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These exposures cause a range of structural and neurological defects, including facial dysmorphologies, collectively known as fetal alcohol spectrum disorders (FASD). While PAE causes FASD, phenotypic outcomes vary widely. It is thought that multifactorial genetic and environmental interactions modify the effects of PAE. However, little is known of the nature of these modifiers. Disruption of the Hedgehog (Hh) signaling pathway has been suggested as a modifier of ethanol teratogenicity. In addition to regulating the morphogenesis of craniofacial tissues commonly disrupted in FASD, a core member of the Hh pathway, Smoothened, is susceptible to modulation by structurally diverse chemicals. These include environmentally prevalent teratogens like piperonyl butoxide (PBO), a synergist found in thousands of pesticide formulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we characterize multifactorial genetic and environmental interactions using a zebrafish model of craniofacial development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that loss of a single allele of <jats:italic>shha<\/jats:italic> sensitized embryos to both alcohol\u2010 and PBO\u2010induced facial defects. Co\u2010exposure of PBO and alcohol synergized to cause more frequent and severe defects. The effects of this co\u2010exposure were even more profound in the genetically susceptible <jats:italic>shha<\/jats:italic> heterozygotes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Together, these findings shed light on the multifactorial basis of alcohol\u2010induced craniofacial defects. In addition to further implicating genetic disruption of the Hh pathway in alcohol teratogenicity, our findings suggest that co\u2010exposure to environmental chemicals that perturb Hh signaling may be important variables in FASD and related craniofacial disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14427","type":"journal-article","created":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T05:39:50Z","timestamp":1596865190000},"page":"1988-1996","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol\u2010Induced Craniofacial Defects"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2887-8574","authenticated-orcid":false,"given":"Joshua L.","family":"Everson","sequence":"first","affiliation":[{"name":"From the Department of Molecular Biosciences School of Natural Sciences 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