Maternal Genetic Effects on Ethanol Teratogenesis and Dominance of Relative Embryonic Resistance to Malformations

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Abstract
Maternal genetic factors and/or fetal genetic factors contribute to variations in response to prenatal alcohol exposure. To assess the contribution of maternal genotype to ethanol teratogenesis, a reciprocal cross study was conducted in an animal model using C57BL/6J (B6) and long‐sleep (LS) mice. B6 mice are more susceptible than LS mice to prenatal ethanol‐induced malformations but both mouse stocks are susceptible to fetal weight deficits following in utero alcohol exposure. B6 and LS dams were reciprocally mated to B6 or LS males producing four embryonic genotype groups: the true‐bred B6B6 and LSLS genotypes, and the genetically similar B6LS and LSB6 genotypes (the F1 genotype). Dams were intubated with either 5.8 g/kg ethanol (E) or an isocaloric amount of sucrose (S) on day 9 of pregnancy. Fetuses were removed on gestation day 18, weighed, and assessed for soft tissue or skeletal malformations. Results showed a greater litter weight deficit and increased total malformation rate in ethanol‐exposed F1 litters carried by B6 mothers compared to ethanol‐exposed F1 litters carried by LS mothers. This result would be expected only if maternal genetic factors contribute significantly towards susceptibility to ethanol teratogenesis. The influence of the LS mother was to decrease susceptibility to ethanol teratogenesis compared to the B6 mother while the influence of the B6 mother was to increase susceptibility to ethanol teratogenesis compared to the LS mother.The average malformation rate for F1 litters was significantly less than the predicted midparental value. This shows that the F1 genotype exhibited dominance towards resistance to prenatal alcohol effects. There was no differential effect of prenatal treatment on male and female fetuses for any embryonic genotype, indicating that the differential teratogenic response between F1 litters was not due to sex‐linked traits. Likewise, weight gain due to pregnancy and maternal blood ethanol levels did not differ among genotypes.It was concluded that genetic factors differentially influence maternal physiological response to ethanol, which in turn affects teratogenic responses in F1 litters. Separation of maternal physiological mechanisms from fetal mechanisms responsible for ethanol teratogenic susceptibility is needed for targeting women and infants at risk. Such knowledge will help in formulating effective therapeutic intervention strategies.