Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol‐Induced Craniofacial Defects. (30th August 2020)

• Record Type: Journal Article
• Authors: Everson, Joshua L.; Batchu, Rithik; Eberhart, Johann K.
• Is Part Of: Alcoholism. Volume 44:Number 10(2020)
• Page Start: 1988
• Page End: 1996
• Publication Date: 2020-08-30
• Subjects: Birth Defect -- Prenatal Alcohol Exposure -- Fetal Alcohol Spectrum Disorders -- Gene -- Environment Interactions -- Craniofacial; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14427
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract : Background: Prenatal alcohol exposure (PAE) is perhaps the most common environmental cause of human birth defects. 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. Methods: Here, we characterize multifactorial genetic and environmental interactions using a zebrafish model of craniofacial development. Results: We show that loss of a single allele of shha sensitized embryos to both alcohol‐ and PBO‐induced facial defects. Co‐exposure of PBO and alcohol synergized to cause more frequent and severe defects. The effects of this co‐exposure were even more profound in the genetically susceptible shha heterozygotes. Conclusions: Together, these findings shed light on the multifactorial basis of alcohol‐induced craniofacial defects. In addition to further implicating genetic disruption of the Hh pathway in alcohol teratogenicity, our findings suggest that co‐exposure to environmental chemicals that perturb Hh signaling may be important variables in FASD and related craniofacial disorders. Abstract : Prenatal alcohol exposure is a major cause of craniofacial birth defects in humans, but outcomes vary widely. Using zebrafish, we tested the hypothesis that genetic predisposition or co‐exposure to additional environmental toxicants can interact with alcohol to worsen craniofacial defects. We identified synergistic interactions between three factors: alcohol, the common pesticide synergist and recently identified Hedgehog pathway inhibitor piperonyl butoxide (PBO), and mutations in the Hedgehog pathway. Together, this work demonstrates multifactorial interactions can exacerbate alcohol‐induced craniofacial defects.