Toxicology Mechanisms and Methods最新文献

{"title":"Brij 35 inhibited the CYP2E1-mediated metabolism and P-gp mediated transport of paracetamol in rats and <i>in vitro</i> models: amelioration of paracetamol toxicity.","authors":"Nagabhushanam Chunduru, Ravindra Babu Pingili, Vijaya R Dirisala, Prasad K","doi":"10.1080/15376516.2025.2457331","DOIUrl":"10.1080/15376516.2025.2457331","url":null,"abstract":"<p><p>The harmful by-product of paracetamol is known as N-Acetyl-p-benzoquinoneimine, (NAPQI). When paracetamol is given at therapeutic dosages or in excess, it undergoes Phase I metabolism in the liver <i>via</i> Cytochrome P-450 2E1 (CYP2E1), and then it produces NAPQI. Previous studies reported that a nonionic surfactant known as Brij 35 (Polyoxyethylene lauryl ether) has been shown to be an effective inhibitor of CYP2E1 and P-glycoprotein (P-gp). Hence, this <i>in vitro</i> and <i>in vivo</i> investigation set out to assess Brij 35 impact on paracetamol CYP2E1-mediated metabolism. For the <i>in vitro</i> investigation, isolated rat hepatocytes were used. Male Wistar rats were used for <i>in vivo</i> studies. There were 30 rats in total, with six individuals each group distributed among the five groups. The first group animals received 0.5% sodium carboxy methyl cellulose (control group); the second group animals treated with 300 mg/kg of paracetamol; the third group animals treated with Brij 35 (5 mg/kg) along with 300 mg/kg of paracetamol; the fourth group animals treated with 10 mg/kg of Brij 35 along with 300 mg/kg of paracetamol, and the fifth group animals treated with 20 mg/kg of Brij 35 along with 300 mg/kg of paracetamol for consecutive 21 days. The current study found that paracetamol plasma concentrations were much higher and NAPQI plasma concentrations were much lower when Brij 35 was co-administered may be due to inhibition of CYP2E1-mediated metabolism and P-gp-mediated intestinal transport of paracetamol. Brij 35 also reduced the increased hepatic and renal markers with significant hepatoprotective and nephroprotective changes in the histopathological investigation.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-10"},"PeriodicalIF":3.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012090","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":"Mechanisms involved in the valproic acid-induced hepatotoxicity: a comprehensive review.","authors":"Rohan Kadam, Mahesh Palkar, Ravindra Babu Pingili","doi":"10.1080/15376516.2025.2459176","DOIUrl":"10.1080/15376516.2025.2459176","url":null,"abstract":"<p><p>Adverse drug reactions (ADR) remain a challenge in modern healthcare, particularly given the increasing complexity of therapeutics. An anticonvulsant medicine which is frequently used in treatment of epilepsy and other neurological conditions is valproic acid (VPA), is frequently associated with hepatotoxicity, a severe ADR that complicates its clinical use, which can take two different forms: Type I, which is defined by dose-dependent and reversible liver damage, and Type II, an idiosyncratic reaction that can result in severe liver failure, frequently complicates its clinical application. Oxidative stress, the creation of reactive metabolites, mitochondrial dysfunction, carnitine shortage, immune-mediated reactions, glutathione depletion, and blockage of the bile salt export pump (BSEP) are some of the numerous underlying mechanisms of VA-induced hepatic damage. The production of reactive oxygen species and the liver's antioxidant protection are out of balance as a cause of oxidative stress, which is a significant factor in VPA intoxication. VPA can also accelerate the build-up of fatty acids, which increases the risk of steatosis, due to its interaction with the metabolism of carnitine. Immune-mediated processes have been shown to increase liver injury, implying that the immunity system may possibly be involved in VPA hepatotoxicity. Hepatocyte injury and cholestasis are caused by BSEP inhibition, which impairs bile flow. The complex interaction between biochemical and cellular mechanisms that underlie valproic acid's hepatotoxic potential calls for additional research to clarify the precise pathways implicated and create mitigation techniques for this ADR.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-16"},"PeriodicalIF":3.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053779","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":"Clinical and safety outcomes associated with aristolochic acid exposure: a systematic review and meta-analysis.","authors":"Ting Cui, Shumei Che, Xingxu Yan, Rongrong Yang, Zhenna Xu, Sijia Liu, Ying Li, Chenyu Hao, Junhan Jiang, Lili Song, Hua Jin, Yubo Li","doi":"10.1080/15376516.2025.2457340","DOIUrl":"10.1080/15376516.2025.2457340","url":null,"abstract":"<p><p>Current studies have clearly shown that aristolochic acid (AA) exposure can induce a variety of diseases, such as kidney disease, liver cancer, and urinary tract cancer (UTC). However, no studies have systematically analyzed and integrated these results. Therefore, we aimed to elucidate the association between AA exposure and the risk of safety outcomes for AA-related overall disease and different types of disease it causes. We conducted an exhaustive search of PubMed, EMBASE, Web of Science, and the Cochrane Library for relevant material up to April 2024. For AA-related overall disease, AA exposure was significantly associated with an increased incidence of AA-related overall disease (OR: 1.289, 95% CI: 1.183-1.404). For different types of disease, AA exposure was significantly associated with increased incidence of kidney disease (OR: 1.279, 95% CI: 1.029-1.590), UTC (OR: 1.842, 95% CI: 1.376-2.465), and liver cancer (OR: 1.146, 95% CI: 1.040-1.262). No significant association was found between AA exposure and the incidence of brain disease (OR: 1.161, 95% CI: 0.989-1.362). This study systematically analyzed various safety outcomes associated with AA exposure to provide a solid scientific basis for future prevention strategies and clinical management.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-11"},"PeriodicalIF":3.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024807","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":"Evaluation and comparison of DNA alkylation and oxidative damage in e-cigarette and heated tobacco users.","authors":"Göksel Koç Morgil, İsmet Çok","doi":"10.1080/15376516.2024.2390028","DOIUrl":"10.1080/15376516.2024.2390028","url":null,"abstract":"<p><strong>Objectives: </strong>This study, aimed to determine and compare DNA damage in e-cigarette and HTP (IQOS) users by assessing DNA-adducts, which are biomarkers of various DNA alkylation and oxidation.</p><p><strong>Methods: </strong>For the evaluation of DNA alkylation, N³-Ethyladenine (N³-EtA) and N³-Methyladenine (N³-MeA) adducts were used. DNA oxidation was assessed using, 8-hydroxy-2'-deoxyguanosine(8-OHdG). The urinary cotinine, N³-MeA, N³-EtA, and 8-OHdG concentrations of the cigarette smokers (n:39), e-cigarette users (n:28), IQOS users (n:20), passive smokers (n:32), and nonsmokers(n:41) who lived Ankara, Turkiye were determined using, liquid chromatography-tandem mass spectrometry (LC-MS/MS).</p><p><strong>Results: </strong>In light of the detected 8-OHdG levels, e-cigarette (3.19 ng/g creatinine) and IQOS (4.38 ng/g creatinine) users had higher oxidative DNA damage than healthy nonsmokers (2.51 ng/g creatinine). Alkylated DNA-adducts were identified in the urine of e-cigarette (N³-MeA: 3.92 ng/g creatinine; N³-EtA: 0.23 ng/g creatinine) and IQOS (N³-MeA: 7.54 ng/g creatinine; N³-EtA: 0.29 ng/g creatinine) users. In the generation of N³-MeA adducts, a significant difference was found between IQOS users and e-cigarette users (<i>p</i> < 0.05). Also, DNA alkylation in flavored e-cigarette users (N³-MeA: 4.51 ng/g creatinine; N³-EtA: 0.27 ng/g creatinine) was higher than in non-flavored e-cigarette users (N³-MeA: 2.27 ng/g creatinine; N³-EtA: 0.06 ng/g creatinine). The highest cotinine levels were found in cigarette smokers (16.1316 ng/g creatinine). No significant difference was found when e-cigarette (1163.02 ng/g creatinine) and IQOS smokers were compared (1088.3 ng/g creatinine).</p><p><strong>Conclusion: </strong>People who use e-cigarettes and IQOS may be at higher risk of genotoxicity than those who do not use and are not exposed to any tobacco products. Furthermore, the usage of flavoring additives in e-cigarettes contributed to additional genotoxic damage risks.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"125-135"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976701","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":"Chronic ethanol exposure induces cardiac fibroblast transdifferentiation via ceramide accumulation and oxidative stress.","authors":"Tianyi Zhang, Yile Qian, Lingjie Mo, Xiaoru Dong, Qiupeng Xue, Nianchang Zheng, Yanyu Qi, Yan Jiang","doi":"10.1080/15376516.2024.2388762","DOIUrl":"10.1080/15376516.2024.2388762","url":null,"abstract":"<p><strong>Aims: </strong>Excessive alcohol consumption is associated with cardiac dysfunction and the development of myocardial fibrosis. In this study, we aimed to investigate the direct impacts of ethanol on myocardial fibroblasts and elucidate the underlying mechanism responsible for chronic ethanol-induced myocardial fibrosis.</p><p><strong>Methods: </strong>Rat primary cardiac fibroblasts exposed to ethanol for 24 h and C57BL/6J mice fed on Lieber-DeCarli diet to establish an ethanol intoxication model in vitro and in vivo, respectively. Histological analyses, molecular biology techniques, and analytical chemistry methods were then conducted.</p><p><strong>Results and conclusion: </strong>In vivo and vitro experiments revealed that chronic ethanol exposure induced increased myocardial fibrosis and augmented the transdifferentiation of myocardial fibroblasts. Simultaneously, it elicited an upregulation in the production of long-chain and very-long-chain ceramides in cardiac fibroblasts. The excessive accumulation of ceramide leads to elevated levels of intracellular oxidative stress, culminating in the activation of TGF-β-SMAD3 signaling and the development of fibrosis. Intervention of these pathways with pharmacological inhibitors <i>in vitro</i> or <i>in vivo</i> inhibited fibrosis. In conclusion, ethanol increased ceramides and reactive oxygen species (ROS) in cardiac fibroblasts, resulting in the activation of TGF-β-SMAD3 signaling, transdifferentiation of fibroblasts, and myocardial fibrosis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"113-124"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983226","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":"Establishing a link between the chemical composition and biological activities of <i>Gladiolus italicus</i> Mill. from the Turkish flora utilizing <i>in vitro</i>, <i>in silico</i> and network pharmacological methodologies.","authors":"Gokhan Zengin, Mehmet Veysi Cetiz, Nurgul Abul, Ilhami Gulcin, Giovanni Caprioli, Diletta Piatti, Massimo Ricciutelli, Ismail Koyuncu, Ozgur Yuksekdag, Muammer Bahşi, Osman Güler, Muhammad Zakariyyah Aumeeruddy, Mohamad Fawzi Mahomoodally","doi":"10.1080/15376516.2024.2397387","DOIUrl":"10.1080/15376516.2024.2397387","url":null,"abstract":"<p><strong>Objectives: </strong>Five solvent extracts (n-hexane, ethyl acetate, ethanol, ethanol/water (70%), and water) of <i>Gladiolus italicus</i> Mill. from Turkey were evaluated for chemical and biological properties.</p><p><strong>Methods: </strong>Antioxidant activities, inhibitory properties against key enzymes involved in the etiology of chronic diseases were tested, as well as cytotoxic effects on different cell lines. Chemical characterization was also carried out to determine the most abundant compounds of each extract.</p><p><strong>Results: </strong>The highest total phenolic content (TPC) was observed in the water extract while highest TFC in ethanol/water extract. The most abundant compounds in the extracts were hyperoside (69041.06 mg kg^-1), isoquercitrin (46239.49 mg kg^-1), delphindin-3,5-diglucoside (42043.81 mg kg^-1), myricetin (21486.61 mg kg^-1), and kaempferol-3-glucoside (21199.76 mg kg^-1). Molecular dynamic (MD) simulations confirmed the structural stability and dynamic conformational integrity of these complexes over a period of 100 ns. In network pharmacology, A total of 657 unique target genes were screened: 52 associated with programmed cell death-1 (PD-1), 85 with vascular endothelial growth factor receptor-2 (VEGFR2), and 130 with fibroblast growth factor receptor-2 (FGFR2), identifying crucial gene interactions for these proteins. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, revealing significant interactions and pathways such as the advanced glycation end products (AGE) and their receptors (RAGE) signaling pathway in diabetic complications and T- helper 17 (Th17) cell differentiation, among others. This elucidation of complex networks involving key genes like AKT Serine/Threonine Kinase 1 (AKT1), MYC proto-oncogene (MYC), tumor protein 53 (TP53), Interleukin 6 (IL6), and tumor necrosis factor (TNF) provides a promising foundation for the development of targeted therapies in the treatment of non-communicable diseases.</p><p><strong>Conclusion: </strong>These results show that <i>G. italicus</i> could be a natural source of potent antioxidants and enzyme inhibitors which need to be further explored for the development of biopharmaceuticals.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"146-166"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142155034","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":"Silica-induced ROS in alveolar macrophages and its role on the formation of pulmonary fibrosis via polarizing macrophages into M2 phenotype: a review.","authors":"Shu-Ling Du, Yu-Ting Zhou, Hui-Jie Hu, Li Lin, Zhao-Qiang Zhang","doi":"10.1080/15376516.2024.2400323","DOIUrl":"10.1080/15376516.2024.2400323","url":null,"abstract":"<p><p>Alveolar macrophages (AMs), the first line against the invasion of foreign invaders, play a predominant role in the pathogenesis of silicosis. Studies have shown that inhaled silica dust is recognized and engulfed by AMs, resulting in the production of large amounts of silica-induced reactive oxygen species (ROS), including particle-derived ROS and macrophage-derived ROS. These ROS change the microenvironment of the AMs where the macrophage phenotype is stimulated to swift from M0 to M1 and/or M2, and ultimately emerge as the M2 phenotype to trigger silicosis. This is a complex process accompanied by various molecular biological events. Unfortunately, the detailed processes and mechanisms have not been systematically described. In this review, we first systematically introduce the process of ROS induced by silica in AMs. Then, describe the role and molecular mechanism of M2-type macrophage polarization caused by silica-induced ROS. Finally, we review the mechanism of pulmonary fibrosis induced by M2 polarized AMs. We conclude that silica-induced ROS initiate the fibrotic process of silicosis by inducing macrophage into M2 phenotype, and that targeted intervention of silica-induced ROS in AMs can reprogram the macrophage polarization and ameliorate the pathogenesis of silicosis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"89-100"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120690","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 transcriptomic and proteomic analyses reveal the effects of chronic benzene exposure on the central nervous system in mice.","authors":"Hongwei Li, Zhenqian Zhang, Qiannan Xu, Enhao Fu, Ping Lyu, Xinmin Pan, Zhe Zheng, Haojie Qin","doi":"10.1080/15376516.2024.2387740","DOIUrl":"10.1080/15376516.2024.2387740","url":null,"abstract":"<p><p>Benzene exposure is known to cause serious damage to the human hematopoietic system. However, recent studies have found that chronic benzene exposure may also cause neurological damage, but there were few studies in this issue. The aim of this study was to investigate the mechanism of damage to the central nervous system (CNS) by chronic benzene exposure with a multi-omics analysis. We established a chronic benzene exposure model in C57BL/6J mice by gavage of benzene-corn oil suspension, identified the differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) in mice brain using 4D Label-free proteomic and RNA-seq transcriptomic. We observed that the benzene exposure mice had a significant loss of body weight, reduction in complete blood counts, abnormally high MRI signals in brain white matter, as well as extensive brain edema and neural demyelination. 162 DEPs were identified by the proteome, including 98 up-regulated and 64 down-regulated proteins. KEGG pathway analysis of DEPs showed that they were mainly involved in the neuro-related signaling pathways such as metabolic pathways, pathways of neurodegeneration, chemical carcinogenesis, Alzheimer disease, and autophagy. <i>EPHX1</i>, <i>GSTM1</i>, and <i>LIMK1</i> were identified as important candidate DEGs/DEPs by integrated proteomic and transcriptomic analyses. We further performed multiple validation of the above DEGs/DEPs using fluorescence quantitative PCR (qPCR), parallel reaction monitoring (PRM), immunohistochemistry, and immunoblotting to confirm the reliability of the multi-omics study. The functions of these DEGs/DEPs were further explored and analyzed, providing a theoretical basis for the mechanism of nerve damage caused by benzene exposure.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"101-112"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890177","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":"Insights into mitochondrial creatine kinase: examining preventive role of creatine supplement in doxorubicin-induced cardiotoxicity.","authors":"Salaheddin M Sharif, David Hydock","doi":"10.1080/15376516.2024.2393825","DOIUrl":"10.1080/15376516.2024.2393825","url":null,"abstract":"<p><p>Doxorubicin (Dox) is an effective and commonly used anticancer drug; however, it leads to several side effects including cardiotoxicity which contributes to poor quality of life for cancer patients. Creatine (Cr) is a promising intervention to alleviate Dox-induced cardiotoxicity. This study aimed to examine the effects of Cr beforeDox on cardiac mitochondrial creatine kinase (MtCK). Male rats were randomly assigned to one of two 4-week Cr feeding interventions (standard Cr diet or Cr loading diet) or a control diet (Con, <i>n</i> = 20). Rats in the standard Cr diet (Cr1, <i>n</i> = 20) were fed 2% Cr for 4-weeks. Rats in the Cr loading diet (Cr2, <i>n</i> = 20) were fed 4% Cr for 1-week followed by 2% Cr for 3-weeks. After 4-weeks, rats received either a bolus injection of 15 mg/kg Dox or a placebo saline injection (Sal). Five days post-injections left ventricle (LV) was excised and analyzed for MtCK expression using Western blot and ELISA. A significant drug effect was observed for LV mass (<i>p</i> < 0.05), <i>post hoc</i> testing revealed LV mass of Con + Dox and Cr2 + Dox was significantly lower than Con + Sal (<i>p</i> < 0.05). A significant drug effect was observed for MtCK (<i>p</i> = 0.03) through Western blot. A significant drug effect (<i>p</i> = 0.03) and interaction (<i>p</i> = 0.02) was observed for MtCK using ELISA. <i>Post hoc</i> testing revealed that Cr2 + Dox had significantly higher MtCK than Cr1 + Sal and Cr2 + Sal. Data suggest that a reduction in LV mass and MtCK may contribute to Dox-induced cardiotoxicity, and Cr supplementation may play a potential role in mitigating cardiotoxicity by preserving mitochondrial CK.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"136-145"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018704","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":"Leveraging new approach methodologies: ecotoxicological modelling of endocrine disrupting chemicals to Danio rerio through machine learning and toxicity studies.","authors":"Gopal Italiya, Sangeetha Subramanian","doi":"10.1080/15376516.2024.2400324","DOIUrl":"10.1080/15376516.2024.2400324","url":null,"abstract":"<p><p>New approach methodologies (NAMs) offer information tailored to the intended application while reducing the use of animals. NAMs aim to develop quantitative structure-activity relationship (QSAR) and quantitive-Read-Across structure-activity relationship (q-RASAR) models to predict and categorize the acute toxicity of known and unknown endocrine-disrupting chemicals (EDCs) against zebrafish. EDCs are a diverse group of toxic substances that disrupt the endocrine system of humans and animals. The q-RASAR model was constructed and verified using validation metrics (<i>R</i>² = 0.886 and <i>Q</i>² = 0.814) which found to be more reliable model compare to QSAR model. The substructure fingerprint was well-fitted for the classification model and it was validated using 10-fold average accuracy (<i>Q</i> = 86.88%), specificity (Sp = 88.89%), Matthew's correlation curve (MCC = 0.621) and receiver operating characteristics (ROC = 0.828). The dataset of unknown substances revealed that phenolphthalein (Php) exhibited a significant level of toxicity based on q-RASAR model. The docking and simulation study indicated that the computationally derived important features successfully bound to the target zebrafish sex hormone binding globulin (zfSHBG). The experimental LC50 value of 0.790 mg L^-1 was very close to the predicted value of 0.763 mg L^-1, which provides high confidence to the developed model.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"197-213"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120689","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}