Toxicology and applied pharmacology最新文献

{"title":"Doxorubicin-induced cardiotoxicity under 28 GHz 5G-band electromagnetic radiation in rats: Insights into the mitigative role of vitamin C","authors":"Atefeh Rahimi ,&nbsp;Ali Rafati ,&nbsp;S.M.J. Mortazavi ,&nbsp;Fahime Edalat ,&nbsp;Najme Jooyan ,&nbsp;Maryam Naseh ,&nbsp;Somaye Keshavarz ,&nbsp;Hadi Moatamed Jahromi ,&nbsp;Ardeshir Nabizadeh ,&nbsp;Sanaz Dastghaib ,&nbsp;Narges Karbalaei","doi":"10.1016/j.taap.2025.117703","DOIUrl":"10.1016/j.taap.2025.117703","url":null,"abstract":"<div><div>Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, induces cardiotoxicity through oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. As millimeter-wave frequencies used in fifth-generation (5G) communication systems continue to expand, experimental data on potential biological interactions under clinically relevant conditions remain limited. This study investigated whether short-term 28-GHz electromagnetic radiation (EMR) modifies the cardiac response to DOX and evaluated the potential protective role of vitamin C. Thirty male Sprague–Dawley rats were assigned to five groups (<em>n</em> = 6): Sham, DOX, DOX + Vit C, DOX + 5G, and DOX + 5G + Vit C. DOX (15 mg/kg intraperitoneally, six injections) induced cardiotoxicity, while vitamin C (250 mg/kg orally) was administered daily for 14 days. EMR exposure consisted of three 10-min cycles per day at 28 GHz for 14 days. Cardiac injury was assessed using electrocardiography, serum cTnI, oxidative markers (MDA, GSH, SOD, CAT), apoptotic and inflammatory gene expression (BAX, CASP3, BCL-2, TNF-α), and design-based stereology.</div><div>DOX induced significant functional, biochemical, molecular, and structural alterations. Co-exposure to 28-GHz EMR amplified reductions in CAT (<em>p</em> &lt; 0.001), and enhanced pro-apoptotic BAX gene expression (<em>p</em> &lt; 0.0001), accompanied by QT interval prolongation (<em>p</em> &lt; 0.05). Vitamin C provided partial protection across these endpoints. Under the specific short-term pre-clinical conditions tested, these findings indicate that 28-GHz EMR can modulate the severity of DOX-induced cardiotoxicity, while vitamin C confers modest attenuation. Further long-term and clinical studies are needed to clarify mechanisms and refine translational relevance.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117703"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884331","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":"Saxagliptin mitigates doxorubicin-induced cardiotoxicity by modulating NLRP3/caspase-1/IL-1β and TLR-4/NF-κB pathways","authors":"Maha M. Abdel-Fattah,&nbsp;Yasmeen M. Abozaid,&nbsp;Basim Anwar Shehata Messiha,&nbsp;Marwa M. Khalaf","doi":"10.1016/j.taap.2025.117697","DOIUrl":"10.1016/j.taap.2025.117697","url":null,"abstract":"<div><div>Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is restricted as cardiac toxicity proportional to the drug dosage. Saxagliptin (SAXA) is a selective and potent member of the dipeptidyl peptidase (DPP)-IV inhibitor family utilized in the management of type two diabetes. It also possesses several biological actions, involving anti-inflammatory and antioxidant properties. This work sought to ascertain the underlying molecular mechanisms and determine the shielding role of SAXA against DOX-induced cardiotoxicity. Thirty-two rats were randomly assigned to four experimental groups, including a normal control group administered the vehicle only, a SAXA group receiving SAXA alone (10 mg/kg), a DOX control group receiving DOX (20 mg/kg) as a single dose, and a SAXA treatment group receiving SAXA plus DOX. Compared to DOX control group, pretreatment with SAXA (10 mg/kg) significantly reduced serum concentrations of CK-MB and CTnI by 37.11 % and 46.32 %, respectively, in addition to a marked improvement in the histopathological features of heart tissues. Moreover, SAXA significantly decreased MDA by 56.05 % and increased GSH and SOD in DOX-intoxicated rats by 493.28 % and 458.32 %, respectively. Additionally, western blot analysis revealed that SAXA pretreatment significantly down-regulated TLR-4 and NLRP3 by 34.9 % and 33.99 %, respectively. Furthermore, ELISA analysis showed that SAXA pretreatment significantly down-regulated NF-κB, caspase-1, and IL-1β by 44.04 %, 78.7 %, and 57.7 %, respectively. The findings of this study suggest that SAXA may exert a cardioprotective effect against DOX-induced toxicity, likely through its antioxidant and anti-inflammatory properties.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117697"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840717","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":"Nicotinamide N-oxide alleviates sepsis-induced hepatic inflammation, oxidative stress, and mitochondrial damage depends on SIRT3/AKT signaling pathway","authors":"Shujuan Liu ,&nbsp;Pan Shi ,&nbsp;Yichen Jin ,&nbsp;Liwen Fan ,&nbsp;Qingyan Ni ,&nbsp;Jinyi Mao ,&nbsp;Zhaoxue Shao ,&nbsp;Xinyi Du ,&nbsp;Huizhen Chen ,&nbsp;Mian Fu","doi":"10.1016/j.taap.2026.117709","DOIUrl":"10.1016/j.taap.2026.117709","url":null,"abstract":"<div><div>Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In this study, sepsis-induced acute liver injury was modeled in mice using cecum ligation and puncture (CLP) surgery. The therapeutic potential and underlying mechanisms of Nicotinamide nitrogen oxide (NAMO) were evaluated via intraperitoneal injection at doses of 40, 80, and 160 mg/kg. Histological analysis revealed that increasing doses of NAMO led to more orderly hepatocyte arrangement and significantly reduced vacuolar degeneration and inflammatory cell infiltration. NAMO treatment significantly downregulated the mRNA expression of pro-inflammatory cytokines (iNOS, IL-1β, TNF-α, and IL-6) and upregulated the anti-inflammatory cytokine IL-10. Additionally, NAMO enhanced the activity of antioxidant enzymes (CAT, GSH, and T-AOC), while reducing levels of lipid peroxidation markers (MDA) and reactive oxygen species (ROS) in both liver tissues and hepatocytes. Furthermore, NAMO restored the protein expression of mitochondrial regulatory factors NRF1 and PGC-1α and preserved intracellular ATP levels, indicating improved mitochondrial function. Mechanistic investigations showed that NAMO exerted its protective effects by modulating mitochondrial homeostasis and oxidative stress through the SIRT3/AKT signaling pathway being blocked. In conclusion, by minimizing oxidative stress and inflammation, keeping mitochondrial integrity, and managing the SIRT3/AKT pathway, NAMO shields with sepsis-induced acute liver injury. The results indicate that NAMO holds significant potential as a therapeutic agent for managing hepatic impairment associated with sepsis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117709"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925739","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":"Zingiberensis new saponin reverses sorafenib resistance by targeting lncRNA TCONS-00026762/AKR1C1 and modulating autophagy and ferroptosis in hepatocellular carcinoma","authors":"Liang Luo ,&nbsp;Pingsheng Zhou ,&nbsp;Keqing He","doi":"10.1016/j.taap.2025.117664","DOIUrl":"10.1016/j.taap.2025.117664","url":null,"abstract":"<div><h3>Introduction</h3><div>Zingiberensis new saponin (ZnS) extracted from Dioscorea zingiberensis has antitumor activity. Our previous study found that Zns could exert anti- hepatocellular carcinoma (HCC) effects by regulating lncRNA TCONS-00026762. In addition, lncRNA TCONS-00026762 may act synergistically with AKR1C1. However, the relationship between them and their specific molecular mechanism underlying the anti-HCC effects of Zns has not been elucidated. This study aimed to investigate the role of TCONS-00026762/ AKR1C1 axis and ZnS in HCC cells from the perspective of autophagy, ferroptosis, and sorafenib resistance.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was used to assess the prognostic significance and expression level of AKR1C1 in TCGA liver cancer data. In vitro experiments, the effect of TCONS-00026762 knockdown or Zns on AKR1C1 expression, autophagy, and ferroptosis in HCC cells (Huh7) was investigated. Their function was further confirmed by rescue experiments. In addition, a sorafenib-resistant cell line (Huh7-SR) was constructed to explore the regulatory effects of TCONS-0026762 or Zns on cell viability.</div></div><div><h3>Results</h3><div>AKR1C1 was overexpressed in HCC and association with prognosis. It was involved in autophagy and ferroptosis related pathways. TCONS-00026762 knockdown inhibited AKR1C1 expression. TCONS-00026762 knockdown and Zns treatment suppressed the levels of autophagy marker (LC3) and ferroptosis markers (GPX4, SLC7A11) in Huh7 cell, as well as decreased the proliferation and invasion capacities of Huh7-SR cells after sorafenib treatment. Notably, these effects were eliminated by AKR1C1 overexpression or TCONS-00026762 overexpression.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the TCONS-00026762/AKR1C1 axis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117664"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649344","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":"Capsaicin alleviates DEHP-induced testicular dysfunction by suppressing oxidative stress in mice","authors":"Yi Liu ,&nbsp;Xu Yan ,&nbsp;Yinwei Chen ,&nbsp;Longjie Gu ,&nbsp;Lei Jin","doi":"10.1016/j.taap.2025.117655","DOIUrl":"10.1016/j.taap.2025.117655","url":null,"abstract":"<div><div>Di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental endocrine disruptor known to impair testicular function. Capsaicin, the bioactive compound in chili peppers, has not been thoroughly explored for its protective effects against DEHP-induced testicular damage. In this study, male C57BL/6 mice were divided into control, DEHP-exposed (200 mg/kg/day orally for 6 weeks), and DEHP-exposed with varying doses of capsaicin (5, 10, and 20 mg/kg/day orally for 6 weeks). Leydig and Sertoli cells were cultured in vitro with DEHP or capsaicin (0, 25, 50, and 100 μM). Chronic DEHP exposure impaired testicular development, leading to morphological abnormalities and reduced sperm quality, which were largely restored by capsaicin treatment. Both in vivo and in vitro assays revealed that capsaicin modulated the BAX/BCL2 ratio and inhibited testicular apoptosis. Additionally, capsaicin restored DEHP-induced suppression of testosterone biosynthesis in Leydig cells and maintained the integrity of the blood-testis barrier in Sertoli cells. Mechanistically, these protective effects were likely due to the antioxidant properties of capsaicin. In conclusion, our findings suggest that capsaicin may serve as a promising therapeutic agent for mitigating DEHP-induced testicular dysfunction, offering valuable insights for potential clinical applications.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117655"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588389","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":"Enhanced pancreatic toxicity induced by cadmium and a high-fat diet: attenuation by naringin through the modulation of oxidative stress, apoptosis, and inflammatory signaling","authors":"Reza Eslamizadeh ,&nbsp;Ali Akbar Oroojan ,&nbsp;Mohammad Amin Behmanesh ,&nbsp;Ali Reza Azizzadeh ,&nbsp;Amir Hossein Nasiri ,&nbsp;Hoda Vahedi ,&nbsp;Soheila Alboghobeish","doi":"10.1016/j.taap.2025.117603","DOIUrl":"10.1016/j.taap.2025.117603","url":null,"abstract":"<div><div>Increasing exposure to cadmium, an environmental pollutant from industrial and agricultural activities, and changing lifestyles and a tendency to consume high-fat foods, has raised serious concerns about metabolic health. We designed this study to investigate the combined effects of cadmium and a high-fat diet on pancreatic function. We also evaluated the protective potential of naringin, a natural flavonoid with antioxidant and anti-inflammatory properties. In our 12-week experimental study, we exposed 64 female NMRI mice to a high-fat diet (58.8 % calories from fat) and different levels of cadmium (0.5 and 5 ppm in drinking water). We administered naringin at doses of 50 and 100 mg/kg/day via gavage. Our results showed that a high-fat diet and cadmium combination significantly disrupted glucose homeostasis, characterized by increased fasting blood sugar and decreased glucose tolerance. We also observed a decrease in plasma insulin levels and impaired beta-cell function, which we associated with increased oxidative stress, pancreatic inflammation, impaired mitochondrial function, and the induction of cell apoptosis. Notably, the pancreas of the high-fat diet group accumulated more cadmium than the pancreas of the low-fat diet group. Administration of naringin improved glucose and insulin status, reduced oxidative stress and inflammation, protected mitochondrial function, and inhibited apoptosis of pancreatic cells. As the first comprehensive study on the exacerbated effects of cadmium and a high-fat diet, our research provides evidence of naringin's protective effects by examining multiple levels, from metabolic parameters to molecular mechanisms. These findings highlight the potential importance of naringin as a protective agent against metabolic disorders caused by exposure to environmental pollutants and unhealthy diets, but also provide a solid foundation for future clinical applications in the prevention and treatment of these disorders.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117603"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318696","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":"Letter to the editor regarding Huang et al. (2025, 502, 117450): Effect of parental perinatal exposure to L-glutamate monosodium salt of monohydrate on developmental neurotoxicity in rat offspring","authors":"Charles V. Vorhees","doi":"10.1016/j.taap.2025.117598","DOIUrl":"10.1016/j.taap.2025.117598","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117598"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318714","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":"Nomilin ameliorates perfluorooctanoic acid (PFOA)-induced impairment of zebrafish (Danio rerio) ocular development and visual function through PIK3CA activation","authors":"Xing Liu ,&nbsp;Mingzhu Xia ,&nbsp;Xinyi Wu,&nbsp;Ruobing Chen,&nbsp;Yuting Peng,&nbsp;Yi Fan,&nbsp;Junjie Han,&nbsp;Yichun Zhao,&nbsp;Man Qu","doi":"10.1016/j.taap.2025.117660","DOIUrl":"10.1016/j.taap.2025.117660","url":null,"abstract":"<div><div>Perfluorooctanoic acid (PFOA), a pervasive environmental contaminant, is implicated in ocular diseases through prenatal/embryonic exposure. This study investigated the protective effects of nomilin, a citrus-derived bioactive compound with therapeutic properties, against PFOA-induced ocular and visual impairments in zebrafish. Integrating network toxicology and molecular docking, we identified seven shared targets (including PIK3CA and mTOR) linking PFOA, nomilin, and ocular diseases. Experimental results demonstrated that PFOA exposure suppressed the PIK3CA/AKT/mTOR/pax6 axis, significantly downregulated (by approximately 0.23- to 0.65-fold) ocular development genes (rx1, vsx1, rpgra, lhx4), and induced structural defects (reduced eye size, lens diameter and retinal layer thickness) and visual dysfunction. Nomilin treatment dose-dependently reversed these effects by activating the PIK3CA/AKT/mTOR/pax6 axis, restoring the expression of ocular developmental related genes by 1.45- to 2.85-fold compared to the PFOA-exposed group, improving ocular morphology, and enhancing visual response behaviors. Furthermore, nomilin attenuated PFOA-induced apoptosis. These findings reveal that nomilin mitigates PFOA-mediated ocular toxicity via PIK3CA activation, offering novel therapeutic insights for environmental pollutant-related ocular disorders.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117660"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623762","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":"Integrated assessment of the effects of PFOA exposure on hepatic transcriptome and lipid profiles in mice expressing human PPARα","authors":"G. Nielsen ,&nbsp;E. Reed ,&nbsp;B. Lara ,&nbsp;D.H. Sherr ,&nbsp;W.J. Heiger-Bernays ,&nbsp;T. Hyötyläinen ,&nbsp;T.F. Webster ,&nbsp;J.J. Schlezinger","doi":"10.1016/j.taap.2025.117658","DOIUrl":"10.1016/j.taap.2025.117658","url":null,"abstract":"<div><div><em>Per</em>- and polyfluoroalkyl substances (PFAS) are a family of persistent chemicals that continue to be released pervasively into the environment, leading to widespread human exposure. Emerging epidemiological evidence shows adverse effects on liver lipids; however, past toxicological studies have been limited by a focus on peroxisome proliferator activated receptor α (PPARα) driven effects on triglycerides in rodent systems. Here, we use a more agonostic approach incorporating lipidomics and transcriptomics to test the hypothesis that activation of human PPARα by perfluorooctanoic acid (PFOA), disrupts liver lipid homeostasis, broadly, similar to that seen in human liver diseases. Female and male mice expressing human PPARα or that were PPARα null were fed a What We Eat In America diet and exposed to PFOA via drinking water for 6 weeks. Serum PFOA concentrations averaged 48 ± 9 μg/mL. PFOA changed the expression of ∼2000 hepatic genes with changes in expression of a larger number of genes in hPPARα versus PPARα null mice. In this occupational level PFOA exposure scenario, less than 60 % of transcriptional changes induced by PFOA depended on hPPARα expression. CAR was another major molecular initiating event, with other transcription factors pathways more likely to be modulated downstream of hPPARα activation. In hPPARα mice of both sexes, PFOA increased total liver lipids. In addition to triacylglycerides, lipid classes strongly altered by PFOA exposure predominantly belong to the phosphatidylcholine and sphingolipid classes. PFOA significantly decreased sphingomyelin abundance and increased ceramide abundance regardless of genotype, which coincided with an increase in expression of <em>SMase</em>, the enzyme that converts sphingomyelin to ceramide. These results highlight the ability of PFOA to modulate liver lipids beyond triacylglycerides in both an hPPARα-dependent and -independent manner.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117658"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623892","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":"Integrated in silico and in vitro assessment of estrogen and androgen receptor activity of 10 selected PFAS within an Integrated Approach to Testing and Assessment (IATA)","authors":"Darlene Mae D. Ortiz ,&nbsp;Handule Lee ,&nbsp;Ngoc Minh-Hong Hoang ,&nbsp;Hyun Jun Lee ,&nbsp;Jinhee Choi ,&nbsp;Kwangsik Park","doi":"10.1016/j.taap.2025.117628","DOIUrl":"10.1016/j.taap.2025.117628","url":null,"abstract":"<div><div>The potential of <em>per</em>- and polyfluoroalkyl substances (PFAS) to disrupt endocrine systems continues to be a regulatory concern. However, effectively prioritizing these structurally diverse chemicals remains challenging due to inconsistencies in predictive and experimental data. In this study, we employed a multi-tiered evaluation strategy that combines <em>in silico</em> modeling, <em>in vitro</em> assays, and curated mechanistic data within the OECD's Integrated Approach to Testing and Assessment (IATA) framework. Molecular docking using AutoDock Vina, CB-Dock2, and Endocrine Disruptome consistently revealed strong binding affinities of long-chain PFAS, particularly PFDA, PFOA, and 10:2 FTOH, to estrogen and androgen receptors. These predictions were corroborated by ER and AR transactivation assays (OECD TG 455/458), which demonstrated ER agonist and AR antagonist activity for the same compounds. In contrast, short-chain and sulfonated PFAS (PFHxA, PFBS, PFOS) exhibited limited to no activity across platforms. To enhance the biological relevance of the prioritization, we compiled supporting mechanistic evidence by applying the IATA framework to organize data along the adverse outcome pathway from molecular initiating events, through key events, to predicted adverse outcomes. Literature-reported alterations in steroidogenic enzymes and hormone levels were included to enrich mechanistic depth. All lines of evidences were systematically integrated into a weight-of-evidence matrix, enabling a transparent and biologically plausible ranking of PFAS based on receptor interaction, functional activity, and endocrine-disruptive potential. This combined approach identified PFDA and PFOA as high-priority endocrine disruptors and offers a scalable, non-<em>in vivo</em> strategy for the screening and risk-based prioritization of environmentally persistent chemicals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117628"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459870","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}