Chemical Research in Toxicology最新文献

{"title":"Triphenyl Phosphate Alters Methyltransferase Expression and Induces Genome-Wide Aberrant DNA Methylation in Zebrafish Larvae.","authors":"Chander K Negi, Lucie Bláhová, Audrey Phan, Lola Bajard, Ludek Blaha","doi":"10.1021/acs.chemrestox.4c00223","DOIUrl":"10.1021/acs.chemrestox.4c00223","url":null,"abstract":"<p><p>Emerging environmental contaminants, organophosphate flame retardants (OPFRs), pose significant threats to ecosystems and human health. Despite numerous studies reporting the toxic effects of OPFRs, research on their epigenetic alterations remains limited. In this study, we investigated the effects of exposure to 2-ethylhexyl diphenyl phosphate (EHDPP), tricresyl phosphate (TMPP), and triphenyl phosphate (TPHP) on DNA methylation patterns during zebrafish embryonic development. We assessed general toxicity and morphological changes, measured global DNA methylation and hydroxymethylation levels, and evaluated DNA methyltransferase (DNMT) enzyme activity, as well as mRNA expression of DNMTs and ten-eleven translocation (TET) methylcytosine dioxygenase genes. Additionally, we analyzed genome-wide methylation patterns in zebrafish larvae using reduced-representation bisulfite sequencing. Our morphological assessment revealed no general toxicity, but a statistically significant yet subtle decrease in body length following exposure to TMPP and EHDPP, along with a reduction in head height after TPHP exposure, was observed. Eye diameter and head width were unaffected by any of the OPFRs. There were no significant changes in global DNA methylation levels in any exposure group, and TMPP showed no clear effect on DNMT expression. However, EHDPP significantly decreased only DNMT1 expression, while TPHP exposure reduced the expression of several DNMT orthologues and TETs in zebrafish larvae, leading to genome-wide aberrant DNA methylation. Differential methylation occurred primarily in introns (43%) and intergenic regions (37%), with 9% and 10% occurring in exons and promoter regions, respectively. Pathway enrichment analysis of differentially methylated region-associated genes indicated that TPHP exposure enhanced several biological and molecular functions corresponding to metabolism and neurological development. KEGG enrichment analysis further revealed TPHP-mediated potential effects on several signaling pathways including TGFβ, cytokine, and insulin signaling. This study identifies specific changes in DNA methylation in zebrafish larvae after TPHP exposure and brings novel insights into the epigenetic mode of action of TPHP.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1549-1561"},"PeriodicalIF":3.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11409374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of Thymus Atrophy and Disruption of Thymocyte Development by Fipronil through Dysregulation of IL-7-Associated Genes.","authors":"Jui-Fang Kuo, Hsin-Ying Wu, Chun-Wei Tung, Wei-Hsiang Huang, Chen-Si Lin, Chia-Chi Wang","doi":"10.1021/acs.chemrestox.4c00060","DOIUrl":"10.1021/acs.chemrestox.4c00060","url":null,"abstract":"<p><p>The susceptibility of the immune system to immunotoxic chemicals is evident, particularly in the thymus, a vital primary immune organ prone to atrophy due to exposure to toxicants. Fipronil (FPN), a widely used insecticide, is of concern due to its potential neurotoxicity, hepatotoxicity, and immunotoxicity. Our previous study showed that FPN disturbed the antigen-specific T-cell functionality <i>in vivo</i>. As T-cell lineage commitment and thymopoiesis are closely interconnected with the normal function of the T-cell-mediated immune responses, this study aims to further examine the toxic effects of FPN on thymocyte development. In this study, 4-week-old BALB/c mice received seven doses of FPN (1, 5, 10 mg/kg) by gavage. Thymus size, medulla/cortex ratio, total thymocyte counts, double-positive thymocyte population, and IL-7-positive cells decreased dose-dependently. IL-7 aids the differentiation of early T-cell precursors into mature T cells, and several essential genes contribute to the maturation of T cells in the thymus. <i>Foxn</i>1 ensures that the thymic microenvironment is suitable for the maturation of T-cell precursors. <i>Lyl</i>1 is involved in specifying lymphoid cells and maintaining T-cell development in the thymus. The <i>c-Kit/SCF</i> collaboration fosters a supportive thymic milieu to promote the formation of functional T cells. The expression of <i>IL-</i>7, <i>IL-</i>7<i>R</i>, <i>c-Kit</i>, <i>SCF</i>, <i>Foxn</i>1, and <i>Lyl</i>1 genes in the thymus was significantly diminished in FPN-treated groups with the concordance with the reduction of IL-7 signaling proteins (IL-7, IL-7R, c-KIT, SCF, LYL1, FOXO3A, and GABPA), suggesting that the dysregulation of T-cell lineage-related genes may contribute to the thymic atrophy induced by FPN. In addition, FPN disturbed the functionality of thymocytes with an increase of IL-4 and IFN-γ production and a decrease of IL-2 secretion after T-cell mitogen stimulation <i>ex vivo</i>. Collectively, FPN significantly deregulated genes related to T-cell progenitor differentiation, survival, and expansion, potentially leading to impaired thymopoiesis.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1488-1500"},"PeriodicalIF":3.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11409377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical Methodologies to Detect N-Nitrosamine Impurities in Active Pharmaceutical Ingredients, Drug Products and Other Matrices.","authors":"Krishna Moorthy Manchuri, Mahammad Ali Shaik, Venkata Subba Reddy Gopireddy, Naziya Sultana, Sreenivasarao Gogineni","doi":"10.1021/acs.chemrestox.4c00234","DOIUrl":"10.1021/acs.chemrestox.4c00234","url":null,"abstract":"<p><p>Since 2018, N-nitrosamine impurities have become a widespread concern in the global regulatory landscape of pharmaceutical products. This concern arises due to their potential for contamination, toxicity, carcinogenicity, and mutagenicity and their presence in many active pharmaceutical ingredients, drug products, and other matrices. N-Nitrosamine impurities in humans can lead to severe chemical toxicity effects. These include carcinogenic effects, metabolic disruptions, reproductive harm, liver diseases, obesity, DNA damage, cell death, chromosomal alterations, birth defects, and pregnancy loss. They are particularly known to cause cancer (tumors) in various organs and tissues such as the liver, lungs, nasal cavity, esophagus, pancreas, stomach, urinary bladder, colon, kidneys, and central nervous system. Additionally, N-nitrosamine impurities may contribute to the development of Alzheimer's and Parkinson's diseases and type-2 diabetes. Therefore, it is very important to control or avoid them by enhancing effective analytical methodologies using cutting-edge analytical techniques such as LC-MS, GC-MS, CE-MS, SFC, etc. Moreover, these analytical methods need to be sensitive and selective with suitable precision and accuracy, so that the actual amounts of N-nitrosamine impurities can be detected and quantified appropriately in drugs. Regulatory agencies such as the US FDA, EMA, ICH, WHO, etc. need to focus more on the hazards of N-nitrosamine impurities by providing guidance and regular updates to drug manufacturers and applicants. Similarly, drug manufacturers should be more vigilant to avoid nitrosating agents and secondary amines during the manufacturing processes. Numerous review articles have been published recently by various researchers, focusing on N-nitrosamine impurities found in previously notified products, including sartans, metformin, and ranitidine. These impurities have also been detected in a wide range of other products. Consequently, this review aims to concentrate on products recently reported to contain N-nitrosamine impurities. These products include rifampicin, champix, famotidine, nizatidine, atorvastatin, bumetanide, itraconazole, diovan, enalapril, propranolol, lisinopril, duloxetine, rivaroxaban, pioglitazones, glifizones, cilostazol, and sunitinib.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1456-1483"},"PeriodicalIF":3.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998881","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":"Omeprazole-Associated Atypical Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in a Patient with Positive In Vitro Diagnostic Testing to Multiple Proton Pump Inhibitors.","authors":"Sophie Grice, Sean Hammond, Lucy Hampson, Annette Wagner, Dean J Naisbitt","doi":"10.1021/acs.chemrestox.4c00225","DOIUrl":"10.1021/acs.chemrestox.4c00225","url":null,"abstract":"<p><p>Proton pump inhibitors (PPIs) are a commonly used class of drugs with a good safety profile. However, their use is associated with rare cases of severe skin reaction. Herein, we present details of a patient who developed two episodes of omeprazole-induced delayed-onset hypersensitivity (atypical drug reaction with eosinophilia and systemic symptoms [DRESS]). Lymphocytes from the patient were stimulated to proliferate and secrete cytokines and cytolytic molecules when treated with the drug. T-cell cross-reactivity was observed with structurally related PPIs. Hence, other PPIs have the potential to cause further serious immune-related adverse events in patients who present with hypersensitivity to a primary PPI.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1484-1487"},"PeriodicalIF":3.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11409369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One-Week Kava Dietary Supplementation Increases Both Urinary <i>N</i>- and <i>O</i>-Glucuronides of NNAL, a Lung Carcinogen Major Metabolite, among Smokers.","authors":"Qi Hu, Zhixin Tang, Allison Lynch, Breanne Freeman, Naomi Fujioka, Ramzi G Salloum, John Malaty, Frank A Orlando, Taimour Langaee, Zhiguang Huo, Chengguo Xing","doi":"10.1021/acs.chemrestox.4c00109","DOIUrl":"10.1021/acs.chemrestox.4c00109","url":null,"abstract":"<p><p>4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified <i>N</i>-glucuronidated NNAL (NNAL-<i>N</i>-gluc), <i>O</i>-glucuronidated NNAL (NNAL-<i>O</i>-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those <i>UGT</i>2<i>B</i>10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1515-1523"},"PeriodicalIF":3.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602910","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":"In Vitro Screening for ToxCast Chemicals Binding to Thyroxine-Binding Globulin","authors":"Stephanie A. Eytcheson, Alexander D. Zosel, Jennifer H. Olker, Michael W. Hornung, Sigmund J. Degitz","doi":"10.1021/acs.chemrestox.4c00183","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00183","url":null,"abstract":"Thyroid hormone (TH) carrier proteins play an important role in distributing TH to target tissue as well as maintaining the balance of free versus bound TH in the blood. Interference with the TH carrier proteins has been identified as a potential mechanism of thyroid system disruption. To address the lack of data regarding chemicals binding to these carrier proteins and displacing TH, a fluorescence-based <i>in vitro</i> screening assay was utilized to screen over 1,400 chemicals from the U.S. EPA’s ToxCast phase1_v2, phase 2, and e1k libraries for competitive binding to one of the carrier proteins, thyroxine-binding globulin. Initial screening at a single high concentration of 100 μM identified 714 chemicals that decreased signal of the bound fluorescent ligand by 20% or higher. Of these, 297 produced 50% or greater reduction in fluorescence and were further tested in concentration–response (0.004 to 150 μM) to determine relative potency. Ten chemicals were found to have EC50 values &lt;1 μM, 63 &lt; 10 μM, and 141 chemicals between 10 and 100 μM. Utilization of this assay contributes to expanding the number of <i>in vitro</i> assays available for identifying chemicals with the potential to disrupt TH homeostasis. These results support ranking and prioritization of chemicals to be tested <i>in vivo</i> to aid in the development of a framework for predicting <i>in vivo</i> effects from <i>in vitro</i> high-throughput data.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"23 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260485","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":"Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice","authors":"Shengyu Cai, Huizheng Zhu, Lingling Chen, Congcong Yu, Liyuan Su, Kaihua Chen, Yousheng Li","doi":"10.1021/acs.chemrestox.4c00263","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00263","url":null,"abstract":"Inflammation, oxidative stress, fibrosis, and ferroptosis play important roles in diabetic nephropathy development. Krüppel-like factor 4 (KLF4) is a transcriptional factor, which regulates multiple cell processes and is involved in diabetic nephropathy. Berberine has various biological activities, including anti-inflammation, antioxidative stress, and antiferroptosis. Berberine has been shown to inhibit diabetic nephropathy, but whether it involves KLF4 and ferroptosis remains unknown. We established a diabetic nephropathy mice model and administered berberine to the mice. The kidney function, renal structure and fibrosis, expression of KLF4 and DNA methylation enzymes, DNA methylation of the KLF4 promoter, mitochondria structure, and expression of oxidative stress and ferroptosis markers were analyzed. Berberine rescued kidney function and renal structure and prevented renal fibrosis in diabetic nephropathy mice. Berberine suppressed the expression of DNMT1 and DNMT2 and upregulated KLF4 expression by preventing KLF4 promoter methylation. Berberine inhibited the expression of oxidative stress and ferroptosis markers, maintained mitochondria structure, and prevented ferroptosis. Berberine ameliorates diabetic nephropathy by inhibiting Klf4 promoter methylation and ferroptosis.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"19 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181657","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":"Environmentally Sustainable Detection of Arsenic using Convolutional Neural Networks and Imidazole-Based Organic Probes: Application in Food Samples and Arsenic Album","authors":"Ramakrishnan AbhijnaKrishna, Adarsh Valoor, Sivan Velmathi","doi":"10.1021/acs.chemrestox.4c00200","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00200","url":null,"abstract":"Arsenic contamination poses a significant health risk, particularly when it infiltrates water supplies. While current detection methods offer precise analysis, they often involve complex instrumentation not suitable for field use. This study presents a novel approach by developing two probes, A1 and A2, based on 4-diethylaminosalicyladehyde, 2-hydroxy-1-naphthaldehyde, and 1,2-diaminoanthraquinone. These probes are highly sensitive and selective for detecting arsenite (As(III)) and arsenate (As(V)) in water, food samples, and homeopathic medicine with limits of detection in the nanomolar range. To elaborate our contribution to on-site arsenic detection, we introduce a convolutional neural network-based image recognition system. This system interprets images of the probes’ colorimetric response, effectively categorizing different ranges of arsenic concentrations in parts per million (ppm). Our approach offers a real-time, cost-effective, and user-friendly solution for arsenic detection, extending its applicability from scientific laboratories to in-field conditions and even household monitoring. The findings fill critical research gaps in real-time detection methods, potentially revolutionizing the way we monitor environmental contaminants like arsenic.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"13 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181746","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":"Environmentally Sustainable Detection of Arsenic using Convolutional Neural Networks and Imidazole-Based Organic Probes: Application in Food Samples and Arsenic Album","authors":"Ramakrishnan AbhijnaKrishna,&nbsp;Adarsh Valoor and Sivan Velmathi*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0020010.1021/acs.chemrestox.4c00200","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00200https://doi.org/10.1021/acs.chemrestox.4c00200","url":null,"abstract":"<p >Arsenic contamination poses a significant health risk, particularly when it infiltrates water supplies. While current detection methods offer precise analysis, they often involve complex instrumentation not suitable for field use. This study presents a novel approach by developing two probes, A1 and A2, based on 4-diethylaminosalicyladehyde, 2-hydroxy-1-naphthaldehyde, and 1,2-diaminoanthraquinone. These probes are highly sensitive and selective for detecting arsenite (As(III)) and arsenate (As(V)) in water, food samples, and homeopathic medicine with limits of detection in the nanomolar range. To elaborate our contribution to on-site arsenic detection, we introduce a convolutional neural network-based image recognition system. This system interprets images of the probes’ colorimetric response, effectively categorizing different ranges of arsenic concentrations in parts per million (ppm). Our approach offers a real-time, cost-effective, and user-friendly solution for arsenic detection, extending its applicability from scientific laboratories to in-field conditions and even household monitoring. The findings fill critical research gaps in real-time detection methods, potentially revolutionizing the way we monitor environmental contaminants like arsenic.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1934–1943 1934–1943"},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851206","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":"Short-Term Exposure to Foodborne Xenoestrogens Affects Breast Cancer Cell Morphology and Motility Relevant for Metastatic Behavior In Vitro.","authors":"Giorgia Del Favero,Janice Bergen,Lena Palm,Christian Fellinger,Maria Matlaeva,András Szabadi,Ana Sofia Fernandes,Nuno Saraiva,Christian Schröder,Doris Marko","doi":"10.1021/acs.chemrestox.4c00061","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00061","url":null,"abstract":"Breast cancer is highly susceptible to metastasis formation. During the time of disease progression, tumor pathophysiology can be impacted by endogenous factors, like hormonal status, as well as by environmental exposures, such as those related to diet and lifestyle. New lines of evidence point toward a potential role for foodborne endocrine disruptive chemicals in this respect; however, mechanistic understanding remains limited. At the molecular level, crucial steps toward metastasis formation include cell structural changes, alteration of adhesion, and reorganization of cytoskeletal proteins involved in motility. Hence, this study investigates the potential of dietary xenoestrogens to impact selected aspects of breast cancer cell mechanotransduction. Taking the onset of the metastatic cascade as a model, experiments focused on cell-matrix adhesion, single-cell migration, and adaptation of cell morphology. Dietary mycoestrogens alternariol (AOH, 1 μM) and α-zearalenol (α-ZEL, 10 nM), soy isoflavone genistein (GEN, 1 μM), and food packaging plasticizer bisphenol A (BPA, 10 nM) were applied as single compounds or in mixtures. Pursuing the hypothesis that endocrine active molecules could affect cell functions beyond the estrogen receptor-dependent cascade, experiments were performed comparing the MCF-7 cell line to the triple negative breast cancer cells MDA MB-231. Indeed, the four compounds functionally affected the motility and the adhesion of both cell types. These responses were coherent with rearrangements of the actin cytoskeleton and with the modulation of the expression of integrin β1 and cathepsin D. Mechanistically, molecular dynamics simulations confirmed a potential interaction with fragments of the α1 and β1 integrin subunits. In sum, dietary xenoestrogens proved effective in modifying the motility and adhesion of breast cancer cells, as predictive end points for metastatic behavior in vitro. These effects were measurable after short incubation times (1 or 8 h) and contribute to shed novel light on the activity of compounds with hormonal mimicry potential in breast cancer progression.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"55 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181681","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}