Toxicology最新文献

{"title":"Prenatal exposure to di-n-butyl phthalate promotes RIPK1-regulated necroptosis of uroepithelial cells and induces hypospadias through the epithelial-mesenchymal transition process in newborn male rats","authors":"Lei Wu ,&nbsp;Zhiwen Xie ,&nbsp;Tiewen Li ,&nbsp;Xincan Chen ,&nbsp;Juntao Jiang ,&nbsp;Fei Shi ,&nbsp;Yongqing Zhang ,&nbsp;Xinyu Xu ,&nbsp;Shujie Xia ,&nbsp;Wenlan Sun","doi":"10.1016/j.tox.2024.153982","DOIUrl":"10.1016/j.tox.2024.153982","url":null,"abstract":"<div><div>Maternal exposure to di-n-butyl phthalate (DBP) has been linked to the induction of hypospadias; however, the underlying mechanism remains unclear. Necroptosis is reported to be implicated in developmental malformations. This study aimed to investigate the underlying mechanism of necroptosis in the development of hypospadias. DBP was dissolved in corn oil, and pregnant rats were administered a precisely measured dose of DBP (750 mg/kg/day) via gastric intubation from gestation day 14–18. Control rats received only corn oil. The day of birth was considered postnatal day (PND) 1. Male hypospadias rats were identified on PND 7. Genital tubercle tissues were collected and stored at −80°C for subsequent PCR analysis, cryopreserved in liquid nitrogen for western blot, or fixed in formalin for immunohistochemistry (IHC) staining. IHC staining and western blot analysis revealed increased expression of RIPK1 and necroptosis markers in genital tubercle (GT) tissue compared to the control group. Additionally, higher levels of EMT and impaired androgen receptor expression were observed in GT tissue. Exposure to increased DBP concentrations in rat primary uroepithelial cells (PUCs) led to elevated ROS production. Necroptosis markers and EMT expression levels were upregulated in PUCs following DBP incubation. Notably, treatment with DBP combined with necrostatin-1, a necroptosis inhibitor, reduced the expression of EMT markers and ROS production compared to DBP treatment alone. In vitro studies further revealed that DBP-induced necroptosis promoted the degradation of E-cadherin through the ubiquitin-proteasome pathway in PUCs. Our findings suggest that maternal exposure to DBP promotes necroptosis in uroepithelial cells by elevating ROS level and EMT status. Thus, necroptosis may play an essential role in the development of hypospadias.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153982"},"PeriodicalIF":4.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508628","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":"Bag2 protects against doxorubicin-induced cardiotoxicity by maintaining Pink1-mediated mitophagy","authors":"Hongkai Xiao,&nbsp;Siyu Liang,&nbsp;Qinhong Cai,&nbsp;Jinghu Liu,&nbsp;Liang Jin,&nbsp;Xiaochao Chen","doi":"10.1016/j.tox.2024.153980","DOIUrl":"10.1016/j.tox.2024.153980","url":null,"abstract":"<div><div>The clinical application of Doxorubicin (DOX) is limited due to its cardiotoxicity. Mitophagy dysfunction is the primary cause of DOX-induced cardiotoxicity (DIC). However, the precise mechanism by which DOX regulates mitophagy remains elusive. Bag2 (BCL2-associated athanogene 2) is a cochaperone implicated in multiple pathological states. The aim of this study was to investigate the potential cardio-protective effects of Bag2 in DIC. C57BL/6 mice and AC16 cells were used to establish DIC model. The expression of Bag2 were measured by western blotting and immunohistochemical. The effects of Bag2 on DIC were assessed through functional gain and loss experiments. Through in vitro and in vivo experiments, we found that Bag2 expression was significantly reduced after DOX treatment. Both Bag2 knockdown and DOX administration resulted in apoptosis, mitochondrial dysfunction, and impaired mitophagy. Conversely, Bag2 overexpression exerted protective effects against these phenotypes induced by DOX stimulation. Mechanistically, Bag2 maintained mitophagy activation by binding to Pink1 and protecting it from proteasome-dependent degradation, thereby preserving mitochondrial function and protecting against myocardial lesions. Our findings suggest that Bag2 may serve as a promising therapeutic target for the treatment of DIC.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153980"},"PeriodicalIF":4.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508629","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":"Particulate matter induced cognitive impairments via endoplasmic reticulum stress-mediated damage to mitochondria-associated endoplasmic reticulum membranes in immature rats","authors":"Lingman Wang,&nbsp;Jianxiong Gui,&nbsp;Bing Tian,&nbsp;Ran Ding,&nbsp;Wandi Wang,&nbsp;Chunxue Jiang,&nbsp;Shengxuan Zhang,&nbsp;Xiaofang Zhang,&nbsp;Jie Liu ,&nbsp;Li Jiang","doi":"10.1016/j.tox.2024.153979","DOIUrl":"10.1016/j.tox.2024.153979","url":null,"abstract":"<div><div>Particulate matter (PM) exposure has been increasingly recognized as detrimental to cognitive function and is associated with neurodevelopmental disorders. Mitochondria-associated endoplasmic reticulum membranes (MAMs) form an integrated interface between mitochondria and the endoplasmic reticulum (ER), facilitating crucial cellular functions. Prolonged ER stress (ERS) is implicated in various pathological states in the nervous system. MAMs and ERS may play vital roles in adverse effects of early-life PM exposure on cognitive abilities. This study investigated whether ERS plays a role in PM-induced MAMs dysfunction, leading to neuronal damage and cognitive impairments in early postnatal rats. Using a rat model with PM exposure concentrations of 2 and 10 mg/kg from postnatal Day 3 (PND3) to PND28, we observed that PM exposure resulted in anxiety-like behavior and impaired spatial working memory. The protein levels of ERS markers, including GRP78 and CHOP, were significantly increased in response to PM exposure. Western blot, transmission electron microscopy (TEM), and immunofluorescence analyses revealed decreased MAMs-related proteins and disrupted MAM structure and function caused by PM exposure. Administration of the ERS inhibitor 4-phenylbutyric acid (4-PBA) ameliorated these effects, restoring MAMs integrity and improving cognitive deficits. These findings highlighted the key role of ERS-MAMs dysfunction in PM-induced neurotoxicity and cognitive impairments, providing a new perspective and strategy for the prevention of cognitive deficits in early age with PM exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153979"},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508630","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":"PBDEs and dechlorane plus contamination in community e-waste recycling: Environmental and health implications in Northeastern Thailand","authors":"Hana Walaska ,&nbsp;Alice Dvorska ,&nbsp;Jindrich Petrlik ,&nbsp;Thitikorn Boontongmai ,&nbsp;Nichchawan Bubphachat ,&nbsp;Jitka Strakova ,&nbsp;Chutimon Thowsakul ,&nbsp;Akarapon Teebthaisong ,&nbsp;Nikola Jelinek ,&nbsp;Valeriya Grechko ,&nbsp;Penchom Saetang ,&nbsp;Punyathorn Jeungsmarn ,&nbsp;Prakaikan Phanphet ,&nbsp;Surachate Pulawun ,&nbsp;Aneta Sykorova ,&nbsp;Tomas Gramblicka ,&nbsp;Jana Pulkrabova ,&nbsp;David O. Carpenter","doi":"10.1016/j.tox.2024.153972","DOIUrl":"10.1016/j.tox.2024.153972","url":null,"abstract":"<div><div>Electronic waste (e-waste) poses significant environmental and health risks in Thailand due to both domestic production and international imports. A notable portion of this waste is processed in small-scale, community-based workshops, often located in poorer regions, where safety regulations are improperly enforced or entirely ignored. This study focuses on the Kalasin province in Northern Thailand, a region with numerous such workshops, where no comprehensive analysis of exposure to polybrominated diphenyl ethers (PBDEs) and dechlorane plus (DP) has been conducted. The study's objective was to quantify these toxic substances in environmental and biological samples to assess its contamination and human health risks. Environmental samples, including soil, dust, sediment, ash, eggs, crabs, snails, fish, and rice, were collected from e-waste processing sites and compared with control areas. Blood samples from e-waste workers and a control group were also analysed. Gas chromatography coupled with mass spectrometry operated in negative ion chemical ionization (GC-NCI-MS) was used to quantify PBDEs and DP isomers. Results showed significantly higher concentrations of these toxic compounds in e-waste sites compared to control areas. E-waste workers also had elevated levels of these substances in their blood, suggesting exposure through contaminated dust and food. These findings underscore the severe environmental contamination and health risks associated with improper e-waste management, highlighting the urgent need for regulatory measures and improved recycling practices to safeguard both environmental and public health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153972"},"PeriodicalIF":4.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475421","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":"ATF4/PHGDH mediates the effects of ER stress on cadmium-induced autophagy and glycolysis","authors":"Yanqiu Yang ,&nbsp;Shengnan Li ,&nbsp;Yuanxi Yang ,&nbsp;Qiujuan Li ,&nbsp;Yong Liu ,&nbsp;Jun Cao","doi":"10.1016/j.tox.2024.153976","DOIUrl":"10.1016/j.tox.2024.153976","url":null,"abstract":"<div><div>Cadmium (Cd) has been classified as a Class I carcinogen, but the mechanism of its carcinogenicity is still unknown. Our previous study demonstrated that 2 μM CdCl₂ induced autophagy in A549 cells. In this study, we investigated the role of ATF4/PHGDH in Cd-induced autophagy and increased glycolysis. First, BALB/c mice were subcutaneously injected with A549 cells co-treated with or without Cd and siPHGDH to establish a xenograft tumor model, which demonstrated that PHGDH promotes Cd-induced autophagy <em>in vivo</em>. Cd-exposed A549 cells were treated with siPHGDH and 0.4 mM glycine (Gly), respectively. Western blot analysis and Acridine orange staining revealed that PHGDH promotes Cd-induced autophagy. Using 4-PBA (5 mM), the inhibitor of ER stress, or Tm (0.1 μg/ml), the inducer of ER stress, inhibited Cd-induced PHGDH expression. After co-treatment with siPHGDH, PHGDH was determined to mediate ER stress-induced autophagy. Furthermore, transfection with siATF4 inhibited Tm-induced PHGDH expression. ChIP-qPCR experiments demonstrated the transcription regulatory mechanism of ATF4 on PHGDH. Meanwhile, the role of ER stress/PHGDH/autophagy in Cd-promoted cell migration was explored by scratch assay. Finally, the role of ER stress/PHGDH/autophagy in Cd-induced glycolysis was unveiled. In summary, the transcriptional regulation of PHGDH by ATF4 plays a crucial role in Cd-induced autophagy triggered by ER stress. The axis of ER stress/PHGDH/autophagy is important in Cd-induced cell migration by enhancing glycolysis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153976"},"PeriodicalIF":4.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475419","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":"Predictive, integrative, and regulatory aspects of AI-driven computational toxicology – Highlights of the German Pharm-Tox Summit (GPTS) 2024","authors":"Ute Haßmann ,&nbsp;Sigrid Amann ,&nbsp;Nelly Babayan ,&nbsp;Simone Fankhauser ,&nbsp;Tina Hofmaier ,&nbsp;Thomas Jakl ,&nbsp;Monika Nendza ,&nbsp;Helga Stopper ,&nbsp;Sven Marcel Stefan ,&nbsp;Robert Landsiedel","doi":"10.1016/j.tox.2024.153975","DOIUrl":"10.1016/j.tox.2024.153975","url":null,"abstract":"<div><div>The 9th German Pharm-Tox Summit (GPTS) and the 90th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) took place in Munich from March 13–15, 2024. The event brought together over 700 participants from around the world to discuss cutting-edge developments in the fields of pharmacology and toxicology as well as scientific innovations and novel insights. A key focus of the conference was on the rapidly increasing role of computational toxicology, artificial intelligence (AI), and machine learning (ML) into the field, marking a shift away from traditional methods and allowing the reduction of animal testing as primary tool for toxicological risk assessment. Tools such as Toxometris.ai showcased the potential of AI-based risk assessments for predicting carcinogenicity, offering more ethical and efficient alternatives. Additionally, computer-driven models like computer-aided pattern analysis (C@PA) for drug toxicity prediction were presented, emphasizing the growing role of chem- and bioinformatic applications in computational sciences. Throughout the summit, there was a strong focus on the need for regulatory innovation to support the adoption of these advanced technologies and ensure the safety and sustainability of chemical substances and drugs.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153975"},"PeriodicalIF":4.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475423","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":"Knock-down of FOXO3, GATA2, NFE2L2 and AHR promotes doxorubicin-induced cardiotoxicity in human cardiomyocytes","authors":"J.G. Faber,&nbsp;J. Ochoteco Asensio,&nbsp;F. Caiment,&nbsp;T. van den Beucken","doi":"10.1016/j.tox.2024.153977","DOIUrl":"10.1016/j.tox.2024.153977","url":null,"abstract":"<div><div>Recent advances in cancer therapy have substantially increased survival rates among patients, yet the prolonged effect of current treatment regimens with anthracyclines (ACs) often include severe long-term complications, notably in the form of anthracycline-induced cardiotoxicity (AIC). Despite known associations between AC treatment and AIC, a comprehensive understanding of the underlying molecular pathways remains elusive. This gap is highlighted by the scarcity of reliable therapeutic interventions, with dexrazoxane being the sole FDA-approved drug to mitigate AIC risks. This study aims at elucidating the transcriptional response of human cardiomyocytes (hCMs) to AC exposure by analyzing a previously generated RNA-sequencing dataset of cardiac spheroids subjected to clinically relevant doses of ACs. The analysis revealed a robust transcriptional response identified across various time points. We aimed at identifying important transcription factors (TFs) mediating AIC by employing predictive algorithms to highlight key TFs for further experimental validation. Using shRNA constructs, we further assessed the impact of these TFs on hCM response to doxorubicin (DOX) and revealed that these TFs had a notable impact on hCM survival upon DOX exposure. TFs FOXO3, GATA2, AHR and NFE2L2 were further investigated for their role in AIC including cell viability, DOX uptake, DNA damage repair and induction of apoptosis through Cleaved-Caspase 3. Our study demonstrated that eliminating FOXO3 and GATA2 made hCMs more vulnerable to DOX and the lack of GATA2, NFE2L2 and AHR led to significantly higher intracellular levels of DOX. Additionally, FOXO3 played a role in the repair of hCM DNA damage as we observed markedly enhanced levels of <em>CDKN1A</em>. We also noted significant increases in DNA damage through COMET-assays when FOXO3, GATA2, NFE2L2 and AHR were absent. Furthermore, we investigated the clinical relevance by comparing our results with those from a study based on hiPSC-CMs derived from patients with doxorubicin-induced cardiotoxicity, identifying overlapping TFs and their regulatory roles in critical cellular processes like the cell cycle and DNA repair. This approach not only advances the understanding of the molecular mechanisms behind AIC but also opens possible windows for new therapeutic approaches to mitigate the negative side-effects from patient AC treatment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153977"},"PeriodicalIF":4.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475420","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":"A microRNA signature for valproate-induced steatosis in human hepatocytes and its application to predict fatty liver in paediatric epileptic patients on valproate therapy","authors":"Polina Soluyanova ,&nbsp;Marta del Pozo ,&nbsp;Erika Moro-Castaño ,&nbsp;Ana V. Marco-Hernández ,&nbsp;José V. Castell ,&nbsp;Ramiro Jover","doi":"10.1016/j.tox.2024.153974","DOIUrl":"10.1016/j.tox.2024.153974","url":null,"abstract":"<div><div>Valproate (VPA) has been the first-line, most frequently prescribed antiepileptic drug in children over the past 50 years. VPA causes, idiosyncratic hepatotoxicity in some patients, who often presents with hepatic steatosis. Experimental studies also support that VPA has high potential to induce steatosis. However, there is an apparent lack of significant hepatic problems in neuropediatric units, likely because iatrogenic liver steatosis lacks specific biomarkers. Thus, it is possible that a relevant number of children under VPA have asymptomatic fatty liver.</div></div><div><h3>Aims</h3><div>1) to demonstrate VPA-induced triglyceride (TG) accumulation in cultured human upcyte hepatocytes, 2) to identify miRNAs that are deregulated by VPA and associated with TG levels in these cells, and 3) to test these miRNAs, as potential non-invasive biomarkers, in plasma of paediatric epileptic patients on VPA, to identify those with a potential risk of liver steatosis.</div><div>Human upcyte hepatocytes were exposed to subcytotoxic VPA concentrations. Hepatocytes increased intracellular TGs by 27 % and 45 % after 2 and 4 mM VPA for 24 h. The profiling of cellular miRNAs by microarray analysis after 4 mM VPA identified 43 deregulated human miRNAs (fold-change &gt; 1.5 or &lt; −1.5; FDR p&lt;0.05). Some of them (n=11), which were validated by RTqPCR and showed correlation (Pearson r≥ 0.6) with intracellular TG levels, were selected as potential VPA-induced steatosis biomarkers. Next, we investigated the expression of these miRNAs in human plasma and found that 9 of them could be reliably quantified by RTqPCR: miR-485-3p, miR-127-3p, miR-30a-3p, miR-92b-3p, miR-212-3p, miR-182-5p, miR-183-5p, miR-500a-5p and miR-675-5p. Screening of this 9-miRNA signature in 80 paediatric epileptic patients on VPA identified 18 patients (23 %) that clustered separately because of important alterations in the selected plasma miRNAs. These patients were younger and had higher VPA blood concentrations and serum liver enzyme levels.</div><div>In conclusion, VPA induced both TG accumulation and deregulation of a set of miRNAs in cultured human hepatocytes. Nine of these miRNAs have demonstrated potential as circulating biomarkers to identify VPA-induced steatosis in epileptic patients, which should require closer clinical follow-up.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153974"},"PeriodicalIF":4.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475418","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":"Unraveling the ozone impact and oxidative stress on the nervous system","authors":"Paola Rodriguez ,&nbsp;Alejandro López-Landa ,&nbsp;Héctor Romo-Parra ,&nbsp;Moisés Rubio-Osornio ,&nbsp;Carmen Rubio","doi":"10.1016/j.tox.2024.153973","DOIUrl":"10.1016/j.tox.2024.153973","url":null,"abstract":"<div><div>Ozone (O₃), a potent oxidant, can penetrate the body through breathing, generating reactive oxygen species (ROS) and triggering inflammatory processes. Oxidative stress, an imbalance between the production of ROS and the body’s antioxidant capacity, plays a crucial role in the pathophysiology of various neurodegenerative diseases. This phenomenon can negatively impact the Central Nervous System (CNS), inducing structural and functional alterations that contribute to the development of neurological pathologies. This review examines how O₃-induced oxidative stress affects the nervous system by analyzing existing literature on the involved molecular mechanisms and potential antioxidant systems to mitigate its effects. Through a comprehensive review of experimental studies, our objective is to shed light on the interaction between O₃ and the nervous system, as well as its signaling pathways and altered genes, providing a foundation for future research in this field. Several studies have demonstrated that prolonged exposure to O₃ leads to increased expression of reactive oxygen species, causing alterations in the blood-brain barrier and damage to astrocytes and microglia. These effects can lead to an increase in the production of proinflammatory cytokines, neurotoxins, and genes, exacerbating neuronal damage and accelerating the progression of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and other neurological disorders. The results of this review suggest that exposure to O₃ may induce oxidative damage to the nervous system, which could have significant implications for public health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153973"},"PeriodicalIF":4.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of fumonisin B1 on intercellular communications and miRNA modulations: Non-genotoxic carcinogenesis mechanisms in human kidney cells","authors":"Ecem Fatma Karaman ,&nbsp;Mahmoud Abudayyak ,&nbsp;Zeynep Rana Guler ,&nbsp;Suna Bektas ,&nbsp;Engin Kaptan ,&nbsp;Sibel Ozden","doi":"10.1016/j.tox.2024.153968","DOIUrl":"10.1016/j.tox.2024.153968","url":null,"abstract":"<div><div>Fumonisin B1 (FB1), which is produced by <em>Fusarium</em> species, is one of the most prevalent mycotoxins known to exert several toxic effects, particularly nephrotoxicity. While its genotoxic carcinogenic mechanisms have been extensively studied, its influence on non-genotoxic pathways including intercellular communication and microRNA (miRNA) regulation remain underexplored. The present study investigates the effects of FB1 on gap junctions, miRNA expression profiles, and their relationship in human kidney cells (HK-2 and HEK293). Both cell lines showed increased apoptosis rates at 50 and 100 µM, while FB1 exposure significantly reduced gap junctional intercellular communication (GJIC) and decreased the expression levels of related genes, including <em>Cx43</em>, <em>Cx45</em>, <em>e-cadherin</em>, <em>Cadherin-2</em>, and <em>β-catenin</em>. After FB1 treatments alteration on the regulation of miRNAs including let-7a-5p, miR-125a-5p, miR-222–3p, miR-92a-3p, let-7b-5p, let-7e-5p, miR-21–5p, miR-155–5p, let-7i-5p, let-7d-5p, let-7f-5p, miR-181b-5p, miR-15b-5p, miR-23b-3p, miR-20b-5p, miR-196a-5p miRNAs have been shown. Let-7a-5p was selected among the altered miRNAs to elucidate the relationship between miRNAs and GJIC after FB1 exposure as it is one of the common miRNAs that changes in both cell lines and one of its target genes is <em>Cx45</em>, which is an important gene for GJIC. However, transfection analysis did not show any differences, resulting in <em>Cx45</em> not being a direct target of let-7a-5p in HK-2 and HEK-293 cells. Through comprehensive analysis, we elucidated that FB1's impact on intercellular signaling cascades and its regulatory role on miRNA expression profiles, offering valuable insights into carcinogenesis beyond traditional genotoxic paradigms. Understanding these mechanisms is crucial for elucidating the mechanisms of FB1-induced toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153968"},"PeriodicalIF":4.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475422","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}