{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:42:34Z","timestamp":1790714554813,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,3,4]],"date-time":"2016-03-04T00:00:00Z","timestamp":1457049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5\u2009days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization. Morphological effects of hepatotoxic compounds (acetaminophen, amiodarone, coumarin, methapyrilene and myclobutanil) and saccharin as the negative control were assessed after exposure in zebrafish larvae. The hepatotoxic compounds induced the expected zebrafish liver degeneration or changes in size, whereas saccharin did not have any phenotypic adverse effect. Analytical methods based on liquid chromatography\u2013mass spectrometry were optimized to measure stability of selected compounds in exposure medium and internal concentration in larvae. All compounds were stable, except amiodarone for which precipitation was observed. There was a wide variation between the levels of compound in the zebrafish larvae with a higher uptake of amiodarone, methapyrilene and myclobutanil. Detection of hepatocyte markers (<jats:italic>CP<\/jats:italic>, <jats:italic>CYP3A65<\/jats:italic>, <jats:italic>GC<\/jats:italic> and <jats:italic>TF<\/jats:italic>) was accomplished by <jats:italic>in situ<\/jats:italic> hybridization of larvae to coumarin and myclobutanil and confirmed by real\u2010time reverse transcription\u2013quantitative polymerase chain reaction. Experiments showed decreased expression of all markers. Next, other liver\u2010specific biomarkers (i.e. <jats:italic>FABP10a<\/jats:italic> and <jats:italic>NR1H4<\/jats:italic>) and apoptosis (i.e. <jats:italic>CASP\u20103\u2009A<\/jats:italic> and <jats:italic>TP53<\/jats:italic>) or cytochrome P450\u2010related (<jats:italic>CYP2K19<\/jats:italic>) and oxidoreductase activity\u2010related (<jats:italic>ZGC163022<\/jats:italic>) genes, were screened. Links between basic mechanisms of liver injury and results of biomarker responses are described. Copyright \u00a9 2016 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.3288","type":"journal-article","created":{"date-parts":[[2016,3,6]],"date-time":"2016-03-06T03:38:16Z","timestamp":1457235496000},"page":"1194-1206","source":"Crossref","is-referenced-by-count":37,"title":["Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity"],"prefix":"10.1002","volume":"36","author":[{"given":"Sandra","family":"Verstraelen","sequence":"first","affiliation":[{"name":"VITO NV, Applied Bio &amp; Molecular Systems  Boeretang 200 B\u20102400 Mol Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Peers","sequence":"additional","affiliation":[{"name":"GIGA\u2010R, University of Li\u00e8ge  Avenue de l'Hopital 1, B34 B\u20104000 Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Maho","sequence":"additional","affiliation":[{"name":"Toxicological Center University of Antwerp  Universiteitsplein 1 B\u20102610 Wilrijk Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Hollanders","sequence":"additional","affiliation":[{"name":"VITO NV, Applied Bio &amp; Molecular Systems  Boeretang 200 B\u20102400 Mol Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Remy","sequence":"additional","affiliation":[{"name":"VITO NV, Applied Bio &amp; Molecular Systems  Boeretang 200 B\u20102400 Mol Belgium"},{"name":"Epidemiology and Social Medicine University of Antwerp  Universiteitsplein 1 B\u20102610 Wilrijk Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Berckmans","sequence":"additional","affiliation":[{"name":"VITO NV, Applied Bio &amp; Molecular Systems  Boeretang 200 B\u20102400 Mol Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Covaci","sequence":"additional","affiliation":[{"name":"Toxicological Center University of Antwerp  Universiteitsplein 1 B\u20102610 Wilrijk Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda","family":"Witters","sequence":"additional","affiliation":[{"name":"VITO NV, Applied Bio &amp; Molecular Systems  Boeretang 200 B\u20102400 Mol Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2010.493960"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1191\/0960327102ht247oa"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2005.049908"},{"key":"e_1_2_9_5_1","first-page":"145","article-title":"The role of p53 in apoptosis","volume":"9","author":"Amaral JD","year":"2010","journal-title":"Discov. 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