaches as an indicator of intermediate molecular responses, but it should not be interpreted as a direct measure of pesticide dose or clinical effect.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of the Sensitivity of Histopathological and Immunohistochemical Analyses With That of Serum Hormone Measurements for Early Detection of Antithyroid Effects in Rats Treated With Iodide Uptake Inhibitors.","authors":"Hirotoshi Akane, Shinji Takasu, Yuji Ishii, Kohei Matsushita, Mizuho Uneyama, Tomomi Morikawa, Tadashi Kosaka, Hiroaki Aoyama, Kumiko Ogawa, Takeshi Toyoda","doi":"10.1002/jat.70449","DOIUrl":"https://doi.org/10.1002/jat.70449","url":null,"abstract":"<p><p>Serum thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) measurements are widely used to detect antithyroid effects in rodent toxicity studies. However, the assays used to measure these hormones are costly and highly variable depending on the blood sampling and measurement conditions. We previously demonstrated that histopathological evaluation detects the effects of thyroid peroxidase (TPO) inhibitors and thyroid hormone metabolism promoters more sensitively than serum hormone measurements. Here, we examined whether this approach can also improve early detection of antithyroid chemicals that inhibit iodide uptake, an essential step in thyroid hormone synthesis. We compared histopathological and immunohistochemical findings with serum hormone measurements in 6-week-old male Sprague-Dawley rats (five per group) administered ammonium perchlorate (APC) or potassium thiocyanate (PTC) in drinking water for 28 days. Serum T4 decreased at 1000 ppm APC and 5000 ppm PTC, T3 decreased at 1000 ppm APC, and TSH increased at ≥ 100 ppm APC. In contrast, follicular cell hypertrophy was detected at ≥ 10 ppm APC and 5000 ppm PTC, indicating greater sensitivity compared with serum hormone measurements. Decreased T3 and T4 immunostaining showed a sensitivity comparable with that of serum hormone changes, whereas thyroid sodium/iodide symporter (NIS)-immunopositive areas increased at doses that produced no detectable changes in serum hormone levels, suggesting that NIS immunostaining represents the most sensitive marker of iodide uptake inhibition. These results suggest that combining histopathological and immunohistochemical analyses enables sensitive detection of antithyroid effects and provides mechanistic information that cannot be obtained from serum hormone measurements alone.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}