{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:57:51Z","timestamp":1792673871726,"version":"4.5.0"},"reference-count":51,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,2,11]],"date-time":"2014-02-11T00:00:00Z","timestamp":1392076800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Fetal alcohol spectrum disorders (<jats:styled-content style=\"fixed-case\">FASD<\/jats:styled-content>) are a leading cause of neurodevelopmental disability. Nonhuman animal models offer novel insights into its underlying mechanisms. Although the developing zebrafish has great promise for <jats:styled-content style=\"fixed-case\">FASD<\/jats:styled-content> research, a significant challenge to its wider adoption is the paucity of clear, mechanistic parallels between its ethanol (EtOH) responses and those of nonpiscine, established models. Inconsistencies in the published pharmacodynamics for EtOH\u2010exposed zebrafish, alongside the use of comparatively high EtOH doses, challenge the interpretation of this model's clinical relevance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address these limitations, we developed a binge, single\u2010exposure model of EtOH exposure in the early zebrafish embryo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Brief (3\u2010hour) EtOH exposure is sufficient to cause significant neural crest losses and craniofacial alterations, with peak vulnerability during neurogenesis and early somitogenesis. These losses are apoptotic, documented using <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content> assay and <jats:styled-content style=\"fixed-case\"><jats:italic>secA5<\/jats:italic><\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\"><jats:italic>YFP<\/jats:italic><\/jats:styled-content>\u2010reporter fish. Apoptosis is dose dependent with an EC50\u00a0=\u00a056.2\u00a0\u00b1\u00a014.3\u00a0mM EtOH<jats:sub>int<\/jats:sub>, a clinically relevant value within the range producing apoptosis in chick and mouse neural crest. This apoptosis requires the calcium\u2010dependent activation of <jats:styled-content style=\"fixed-case\">CaMKII<\/jats:styled-content> and recapitulates the well\u2010described EtOH signaling mechanism in avian neural crest. Importantly, we resolve the existing confusion regarding zebrafish EtOH kinetics. We show that steady\u2010state EtOH concentrations within both chorion\u2010intact and dechorionated embryos are maintained at 35.7\u00a0\u00b1\u00a02.8% of EtOH<jats:sub>ext<\/jats:sub> levels across the range from 50 to 300\u00a0mM EtOH<jats:sub>ext<\/jats:sub>, a value consistent with several published reports. Equilibrium is rapid and complete within 5\u00a0minutes of EtOH addition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The calcium\/<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>a<jats:styled-content style=\"fixed-case\">MKII<\/jats:styled-content> mechanism of EtOH's neurotoxicity is shared between an amniote (chick) and teleost fish, indicating that this mechanism is evolutionarily conserved. Our data suggest that EtOH<jats:sub>ext<\/jats:sub> concentrations &gt;2% (v\/v) for chorion\u2010intact embryos and 1.5% (v\/v) for dechorionated embryos have limited clinical relevance. The strong parallels with established models endorse the zebrafish's relevance for mechanistic studies of EtOH's developmental neurotoxicity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.12360","type":"journal-article","created":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T10:35:15Z","timestamp":1392201315000},"page":"1255-1265","source":"Crossref","is-referenced-by-count":53,"title":["An Evolutionarily Conserved Mechanism of Calcium\u2010Dependent Neurotoxicity in a Zebrafish Model of Fetal Alcohol Spectrum Disorders"],"prefix":"10.1111","volume":"38","author":[{"given":"George R.","family":"Flentke","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin\u2010Madison Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah H.","family":"Klingler","sequence":"additional","affiliation":[{"name":"School of Freshwater Sciences University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Tanguay","sequence":"additional","affiliation":[{"name":"Department of Molecular Environmental Toxicology Oregon State University Corvallis Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Michael J.","family":"Carvan","sequence":"additional","affiliation":[{"name":"School of Freshwater Sciences University of Wisconsin\u2010Milwaukee Milwaukee Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin\u2010Madison Madison 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