ArticlePloS one2014
The teratogenic effects of prenatal ethanol exposure are exacerbated by Sonic Hedgehog or GLI2 haploinsufficiency in the mouse.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 124 citations in OpenAlex.
- A cell-based Sonic Hedgehog signaling transduction system to identify additive and synergistic chemical interactions.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- The Role of the Hedgehog Pathway in Alcohol-Induced Birth Defects.Advances in experimental medicine and biology · 2026Review
- Cranial base synostosis in mice caused by upregulation of Wnt following partial inhibition of Shh.BMC biology · 2025Article
- Article
- foxe1 mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations.Developmental dynamics : an official publication of the American Association of Anatomists · 2025Article
- Bone morphogenetic protein signaling pathway- Ethanol interactions disrupt palate formation independent of gata3.Reproductive toxicology (Elmsford, N.Y.) · 2025Article
- Efcab7 deletion sensitizes mice to the teratogenic effects of gastrulation-stage alcohol exposure.Reproductive toxicology (Elmsford, N.Y.) · 2024Article
- Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes.Biomolecules · 2024Article
- Article
- Fetal alcohol spectrum disorders.Nature reviews. Disease primers · 2023Review
- Short-term transcriptomic changes in the mouse neural tube induced by an acute alcohol exposure.Alcohol (Fayetteville, N.Y.) · 2023Article
- High-throughput detection of craniofacial defects in fluorescent zebrafish.Birth defects research · 2023Article
- The role of genes and environment in the etiology of congenital diaphragmatic hernias.Current topics in developmental biology · 2023Review
- Gene-alcohol interactions in birth defects.Current topics in developmental biology · 2023Article
- Gene-environment interactions in birth defect etiology: Challenges and opportunities.Current topics in developmental biology · 2023Review
- Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders.BMC medicine · 2022Article
- Pharmacological activation of the Sonic hedgehog pathway with a Smoothened small molecule agonist ameliorates the severity of alcohol-induced morphological and behavioral birth defects in a zebrafish model of fetal alcohol spectrum disorder.Journal of neuroscience research · 2022Article
- Analysis of Gene-Environment Interactions Related to Developmental Disorders.Frontiers in pharmacology · 2022Review
- Fetal Alcohol Spectrum Disorders: Awareness to Insight in Just 50 Years.Alcohol research : current reviews · 2022Article
- Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube.Reproductive toxicology (Elmsford, N.Y.) · 2021Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Disruption of the Hedgehog signaling pathway has been implicated as an important molecular mechanism in the pathogenesis of fetal alcohol syndrome. In severe cases, the abnormalities of the face and brain that result from prenatal ethanol exposure fall within the spectrum of holoprosencephaly. Single allele mutations in the Hh pathway genes Sonic Hedgehog (SHH) and GLI2 cause holoprosencephaly with extremely variable phenotypic penetrance in humans. Here, we tested whether mutations in these genes alter the frequency or severity of ethanol-induced dysmorphology in a mouse model. Timed pregnancies were established by mating Shh(+/-) or Gli2(+/-) male mice backcrossed to C57BL/6J strain, with wildtype females. On gestational day 7, dams were treated with two i.p. doses of 2.9 g/kg ethanol (or vehicle alone), administered four hrs apart. Fetuses were then genotyped and imaged, and the severity of facial dysmorphology was assessed. Following ethanol exposure, mean dysmorphology scores were increased by 3.2- and 6.6-fold in Shh(+/-) and Gli2(+/-) groups, respectively, relative to their wildtype littermates. Importantly, a cohort of heterozygous fetuses exhibited phenotypes not typically produced in this model but associated with severe holoprosencephaly, including exencephaly, median cleft lip, otocephaly, and proboscis. As expected, a correlation between the severity of facial dysmorphology and medial forebrain deficiency was observed in affected animals. While Shh(+/-) and Gli2(+/-) mice have been described as phenotypically normal, these results illustrate a functional haploinsufficiency of both genes in combination with ethanol exposure. By demonstrating an interaction between specific genetic and environmental risk factors, this study provides important insights into the multifactorial etiology and complex pathogenesis of fetal alcohol syndrome and holoprosencephaly.
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