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The 129S1/SvImJ Mouse Strain Is Resistant to the Effects of Early Embryonic Alcohol and Other Sonic Hedgehog
Ruby L Lapham1, Eric W Fish1, Scott E Parnell1,2
1Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, USA.
Background:
Prenatal alcohol exposure can cause fetal alcohol syndrome, but genetic variation can account for some of the observed differential susceptibility to alcohol-induced birth defects. Here we investigate an inbred mouse strain, 129S1/SvImJ (129S1), for its potential susceptibility to alcohol- and Sonic hedgehog pathway inhibitor-induced craniofacial birth defects and the ways complex genetic factors work to alter susceptibility compared to the highly alcohol-susceptible strain, the C57BL/6J (B6J).
Methods:
129S1 pregnant females were treated with alcohol (two doses of 2.9 g/kg), CP-55,940 (2.0 mg/kg), vismodegib (40 or 80 mg/kg), or smoothened agonist (12 mg/kg) during gastrulation or neurulation, then fetuses were assessed for defects. Gastrulation- and neurulation-stage embryo gene expression and apoptosis were also analyzed.
Results:
129S1 mice are completely resistant to alcohol-induced craniofacial birth defects despite high blood alcohol concentrations compared to other alcohol-susceptible mouse strains. This strain is also resistant to craniofacial birth defects after exposure to a synthetic cannabinoid, CP-55,940, and vismodegib. All three drugs inhibit the Sonic hedgehog (Shh) pathway. 129S1 embryos have higher basal expression of two key Shh-related mRNAs, Smo and Efcab7, and lower apoptosis after alcohol compared to B6J embryos. 129S1 embryos are more susceptible to birth defects after treatment with a Shh pathway agonist, smoothened agonist (SAG), than B6J embryos.
Conclusions:
129S1 embryos have higher expression of key Shh pathway genes and low apoptosis after alcohol, which may contribute to the alcohol-resistant phenotype seen in the 129S1/SvImJ strain, adding to the understanding of protective genetic factors in alcohol teratogenesis.
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