Toxicology最新文献

{"title":"Developments in the field of intestinal toxicity and signaling pathways associated with rodent exposure to micro(nano)plastics","authors":"","doi":"10.1016/j.tox.2024.153883","DOIUrl":"10.1016/j.tox.2024.153883","url":null,"abstract":"<div><p>The broad spread of micro(nano)plastics (MNPs) has garnered significant attention in recent years. MNPs have been detected in numerous human organs, indicating that they may also be hazardous to humans. The toxic effects of MNPs have been demonstrated in marine species and experimental animals. The primary pathway and target organ for MNPs entering the human body is the intestinal system, and increasing research has been done on the harmful effects and subsequent mechanisms of exposure to MNPs. Studies on how MNPs affect gut health in humans are scarce, nevertheless. Since rodents are frequently employed as animal models for human ailments, research on rodents exposed to MNPs can provide a more accurate representation of human circumstances. This study examined the effects of MNPs on intestinal microecology, inflammation, barrier function, and ion transport channels in rodents. It also reviewed the signal pathways involved, such as oxidative stress, nuclear factor (NF)-κB, Toll-like receptor (TLR) 4, inflammatory corpuscles, muscarinic acetylcholine receptors (mAChRs), mitogen-activated protein kinase (MAPK), and cell death. This review will offer a conceptual framework for the management and avoidance of associated illnesses.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601800","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":"Corrigendum to “Genotoxic and cytotoxic effects of aflatoxin on the reproductive system: Focus on cell cycle dynamics and apoptosis in testicular tissue” [Toxicology 504 (2024) 153773]","authors":"","doi":"10.1016/j.tox.2024.153881","DOIUrl":"10.1016/j.tox.2024.153881","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0300483X24001628/pdfft?md5=4a64b1eb3c78d51cdaa3ed2a62627705&pid=1-s2.0-S0300483X24001628-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564430","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":"Inhibitory effects of parabens on human and rat 17β-hydroxysteroid dehydrogenase 1: Mechanisms of action and impact on hormone synthesis","authors":"Zouqi Chen ,&nbsp;Chaochao Gong ,&nbsp;Yunbing Tang ,&nbsp;Yang Zhu ,&nbsp;Shaowei Wang ,&nbsp;Ren-shan Ge ,&nbsp;Yingfen Ying","doi":"10.1016/j.tox.2024.153873","DOIUrl":"10.1016/j.tox.2024.153873","url":null,"abstract":"<div><p>Parabens are commonly used preservatives in cosmetics, food, and pharmaceutical products. The objective of this study was to examine the effect of nine parabens on human and rat 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) in human placental and rat ovarian cytosols, as well as on estradiol synthesis in BeWo cells. The results showed that the IC₅₀ values for these compounds varied from methylparaben with the weakest inhibition (106.42 μM) to hexylparaben with the strongest inhibition (2.05 μM) on human 17β-HSD1. Mode action analysis revealed that these compounds acted as mixed inhibitors. For rats, the IC₅₀ values ranged from the weakest inhibition for methylparaben (no inhibition at 100 μM) to the most potent inhibition for hexylparaben (0.87 μM), and they functioned as mixed inhibitors. Docking analysis indicated that parabens bind to the region bridging the NADPH and steroid binding sites of human 17β-HSD1 and the NADPH binding site of rat 17β-HSD1. Bivariate correlation analysis demonstrated negative correlations between LogP, molecular weight, heavy atoms, and apolar desolvation energy, and the IC₅₀ values of these compounds. In conclusion, this study identified the inhibitory effects of parabens and their binding mechanisms on human and rat 17β-HSD1, as well as their impact on hormone synthesis.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580907","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":"Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats","authors":"","doi":"10.1016/j.tox.2024.153878","DOIUrl":"10.1016/j.tox.2024.153878","url":null,"abstract":"<div><p>The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used <em>in silico</em>, <em>in vivo</em>, and <em>ex vivo</em> approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with <em>in silico</em> predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The <em>in silico</em> findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0300483X24001598/pdfft?md5=1b11e1da7e02bef4cff3ff6796ec917b&pid=1-s2.0-S0300483X24001598-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555504","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":"Degranulation and expression of cytokines were modulated by diazinon in activated mast cells","authors":"Tomoko Ohdachi ,&nbsp;Miyoko Matsushima ,&nbsp;Moeko Ohara ,&nbsp;Hina Kawashima ,&nbsp;Goki Inoue ,&nbsp;Kazuko Atsumi ,&nbsp;Yuka Tsubosaki ,&nbsp;Masahiro Takekoshi ,&nbsp;Jun Ueyama ,&nbsp;Naozumi Hashimoto ,&nbsp;Mitsuo Sato ,&nbsp;Yoshinori Hasegawa ,&nbsp;Makoto Ishii ,&nbsp;Tsutomu Kawabe","doi":"10.1016/j.tox.2024.153882","DOIUrl":"10.1016/j.tox.2024.153882","url":null,"abstract":"<div><p>Diazinon is an organophosphorus (OP) insecticides used in agriculture, home gardening and indoor pest control in Japan. It can activate macrophages and induce pro-inflammatory responses and has been reported to cause airway hyper-reactivity, suggesting the possibility of asthma exacerbation from exposure to OP insecticides. Despite the correlation between insecticide use and the pathogenesis of allergic diseases, there have been no reports on the effects of diazinon on mast cell function. Therefore, in this study, we investigated the effects of diazinon on mast cell function in rat basophilic leukemia (RBL)-2H3 cells. Surprisingly, we found that diazinon inhibited mast cell activation, although the degree of inhibition varied with concentration. Diazinon induced reactive oxygen species (ROS) generation and HO-1 expression at a concentration of 150 µM without affecting cell viability. Diazinon inhibited A23187-mediated degranulation and <em>Tnf</em> and <em>Il4</em> expression in RBL-2H3 cells but did not affect calcium influx. Suppression of degranulation by diazinon was reversed when the culture supernatant was removed. As a signaling event downstream of calcium influx, diazinon inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) induced by A23187, whereas the phosphorylation of p38 had little effect. IgE cross-linking-mediated degranulation as well as the induction of <em>Tnf</em> and <em>IL4</em> expression was significantly inhibited by diazinon, while diazinon had little effect on calcium influx. In conclusion, diazinon inhibited mast cell activation, including degranulation and cytokine expression. When evaluating the <em>in vivo</em> effects of diazinon, its potential to inhibit mast cell activation should be considered in the pathophysiology and development of allergic diseases in terms of basic and clinical aspects, respectively, although the effect of diazinon varies depending on the cell type.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545305","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":"Targeting Nrf2/HO-1 and NF-κB/TNF-α signaling pathways with empagliflozin protects against atrial fibrillation-induced acute kidney injury in rats","authors":"Hussein Badreldin ,&nbsp;Amr El-Karef ,&nbsp;Tarek Ibrahim ,&nbsp;Mahmoud Elshal","doi":"10.1016/j.tox.2024.153879","DOIUrl":"https://doi.org/10.1016/j.tox.2024.153879","url":null,"abstract":"<div><p>A bidirectional relationship exists between atrial fibrillation (AF) and kidney function. Uncontrolled AF may lead to kidney injury, whereas renal dysfunction may contribute to AF initiation and maintenance. This study aimed to investigate the protective effect of the sodium glucose cotransporter-2 inhibitor empagliflozin (EMPA) on acute kidney injury (AKI) associated with AF induced by acetylcholine and calcium chloride (ACh/CaCl₂) in rats and elucidate the potential underlying mechanism. Rats were randomly divided as follows: control (CTRL) group: administered vehicles only; AF group: intravenously injected 1 ml/kg of an ACh/CaCl₂ mixture for seven days to induce AF; EMPA group: orally administered EMPA (30 mg/kg) for seven days; AF+EMPA10 and AF+EMPA30 groups: co-administered the induction mixture and EMPA (10 and 30 mg/kg, respectively) for seven days. Our results showed that EMPA (10 and 30 mg/kg) effectively maintained kidney function and demonstrated a significant antioxidant potential. EMPA also suppressed AF-induced renal tubulointerstitial injury and fibrotic changes concurrently with reducing renal levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6, as well as the pro-fibrotic marker transforming growth factor beta-1 and collagen type I. Mechanistically, EMPA boosted nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) renal tissue expression while repressing nuclear factor kappa B (NF-κB) activation. In addition, these beneficial effects of EMPA on kidneys were concurrent with its ability to effectively inhibit AF-related electrocardiographic changes, reduce incidence and duration of AF episodes, and markedly suppress serum B-type natriuretic peptide and C-reactive protein levels. In conclusion, EMPA protected against AKI associated with AF induced by ACh/CaCl₂ in rats through simultaneous modulation of the Nrf2/HO-1 and the NF-κB/TNF-α signaling pathways, exerting antioxidant, anti-inflammatory, and anti-fibrotic effects.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141543430","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 formation of lamellar body-like structures may be a trigger of cetylpyridinium chloride-induced cell death and inflammatory response","authors":"Wonkyun Jung ,&nbsp;Mi-Jin Yang ,&nbsp;Min-Sung Kang ,&nbsp;Geonwoo Pyo ,&nbsp;Hyosun Choi ,&nbsp;Kexin Li ,&nbsp;Eun-Jung Park","doi":"10.1016/j.tox.2024.153877","DOIUrl":"10.1016/j.tox.2024.153877","url":null,"abstract":"<div><p>Cetylpyridinium chloride (CPC) is a quaternary ammonium compound used widely in health and personal care products. Meanwhile, due to its increasing use, its potential adverse health effects are emerging as a topic of public concern. In this study, we first administered CPC by pharyngeal aspiration to determine the survival level (the maximum concentration at which no death is observed) and then administered CPC to mice repeatedly for 28 days using the survival level as the highest concentration. CPC increased the total number of pulmonary cells secreting pro- and anti-inflammatory cytokines and chemokines. Infiltration of inflammatory cells, production of foamy alveolar macrophages, and chronic inflammatory lesions were found in the lung tissue of male and female mice exposed to the highest dose of CPC. We also investigated the toxicity mechanism using BEAS-2B cells isolated from normal human bronchial epithelium. At 6 h after exposure to CPC, the cells underwent non-apoptotic cell death, especially at concentrations greater than 2 μg/mL. The expression of the transferrin receptor was remarkably enhanced, and the expression of proteins that contribute to intracellular iron storage was inhibited. The expression of both mitochondrial SOD and catalase increased with CPC concentration, and PARP protein was cleaved, suggesting possible DNA damage. In addition, the internal structure of mitochondria was disrupted, and fusion between damaged organelles was observed in the cytoplasm. Most importantly, lamellar body-like structures and autophagosome-like vacuoles were found in CPC-treated cells, with enhanced expression of ABCA3 protein, a marker for lamellar body, and a docking score between ABCA3 protein and CPC was considered to be approximately −6.8969 kcal/mol. From these results, we propose that mitochondrial damage and iron depletion may contribute to CPC-induced non-apoptotic cell death and that pulmonary accumulation of cell debris may be closely associated with the inflammatory response. Furthermore, we hypothesize that the formation of lamellar body-like structures may be a trigger for CPC-induced cell death.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538687","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":"Lycopene alleviates Deoxynivalenol-induced toxicity in Porcine intestinal epithelial cells by mediating mitochondrial function","authors":"Jie Wang ,&nbsp;Fan Lu ,&nbsp;Shanshen Gu ,&nbsp;Changfu Cao ,&nbsp;Yeyi Xiao ,&nbsp;Wenbin Bao ,&nbsp;Haifei Wang","doi":"10.1016/j.tox.2024.153880","DOIUrl":"10.1016/j.tox.2024.153880","url":null,"abstract":"<div><p>Deoxynivalenol (DON) is widely found in food and feed, posing a threat to human and animal health. Lycopene (Lyc) is a natural plant extracts with significant antioxidant properties. This study was conducted to investigate the protective effects of Lyc on IPEC-J2 cells upon DON exposure. The detection of cell viability and trypan blue staining showed that Lyc alleviated cell damage and decreased cell apoptotic rate induced by DON. The analysis of reactive oxygen species (ROS) level and antioxidant parameter measurements showed that Lyc significantly down-regulated the content of ROS and restored antioxidant enzyme activity. Furthermore, mitochondrial membrane potential (ΔΨm) detection, mitochondrial DNA copy number (mtDNAcn) assay and adenosine triphosphate (ATP) concentration detection showed Lyc improved mitochondrial function after DON exposure. The results of transcriptome analysis, ROS detection and CCK8 assay suggested that Lyc may activated the oxidative phosphorylation (OXPHOS) to improve mitochondrial function. Conclusively, our results suggested that Lyc alleviated DON-induced oxidative stress by improving mitochondrial function through OXPHOS signaling pathway.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499093","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":"Toxicity and biokinetics following pulmonary exposure to aluminium (aluminum): A review","authors":"Niels Hadrup ,&nbsp;Jorid B. Sørli ,&nbsp;Bjørn M. Jenssen ,&nbsp;Ulla Vogel ,&nbsp;Anoop K. Sharma","doi":"10.1016/j.tox.2024.153874","DOIUrl":"https://doi.org/10.1016/j.tox.2024.153874","url":null,"abstract":"<div><p>During the manufacture and use of aluminium (aluminum), inhalation exposure may occur. We reviewed the pulmonary toxicity of this metal including its toxicokinetics. The normal serum/plasma level based on 17 studies was 5.7 ± 7.7 µg Al/L (mean ± SD). The normal urine level based on 15 studies was 7.7 ± 5.3 µg/L. Bodily fluid and tissue levels during occupational exposure are also provided, and the urine level was increased in aluminium welders (43 ± 33 µg/L) based on 7 studies. Some studies demonstrated that aluminium from occupational exposure can remain in the body for years. Excretion pathways include urine and faeces. Toxicity studies were mostly on aluminium flakes, aluminium oxide and aluminium chlorohydrate as well as on mixed exposure, e.g. in aluminium smelters. Endpoints affected by pulmonary aluminium exposure include body weight, lung function, lung fibrosis, pulmonary inflammation and neurotoxicity. In men exposed to aluminium oxide particles (3.2 µm) for two hours, lowest observed adverse effect concentration (LOAEC) was 4 mg Al₂O₃/m³ (= 2.1 mg Al/m³), based on increased neutrophils in sputum. With the note that a similar but not statistically significant increase was seen during control exposure. In animal studies LOAECs start at 0.3 mg Al/m³. In intratracheal instillation studies, all done with aluminium oxide and mainly nanomaterials, lowest observed adverse effect levels (LOAELs) started at 1.3 mg Al/kg body weight (bw) (except one study with a LOAEL of ∼0.1 mg Al/kg bw). The collected data provide information regarding hazard identification and characterisation of pulmonary exposure to aluminium.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0300483X24001550/pdfft?md5=fa85424045483831a3441380cd97e70a&pid=1-s2.0-S0300483X24001550-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141487608","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":"Involvement of multiple epigenetic mechanisms by altered DNA methylation from the early stage of renal carcinogenesis before proliferative lesion formation upon repeated administration of ochratoxin A","authors":"Shunsuke Ozawa ,&nbsp;Ryota Ojiro ,&nbsp;Qian Tang ,&nbsp;Xinyu Zou ,&nbsp;Meilan Jin ,&nbsp;Toshinori Yoshida ,&nbsp;Makoto Shibutani","doi":"10.1016/j.tox.2024.153875","DOIUrl":"10.1016/j.tox.2024.153875","url":null,"abstract":"<div><p>Ochratoxin A (OTA) is a rat renal carcinogen that induces karyomegaly and micronuclei in proximal tubular epithelial cells (PTECs). We previously performed comprehensive gene profiling of alterations in promoter-region methylation and gene expression in PTECs of rats treated with OTA for 13 weeks. The OTA-specific gene profile was obtained by excluding genes showing expression changes similar to those upon treatment with 3-chloro-1,2-propanediol, a renal carcinogen not inducing karyomegaly. In this study, we validated the candidate genes using methylated DNA enrichment PCR and real-time RT-PCR, and identified <em>Gen1</em>, <em>Anxa3</em>, <em>Cdkn1a</em>, and <em>Osm</em> as genes showing OTA-specific epigenetic changes. These genes and related molecules were subjected to gene expression and immunohistochemical analyses in the PTECs of rats treated with OTA, other renal carcinogens, or non-carcinogenic renal toxicants for 4 or 13 weeks. <em>Cdkn1a</em> upregulation and increase of p21^WAF1/CIP1+ karyomegalic PTECs were observed with OTA, matching the findings associated with micronucleus-inducing carcinogens. This suggested that the increase of p21^WAF1/CIP1+ karyomegalic PTECs is linked to micronucleus formation, which in turn accelerates chromosomal instability. The upregulation of <em>Cdkn1a</em>-related genes with OTA suggests the acquisition of a senescence-associated secretory phenotype, which promotes the establishment of a carcinogenic environment. Meanwhile, OTA specifically caused a decrease of GEN1⁺ PTECs reflecting <em>Gen1</em> downregulation and an increase of ANXA3⁺ PTECs reflecting <em>Anxa3</em> upregulation, as well as <em>Osm</em> upregulation. OTA may efficiently disrupt pathways for repairing the DNA double-strand breaks that it itself causes, via <em>Gen1</em> downregulation, and enhance cell proliferation through the upregulation of <em>Anxa3</em> and <em>Osm</em>. This may exacerbate the chromosomal instability from the early stage of OTA-induced renal carcinogenesis before proliferative lesions form. OTA may cause renal carcinogenesis involving multiple epigenetic mechanisms.</p></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0300483X24001562/pdfft?md5=9e892b99c1aecc36482b558993501c3e&pid=1-s2.0-S0300483X24001562-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470941","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}