The 129S1 / SvImJ Mouse Strain Is Resistant to the Effects of Early Embryonic Alcohol and Other Sonic Hedgehog Inhibitors

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.