PUBLICATION
Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol-Induced Craniofacial Defects
- Authors
- Everson, J.L., Batchu, R., Eberhart, J.K.
- ID
- ZDB-PUB-200810-28
- Date
- 2020
- Source
- Alcoholism, clinical and experimental research 44(10): 1988-1996 (Journal)
- Registered Authors
- Eberhart, Johann
- Keywords
- Birth defect, FASD, PAE, craniofacial, gene-environment interactions
- MeSH Terms
-
- Animals
- Craniofacial Abnormalities/chemically induced*
- Craniofacial Abnormalities/embryology
- Craniofacial Abnormalities/metabolism
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects
- Ethanol/adverse effects*
- Gene-Environment Interaction*
- Hedgehog Proteins/antagonists & inhibitors*
- Hedgehog Proteins/metabolism
- Piperonyl Butoxide/pharmacology
- Signal Transduction/drug effects*
- Teratogens/pharmacology
- Zebrafish/abnormalities
- Zebrafish/embryology
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/metabolism
- PubMed
- 32767777 Full text @ Alcoholism Clin. Exp. Res.
- CTD
- 32767777
Citation
Everson, J.L., Batchu, R., Eberhart, J.K. (2020) Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol-Induced Craniofacial Defects. Alcoholism, clinical and experimental research. 44(10):1988-1996.
Abstract
Background Prenatal alcohol exposure 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 prenatal alcohol exposure causes FASD, phenotypic outcomes vary widely. It is thought that multifactorial genetic and environmental interactions modify the effects of prenatal alcohol exposure. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping