Archives of Toxicology最新文献

{"title":"Pulmonary exposure to renewable diesel exhaust particles alters protein expression and toxicity profiles in bronchoalveolar lavage fluid and plasma of mice","authors":"Sarah McCarrick,&nbsp;Vilhelm Malmborg,&nbsp;Louise Gren,&nbsp;Pernille Høgh Danielsen,&nbsp;Martin Tunér,&nbsp;Lena Palmberg,&nbsp;Karin Broberg,&nbsp;Joakim Pagels,&nbsp;Ulla Vogel,&nbsp;Anda R. Gliga","doi":"10.1007/s00204-024-03915-y","DOIUrl":"10.1007/s00204-024-03915-y","url":null,"abstract":"<div><p>Exposure to diesel exhaust is associated with increased risk of cardiovascular and lung disease. Substituting petroleum diesel with renewable diesel can alter emission properties but the potential health effects remain unclear. This study aimed to explore toxicity and underlying mechanisms of diesel exhaust from renewable fuels. Using proximity extension assay (Olink), 92 proteins linked to inflammation, cardiovascular function, and cancer were analyzed in bronchoalveolar lavage fluid (BALF) and plasma in mice 1 day after pulmonary exposure to exhaust particles at doses of 6, 18, and 54 µg/mouse. Particles were generated from combustion of renewable (rapeseed methyl ester, RME13, hydrogen-treated vegetable oil, HVO13; both at 13% O₂ engine intake) and petroleum diesel (MK1 ultra-low-sulfur diesel at 13% and 17% O₂ intake; DEP13 and DEP17). We identified positive dose–response relationships between exposure and proteins in BALF using linear models: 33 proteins for HVO13, 24 for DEP17, 22 for DEP13, and 12 for RME13 (<i>p</i> value &lt; 0.05). In BALF, 11 proteins indicating cytokine signaling and inflammation (CCL2, CXCL1, CCL3L3, CSF2, IL1A, CCL20, TPP1, GDNF, LGMN, ITGB6, PDGFB) were common for all exposures. Several proteins in BALF (<i>e.g.,</i> CCL2, CXCL1, CCL3L3, CSF2, IL1A) correlated (<i>r</i>_s ≥ 0.5) with neutrophil cell count and DNA damage in BAL cells. Interestingly, plasma protein profiles were only affected by RME13 and, to lesser extent, by DEP13. Overall, we identified inflammation-related changes in the BALF as a common toxic mechanism for the combustion particles. Our protein-based approach enables sensitive detection of inflammatory protein changes across different matrices enhancing understanding of exhaust particle toxicity.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"797 - 814"},"PeriodicalIF":4.8,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of physiologically based (PBK) modeling to quantify the effect of the antibiotic tobramycin on bile acid levels in human plasma","authors":"Nina Zhang,&nbsp;Ivonne M. C. M. Rietjens,&nbsp;Véronique M. P. de Bruijn","doi":"10.1007/s00204-024-03936-7","DOIUrl":"10.1007/s00204-024-03936-7","url":null,"abstract":"<div><p>Systemic bile acid homeostasis plays an important role in human health. In this study, a physiologically based kinetic (PBK) model that includes microbial bile acid deconjugation and intestinal bile acid reuptake via the apical sodium-dependent bile acid transporter (ASBT) was applied to predict the systemic plasma bile acid concentrations in human upon oral treatment with the antibiotic tobramycin. Tobramycin was previously shown to inhibit intestinal deconjugation and reuptake of bile acids and to affect bile acid homeostasis upon oral exposure of rats. Kinetic parameters to define the effects of tobramycin on intestinal bile acid transport were determined in vitro using a Caco-2 cell layer Transwell model for studying the intestinal translocation of 4 model bile acids including glycochenodeoxycholic acid (GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and deoxycholic acid (DCA), the latter as a model for unconjugated bile acids (uBA). Kinetic constants for the effect of tobramycin on intestinal microbial deconjugation were taken from previous in vitro studies using anaerobic fecal incubations. The PBK model simulations predicted that exposure to tobramycin at the dose level also used in the previous 28 day rat study would reduce human plasma <i>C</i>_max levels of GCA, GCDCA, GDCA, and DCA by 42.4%, 27.7%, 16.9%, and 75.8%. The reduction of conjugated bile acids is governed especially via an effect on ASBT-mediated intestinal uptake, and not via the effect of tobramycin on intestinal conjugation, likely because deconjugation happens to a large extent in the colon which has limited subsequent bile acid reuptake. The results reflect that oral exposure to xenobiotics that are not or poorly bioavailable can affect systemic bile acid homeostasis. Altogether, the PBK model appears to provide a 3R compliant tool to evaluate the effect of oral exposure to xenobiotics on host bile acid homeostasis via effects on intestinal bile acid deconjugation and reuptake.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"1073 - 1083"},"PeriodicalIF":4.8,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms behind the inhibitory effects of ginsenoside Rg3 on hepatic fibrosis: a review","authors":"Zhao-feng Tian,&nbsp;Rui-yi Hu,&nbsp;Zi Wang,&nbsp;Ya-jun Wang,&nbsp;Wei Li","doi":"10.1007/s00204-024-03941-w","DOIUrl":"10.1007/s00204-024-03941-w","url":null,"abstract":"<div><p>Hepatitis is a chronic inflammatory liver disease and an important cause of liver fibrosis, which can progress to cirrhosis and even hepatocellular carcinoma if left untreated. However, liver fibrosis is a reversible disease, so finding new intervention targets and molecular markers is the key to preventing and treating liver fibrosis. Ginseng, the roots of <i>Panax ginseng</i> C. A. Meyer, is a precious Traditional Chinese Medicines with high medicinal value and is known as the “king of all herbs”, and its active ingredient, ginsenoside Rg3 is a rare saponin and a new class of drug, one of the most thoroughly and extensively studied in a large number of studies. Ginsenoside Rg3 is an active ingredient extracted from ginseng that possesses a variety of biological activities, including anti-inflammatory, antioxidant, and anti-fibrotic effects. Several studies have suggested that ginsenoside Rg3 may help reduce hepatic inflammation and oxidative stress, thereby slowing the progression of liver fibrosis. Ginsenoside Rg3 may have some therapeutic effects on liver fibrosis, and the underlying molecular mechanisms behind these effects are attributed to cellular autophagy, apoptosis, and anti-inflammation, as well as the modulation of antioxidant activity and multiple signaling pathways. The molecular mechanisms behind the inhibitory effect of ginsenoside Rg3 on hepatic fibrosis are reviewed, with a view to providing reference for related studies.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"541 - 561"},"PeriodicalIF":4.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatoprotective effects of phytochemicals and plant extracts against chemotherapy-induced liver damage in animal models: a systematic review","authors":"Jignesh Prajapati,&nbsp;Narendra Bhatt,&nbsp;Rakesh Rawal","doi":"10.1007/s00204-024-03928-7","DOIUrl":"10.1007/s00204-024-03928-7","url":null,"abstract":"<div><p>Chemotherapy, a cornerstone of cancer treatment, is frequently marred by its hepatotoxic effects, which can significantly impede therapeutic efficacy. This systematic review meticulously evaluates the hepatoprotective properties of phytochemicals and plant extracts against chemotherapy-induced liver damage, primarily in experimental animal models. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, an exhaustive search was conducted across databases like SCOPUS, PubMed, and Web of Science, culminating in the inclusion of 61 pertinent studies. These studies illustrate those natural compounds, spanning a diverse array of phytochemicals and plant extracts that can effectively mitigate biochemical markers of liver damage, enhance antioxidant defences, and modulate inflammatory responses in model organisms subjected to hepatotoxic chemotherapeutic agents such as cyclophosphamide, cisplatin, and doxorubicin. Notably, the natural agents reviewed have demonstrated significant reductions in liver enzymes, improved histopathological outcomes, and bolstered cellular antioxidant capacities. The systematic synthesis of data underscores the potential of these natural substances to diminish liver toxicity associated with chemotherapy in preclinical settings. However, the review also highlights critical gaps in research, notably the underreporting of molecular mechanisms and inconsistent data on clinical translatability. To optimize the therapeutic utility of these compounds, future studies should focus on detailed molecular analyses and rigorous clinical trials to validate efficacy and safety, paving the way for integrated approaches in oncological care that minimize hepatic complications.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"887 - 914"},"PeriodicalIF":4.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerating antiviral drug discovery: early hazard detection with a dual zebrafish and cell culture screen of a 403 compound library","authors":"Lisa Truong,&nbsp;Andrew A. Bieberich,&nbsp;Raymond O. Fatig III,&nbsp;Bartek Rajwa,&nbsp;Michael T. Simonich,&nbsp;Robyn L. Tanguay","doi":"10.1007/s00204-024-03948-3","DOIUrl":"10.1007/s00204-024-03948-3","url":null,"abstract":"<div><p>The constant emergence of new viral pathogens underscores the need for continually evolving, effective antiviral drugs. A key challenge is identifying compounds that are both efficacious and safe, as many candidates fail during development due to unforeseen toxicity. To address this, the embryonic zebrafish morphology, mortality, and behavior (ZBE) screen and the SYSTEMETRIC® Cell Health Screen (CHS) were employed to evaluate the safety of 403 compounds from the Cayman Antiviral Screening Library. Of these compounds, 114 were FDA-approved, 17 were discontinued, and 97 remained on the market. CHS identified 25% (104 compounds) as toxic, with a Cell Health Index™ (CHI) &gt; 0.5. The embryonic zebrafish model identified an additional 20% as toxic (79), bringing the total to 183. ZBEscreen flagged 19 toxic hits among compounds still on the market, seven of which were also identified by CHS. The combined use of CHS and zebrafish models enhanced hazard detection. Together, CHS and ZBEscreen identified 45.5% of the library as potentially hazardous. Notably, the zebrafish non-hazardous compounds correlated strongly with over-the-counter or prescribed antiviral drugs, confirming their known safety profile. Over 130 hazard-associated compounds warranted further investigation. Using self-organizing maps, six distinct neighborhoods of compound similarity were identified. This dual approach streamlined the early detection of hazards associated with promising leads and is expected to facilitate faster, safer antiviral discovery.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"1029 - 1041"},"PeriodicalIF":4.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03948-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigation of depleted uranium-induced mitochondrial damage by ethylmalonic encephalopathy 1 protein via modulation of hydrogen sulfide and glutathione pathways","authors":"Juan Li,&nbsp;Yong Li,&nbsp;Yazhen Zhao,&nbsp;Suiyi Liu,&nbsp;Wenrun Li,&nbsp;Huanhuan Tan,&nbsp;Li Shen,&nbsp;Yonghong Ran,&nbsp;Yuhui Hao","doi":"10.1007/s00204-024-03949-2","DOIUrl":"10.1007/s00204-024-03949-2","url":null,"abstract":"<div><p>Depleted uranium (DU) is a byproduct of uranium enrichment, which can cause heavy-metal toxicity and radiation toxicity as well as serious damage to the kidneys. However, the mechanism of renal injury induced by DU is still unclear. This study aimed to explore the role of ethylmalonic encephalopathy 1 (ETHE1) in DU-induced mitochondrial dysfunction and elucidate the underlying mechanisms. Using ETHE1 gene knockout C57BL/6 mice (10 mg/kg DU) and renal cell models (500 µM DU) exposed to DU, we observed significantly reduced levels of hydrogen sulfide (H₂S) and glutathione (GSH), alongside decreased adenosine triphosphate (ATP) content and increased oxidative stress. Our results demonstrated that knocking out or silencing ETHE1 led to a significant reduction in H₂S and GSH levels, whereas the opposite occurred when was ETHE1 overexpressed. When the H₂S donor sodium hydrosulfide and GSH precursor N-acetylcysteine were used to treat animals or cells, cellular ATP levels were increased, oxidative stress markers were reduced, and kidney damage was mitigated. In addition, H₂S and GSH interacted with each other after DU poisoning. These findings suggest that the ETHE1/H₂S/GSH pathway plays a critical role in mediating DU-induced mitochondrial dysfunction in renal cells, highlighting potential therapeutic targets for mitigating the harmful effects of DU. Thus, this study expands our understanding of DU-induced renal damage pathways, providing avenues for further research and intervention strategies.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"1133 - 1141"},"PeriodicalIF":4.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug protection against radiation-induced neurological injury: mechanisms and developments","authors":"Qingyu Wang,&nbsp;Caimao Guo,&nbsp;Tiantian Wang,&nbsp;Peimeng Shuai,&nbsp;Wenyu Wu,&nbsp;Shuqi Huang,&nbsp;Yuanyuan Li,&nbsp;Pei Zhao,&nbsp;Chengkai Zeng,&nbsp;Lan Yi","doi":"10.1007/s00204-024-03933-w","DOIUrl":"10.1007/s00204-024-03933-w","url":null,"abstract":"<div><p>In daily life, individuals are frequently exposed to various forms of radiation, which, when adhering to safety standards, typically result in relatively minor health effects. However, accidental exposure to radiation levels that exceed these safety standards can lead to significant health consequences. This study focuses on the analysis of radiation-induced damage to the nervous system and the mechanisms of pharmacological protection. The findings indicate that radiation can adversely affect neural structures, memory, and neurobehaviour. A range of pharmacological agents, including traditional Chinese medicine, Western medicine, and other therapeutic drugs, can be employed to safeguard the nervous system from radiation damage. The primary protective mechanisms of these agents encompass antioxidant effects, attenuation of apoptosis, and reduction of neurogenesis. A comprehensive review of these topics will offer new insights for the development and investigation of drugs aimed at mitigating radiation-induced damage to the nervous system.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"851 - 863"},"PeriodicalIF":4.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-induced hepatic sinusoidal obstruction syndrome: current advances and future perspectives","authors":"Zaoqin Yu,&nbsp;Wei Li,&nbsp;Cheng Tian,&nbsp;Yan Cao,&nbsp;Chengliang Zhang","doi":"10.1007/s00204-024-03950-9","DOIUrl":"10.1007/s00204-024-03950-9","url":null,"abstract":"<div><p>Hepatic sinusoidal obstruction syndrome (HSOS) has gained recognition as a rare form of drug-induced liver injury (DILI) in recent years. Although extensively studied in the context of hematopoietic stem cell transplantation (HSCT), the applicability of this knowledge to drug-induced HSOS remains limited due to distinct etiological factors. The primary causes of drug-induced HSOS include the ingestion of pyrrolizidine alkaloid (PA)-containing plants, as well as the use of chemotherapeutic agents and immunosuppressive drugs. The underlying pathogenesis is not yet fully understood. Noninvasive diagnostic imaging modalities such as ultrasonography, computed tomography, and magnetic resonance imaging play a valuable role in diagnosis. Further research is essential to develop standardized severity grading systems and optimize treatment strategies. This review summarizes the key etiologies, pathological mechanisms, clinical features, diagnostic approaches, severity assessment, and therapeutic options for drug-induced HSOS.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"835 - 850"},"PeriodicalIF":4.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fungicide propiconazole induces hepatic steatosis and activates PXR in a mouse model of diet-induced obesity","authors":"Brecht Attema,&nbsp;Outi Kummu,&nbsp;Mária Krutáková,&nbsp;Petr Pavek,&nbsp;Jukka Hakkola,&nbsp;Guido J. E. J. Hooiveld,&nbsp;Sander Kersten","doi":"10.1007/s00204-024-03942-9","DOIUrl":"10.1007/s00204-024-03942-9","url":null,"abstract":"<div><p>Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell–cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 3","pages":"1203 - 1221"},"PeriodicalIF":4.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the cyto- and genotoxicity of two types of cellulose nanomaterials using human intestinal cells and in vitro digestion simulation","authors":"Nádia Vital,&nbsp;Maria Cardoso,&nbsp;Michel Kranendonk,&nbsp;Maria João Silva,&nbsp;Henriqueta Louro","doi":"10.1007/s00204-024-03911-2","DOIUrl":"10.1007/s00204-024-03911-2","url":null,"abstract":"<div><p>Emerging cellulose nanomaterials (CNMs) may have commercial impacts in multiple sectors, being their application particularly explored in the food sector. Thus, their potential adverse effects in the gastrointestinal tract should be evaluated before marketing. This work aimed to assess the safety of two CNMs (CNF–TEMPO and CMF–ENZ) through the investigation of their cytotoxicity, genotoxicity (comet and micronucleus assays), and capacity to induce reactive oxygen species in human intestinal cells, and their mutagenic effect using the <i>Hprt</i> gene mutation assay. Each toxicity endpoint was analysed after cells exposure to a concentration-range of each CNM or to its digested product, obtained by the application of a standardized static in vitro digestion method. The results showed an absence of cytotoxic effects in intestinal cells, up to the highest concentration tested (200 µg/mL or 25 µg/mL, for non-digested and digested CNMs, respectively). Of note, the cytotoxicity of the digestion control limited the top concentration of digested samples (25 µg/mL) for subsequent assays. Application of a battery of in vitro assays showed that CNF–TEMPO and CMF–ENZ do not induce gene mutations or aneugenic/clastogenic effects. However, due to the observed DNA damage induction, a genotoxic potential cannot be excluded, even though in vitro digestion seems to attenuate the effect. The lowest digested CNF–TEMPO concentration induced chromosomal damage in Caco-2 cells, leading to an equivocal outcome. Ongoing research on epigenotoxic effects of these CNMs samples may strengthen the lines of evidence on their safety when ingested, paving the way for their innovative application in the food industry.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"575 - 596"},"PeriodicalIF":4.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}