Toxicological Sciences最新文献

{"title":"Copper-mediated neurotoxicity and genetic vulnerability in the background of neurodegenerative diseases in C. elegans","authors":"Ann-Kathrin Weishaupt, Lysann Ruecker, Torben Meiners, Tanja Schwerdtle, Daiana Silva Avila, Michael Aschner, Julia Bornhorst","doi":"10.1093/toxsci/kfae092","DOIUrl":"https://doi.org/10.1093/toxsci/kfae092","url":null,"abstract":"The mechanisms associated with neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have yet to be fully characterized, and genetic as well as environmental factors in their disease etiology are under appreciated. While mutations in genes such as PARKIN and LRRK2 have been linked to PD, the idiopathic component of the disease suggests a contribution of environmental risk factors, including metals, such as copper (Cu). Cu overexposure has been reported to cause oxidative stress and neurotoxicity, but its role in neurodegenerative diseases is rarely studied. Using Caenorhabditis elegans (C. elegans) as a model organism for neurotoxicity, we assessed the effects of Cu oversupply in AD and PD models. Our findings reveal that while copper treatment did not induce neurodegeneration in wildtype worms or the AD model, it significantly exacerbated neurodegeneration in the PD-associated mutants PARKIN and LRRK2. These results suggest that genetic predisposition for PD enhances the sensitivity to copper toxicity, highlighting the multifactorial nature of neurodegenerative diseases. Furthermore, our study provides insight into the mechanisms underlying Cu-induced neurotoxicity in PD models, including disruptions in dopamine levels, altered dopamine-dependent behavior and degraded dopaminergic neurons. Overall, our novel findings contribute to a better understanding of the complex interactions between genetic susceptibility, environmental factors, and neurodegenerative disease pathogenesis, emphasizing the importance of a tightly regulated Cu homeostasis in the etiology of PD.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141775620","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 Brominated Flame Retardant Hexabromocyclododecane Causes Systemic Changes in Polyunsaturated Fatty Acid Incorporation in Mouse Lipids.","authors":"Naomi E Kramer, Jacob Siracusa, Hannah Xu, Lillie Barnett, Morgan C Finnerty, Tai L Guo, John J Wagner, Franklin E Leach, Brian S Cummings","doi":"10.1093/toxsci/kfae094","DOIUrl":"https://doi.org/10.1093/toxsci/kfae094","url":null,"abstract":"<p><p>Brominated flame retardants are used in many household products to reduce flammability, but often leach into the surrounding environment over time. Hexabromocyclododecane (HBCD) is one brominated flame retardant detected in human blood across the world. HBCD exposure can result in neurological problems and altered lipid metabolism, but to date the two remain unlinked. As lipids constitute ∼50% of brain dry weight, lipid metabolism plays a critical role in neuronal function and homeostasis. To determine the effect of HBCD exposure on brain lipid metabolism, young adult male C57BL/6 mice were exposed to 1 mg/kg HBCD every 3 days for 28 days. Major lipid classes were found to change across brain regions, including the membrane glycerolipids phosphatidylcholine and phosphatidylethanolamine, and sphingolipids such as hexosylceramide. In addition, saturated, monounsaturated, and polyunsaturated fatty acids were enriched within brain lipid species. To understand the source of the brain lipidomic alterations, the blood and liver lipidomes and the cecal microbiome were evaluated. The liver and blood demonstrated changes amongst multiple lipid classes, including triacylglycerol suppression, as well as altered esterified fatty acid content. Significant alterations were also detected in the cecal microbiome, with decreases in the Firmicutes to Bacteriodetes ratio, changes in beta diversity, and pathway alterations associated with metabolic pathways and amino acid biosynthesis. These data demonstrate that HBCD can induce lipidomic alterations across brain regions and organs and supports a potential role of the microbiome in these alterations.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749087","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":"Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis.","authors":"Marc Pallardy, Rami Bechara, Jessica Whritenour, Shermaine Mitchell-Ryan, Danuta Herzyk, Herve Lebrec, Hans Merk, Ian Gourley, Wendy J Komocsar, Joseph R Piccotti, Mercedesz Balazs, Amy Sharma, Dana B Walker, Daniel Weinstock","doi":"10.1093/toxsci/kfae046","DOIUrl":"10.1093/toxsci/kfae046","url":null,"abstract":"<p><p>Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response. Consequently, drug allergies are DHRs for which an immunological mechanism, with antibody and/or T cell, is demonstrated. Despite decades of research, methods to predict the potential for a new chemical entity to cause DHRs or to correctly attribute DHRs to a specific mechanism and a specific molecule are not well-established. This review will focus on allergic reactions induced by systemically administered low-molecular weight drugs with an emphasis on drug- and patient-specific factors that could influence the development of DHRs. Strategies for predicting and diagnosing DHRs, including potential tools based on the current state of the science, will also be discussed.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865872","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":"Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs-a proof-of-concept study with doxorubicin.","authors":"Li Pang, Chengzhong Cai, Praful Aggarwal, Dong Wang, Vikrant Vijay, Prathyusha Bagam, Jacob Blamer, Andrea Matter, Amy Turner, Lijun Ren, Katy Papineau, Vinodh Srinivasasainagendra, Hemant K Tiwari, Xi Yang, Laura Schnackenberg, William Mattes, Ulrich Broeckel","doi":"10.1093/toxsci/kfae041","DOIUrl":"10.1093/toxsci/kfae041","url":null,"abstract":"<p><p>Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intraindividual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing interindividual differences in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319225","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":"Towards a more effective REACH legislation in protecting human health.","authors":"Lode Godderis, Evi De Ryck, Willy Baeyens, Lieve Geerts, Griet Jacobs, Phillippe Maesen, Birgit Mertens, Guy Schroyen, Frank Van Belleghem, Jeroen Vanoirbeek, Nicolas Van Larebeke","doi":"10.1093/toxsci/kfae025","DOIUrl":"10.1093/toxsci/kfae025","url":null,"abstract":"<p><p>There is growing evidence indicating the substantial contribution of man-made products to an increase in the risk of diseases of civilization. In this article, the Belgian Scientific Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) Committee gives a critical view on the working of REACH. The current regulatory framework needs to further evolve taking into account data generated using modern science and technology. There is a need for improved assessment process not only before but also after entering the market. Objectivity, transparency, and the follow-up after market access can be optimized. Additionally, no guidance documents exist for regulation of mixture effects. Further, the lengthiness before regulatory action is a big concern. Decision-making often takes several years leading to uncertainties for both producers and end users. A first proposed improvement is the implementation of independent toxicity testing, to assure objectivity, transparency, and check and improve compliance. A \"no data, no market\" principle could prevent access of hazardous chemicals to the market. Additionally, the introduction of novel testing could improve information on endpoints such as endocrine disrupting abilities, neurotoxicity, and immunotoxicity. An adapted regulatory framework that integrates data from different sources and comparing the outputs with estimates of exposure is required. Fast toxicology battery testing and toxicokinetic testing could improve speed of decision-making. Hereby, several improvements have been proposed that could improve the current REACH legislation.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139991272","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":"Trichloroethylene metabolite modulates DNA methylation-dependent gene expression in Th1-polarized CD4+ T cells from autoimmune-prone mice.","authors":"Samrat Roy Choudhury, Stephanie D Byrum, Sarah J Blossom","doi":"10.1093/toxsci/kfae032","DOIUrl":"10.1093/toxsci/kfae032","url":null,"abstract":"<p><p>Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant associated with CD4+ T-cell activation and autoimmune disease. Prior studies showed that exposure to TCE in the drinking water of autoimmune-prone mice expanded effector/memory CD4+ T cells with an interferon-γ (IFN-γ)-secreting Th1-like phenotype. However, very little is known how TCE exposure skews CD4+ T cells towards this pro-inflammatory Th1 subset. As observed previously, TCE exposure was associated with hypermethylation of regions of the genome related to transcriptional repression in purified effector/memory CD4 T cells. We hypothesized that TCE modulates transcriptional and/or epigenetic programming of CD4+ T cells as they differentiate from a naive to effector phenotype. In the current study, purified naive CD4 T cells from both male and female autoimmune-prone MRL/MpJ mice were activated ex vivo and polarized towards a Th1 subset for 4 days in the presence or absence of the oxidative metabolite of TCE, trichloroacetaldehyde hydrate (TCAH) in vitro. An RNA-seq assessment and reduced representation bisulfite sequencing for DNA methylation were conducted on Th1 cells or activated, non-polarized cells. The results demonstrated TCAH's ability to regulate key genes involved in the immune response and autoimmunity, including Ifng, by altering the level of DNA methylation at the gene promoter. Intriguing sex differences were observed and for the most part, the effects were more robust in females compared to males. In conclusion, TCE via TCAH epigenetically regulates gene expression in CD4+ T cells. These results may have implications for mechanistic understanding or future therapeutics for autoimmunity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190149","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":"Emissions from plastic incineration induce inflammation, oxidative stress, and impaired bioenergetics in primary human respiratory epithelial cells.","authors":"Keith Rogers, Elisa WaMaina, Andrew Barber, Syed Masood, Charlotte Love, Yong Ho Kim, M Ian Gilmour, Ilona Jaspers","doi":"10.1093/toxsci/kfae038","DOIUrl":"10.1093/toxsci/kfae038","url":null,"abstract":"<p><p>Inhalation exposure to plastic incineration emissions (PIEs) is a problem of increasing human relevance, as plastic production and waste creation have drastically increased since mainstream integration during the 20th century. We investigated the effects of PIEs on human nasal epithelial cells (HNECs) to understand if such exposures cause damage and dysfunction to respiratory epithelia. Primary HNECs from male and female donors were cultured at air-liquid interface (ALI), and 16HBE cells were cultured on coverslips. Smoke condensates were generated from incineration of plastic at flaming (640°C) and smoldering (500°C) temperatures, and cells were subsequently exposed to these materials at 5-50 μg/cm2 concentrations. HNECs were assessed for mitochondrial dysfunction and 16HBE cells for glutathione oxidation in real-time analyses. HNEC culture supernatants and total RNA were collected at 4-h postexposure for cytokine and gene expression analysis, and results show that PIEs can acutely induce inflammation, oxidative stress, and mitochondrial dysfunction in HNECs, and that incineration temperature modifies biological responses. Specifically, condensates from flaming and smoldering PIEs significantly increased HNEC secretion of cytokines IL-8, IL-1β, and IL-13, as well as expression of xenobiotic metabolism pathways and genes such as CYP1A1 and CYP1B1 at 5 and 20 μg/cm2 concentrations. Only 50 μg/cm2 flaming PIEs significantly increased glutathione oxidation in 16HBEs, and decreased respiration and ATP production in HNEC mitochondria. Impact Statement: Our data reveal the impact of incineration temperatures on biological outcomes associated with PIE exposures, emphasizing the importance of temperature as a factor when evaluating respiratory disease associated with PIEs exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140307028","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":"Assessment of associations between inhaled formaldehyde and lymphohematopoietic cancer through the integration of epidemiological and toxicological evidence with biological plausibility.","authors":"Melissa J Vincent, Seneca Fitch, Lauren Bylsma, Chad Thompson, Sarah Rogers, Janice Britt, Daniele Wikoff","doi":"10.1093/toxsci/kfae039","DOIUrl":"10.1093/toxsci/kfae039","url":null,"abstract":"<p><p>Formaldehyde is recognized as carcinogenic for the portal of entry sites, though conclusions are mixed regarding lymphohematopoietic (LHP) cancers. This systematic review assesses the likelihood of a causal relationship between formaldehyde and LHP cancers by integrating components recommended by NASEM. Four experimental rodent bioassays and 16 observational studies in humans were included following the implementation of the a priori protocol. All studies were assessed for risk of bias (RoB), and meta-analyses were conducted on epidemiological studies, followed by a structured assessment of causation based on GRADE and Bradford Hill. RoB analysis identified systemic limitations precluding confidence in the epidemiological evidence due to inadequate characterization of formaldehyde exposure and a failure to adequately adjust for confounders or effect modifiers, thus suggesting that effect estimates are likely to be impacted by systemic bias. Mixed findings were reported in individual studies; meta-analyses did not identify significant associations between formaldehyde inhalation (when measured as ever/never exposure) and LHP outcomes, with meta-SMRs ranging from 0.50 to 1.51, depending on LHP subtype. No associations with LHP-related lesions were reported in reliable animal bioassays. No biologically plausible explanation linking the inhalation of FA and LHP was identified, supported primarily by the lack of systemic distribution and in vivo genotoxicity. In conclusion, the inconsistent associations reported in a subset of the evidence were not considered causal when integrated with the totality of the epidemiological evidence, toxicological data, and considerations of biological plausibility. The impact of systemic biases identified herein could be quantitatively assessed to better inform causality and use in risk assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319223","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":"The aryl hydrocarbon receptor differentially modulates the expression profile of antibody isotypes in a human B-cell line.","authors":"Mili S Bhakta-Yadav, Kaulini Burra, Nasser Alhamdan, Clayton P Allex-Buckner, Courtney E W Sulentic","doi":"10.1093/toxsci/kfae035","DOIUrl":"10.1093/toxsci/kfae035","url":null,"abstract":"<p><p>2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high affinity ligand for the aryl hydrocarbon receptor (AhR). In animal models, AhR activation by TCDD generally inhibits antibody secretion. However, it is less clear if this translates to human antibody production. Using a human Burkitt lymphoma B-cell line (CL-01) that can be stimulated to secrete Ig and undergo class switch recombination to other Ig isotypes, the current study evaluated the effects of AhR activation or antagonism on the human Ig isotypic expression profile with CD40L+IL-4 stimulation. Our results suggest that AhR agonists (TCDD and indirubin) have little to no effect on IgM or IgA secretion, which were also not induced with stimulation. However, AhR activation significantly inhibited stimulation-induced IgG secretion, an effect reversed by the AhR antagonist CH223191. Evaluation of Ig heavy chain (IgH) constant region gene expression (ie Cμ, Cγ1-4, Cα1-2, and Cε that encode for IgM, IgG1-4, IgA1-2, and IgE, respectively) demonstrated differential effects. While Cμ and Cα2 transcripts were unaffected by stimulation or AhR agonists, AhR activation significantly inhibited stimulation-induced Cγ2-4 and Cε mRNA transcripts, which was reversed by AhR antagonism. Notably, AhR antagonism in the absence of exogenous AhR ligands significantly increased IgG and IgA secretion as well as the expression of Cγ2-4 and Cε. These results suggest that modulation of AhR activity differentially alters the IgH isotypic expression profile and antibody secretion that may be partly dependent on cellular stimulation. Since a variety of chemicals from anthropogenic, industrial, pharmaceutical, dietary, and bacterial sources bind the AhR, the ability of environmental exposures to alter AhR activity (i.e. activate or inhibit) may have a direct influence on immune function and antibody-relevant disease conditions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140207671","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":"Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker substudy).","authors":"Kathleen M Scullion, Iain M MacIntyre, Sian Sloan-Dennison, Benjamin Clark, Paul Fineran, Joanne Mair, David Creasey, Cicely Rathmell, Karen Faulds, Duncan Graham, David J Webb, James W Dear","doi":"10.1093/toxsci/kfae031","DOIUrl":"10.1093/toxsci/kfae031","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194601","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}