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In a zebrafish model, we have shown that acute ethanol exposure at 8\u201310\u00a0hr postfertilization (hpf), a critical time of development, produces birth defects similar to those clinically characterized in FASD. Dysregulation of the Sonic hedgehog (Shh) pathway has been implicated as a molecular basis for many of the birth defects caused by prenatal alcohol exposure. We observed in zebrafish embryos that\n                    <jats:italic>shh<\/jats:italic>\n                    expression was significantly decreased by ethanol exposure at 8\u201310 hpf, while\n                    <jats:italic>smo<\/jats:italic>\n                    expression was much less affected. Treatment of zebrafish embryos with SAG or purmorphamine, small molecule Smoothened agonists that activate Shh signaling, ameliorated the severity of ethanol\u2010induced developmental malformations including altered eye size and midline brain development. Furthermore, this rescue effect of Smo activation was dose dependent and occurred primarily when treatment was given after ethanol exposure. Markers of Shh signaling (\n                    <jats:italic>gli1\/2<\/jats:italic>\n                    ) and eye development (\n                    <jats:italic>pax6a<\/jats:italic>\n                    ) were restored in embryos treated with SAG post\u2010ethanol exposure. Since embryonic ethanol exposure has been shown to produce later\u2010life neurobehavioral impairments, juvenile zebrafish were examined in the novel tank diving test. Our results further demonstrated that in zebrafish embryos exposed to ethanol, SAG treatment was able to mitigate long\u2010term neurodevelopmental impairments related to anxiety and risk\u2010taking behavior. Our results indicate that pharmacological activation of the Shh pathway at specific developmental timing markedly diminishes the severity of alcohol\u2010induced birth defects.\n                  <\/jats:p>","DOI":"10.1002\/jnr.25008","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T04:09:32Z","timestamp":1641874172000},"page":"1585-1601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Pharmacological activation of the Sonic hedgehog pathway with a Smoothened small molecule agonist ameliorates the severity of alcohol\u2010induced morphological and behavioral birth defects in a zebrafish model of fetal alcohol spectrum disorder"],"prefix":"10.1002","volume":"100","author":[{"given":"Derek F.","family":"Burton","sequence":"first","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oswald M.","family":"Boa\u2010Amponsem","sequence":"additional","affiliation":[{"name":"Integrated Biosciences PhD Program North Carolina Central University  Durham North Carolina USA"},{"name":"Julius L. Chambers Biomedical\/Biotechnology Research Institute North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria S.","family":"Dixon","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Te\u2010Andre","family":"Herbin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiquita","family":"Toney","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Tarpley","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise North Carolina Central University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca V.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric W.","family":"Fish","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott E.","family":"Parnell","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina  Chapel Hill North Carolina USA"},{"name":"Department of Cell Biology and Physiology University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory J.","family":"Cole","sequence":"additional","affiliation":[{"name":"Julius L. 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