Maternal effects on ethanol teratogenesis in a cross between A/J and C57BL/6J mice

Genetic factors influence adverse pregnancy outcome in both humans and animal models. Animal research reveals that both the maternal and fetal genetic profiles are important for determining the risk of physical birth defects and prenatal mortality. Using a reciprocal-cross breeding design, we investigated whether the mother's genes may be more important than fetal genes in determining risk for ethanol teratogenesis. Examination of possible synergistic genetic effects on ethanol teratogenesis was made possible by using two mouse strains known to be susceptible to specific malformations. Inbred A/J (A) and C5713L/6J (B6) mice were mated to produce four fetal genotype groups: the true-bred A.A and B6.B6 genotypes and the genetically identical A.B6 and B6.A genotypes (the F(1) genotype). Dams were administered either 5.8 g/kg ethanol or an isocaloric amount of maltose-dextrin on day 9 of pregnancy. Fetuses were removed by laparotomy on gestation day 18, weighed, and assessed for digit, vertebral, and kidney malformations. Digit malformations in the genetically identical F(1) ethanol-exposed litters showed a pattern consistent with a maternal genetic effect (A.B6 [2%] and B6.A [30%]). In contrast, vertebral malformations were similar in all ethanol-exposed litters (A.A 26%], A.B6 [18%], B6.A [22%], and B6.B6 [33%]). The percentage of malformations did not differ between male and female fetuses, indicating sex-linked factors are not responsible for the maternal effect. Ethanol exposure decreased litter weights but did not affect litter mortality compared with maltose-exposed controls. This study supports the idea that genes influence malformation risk following in utero alcohol exposure. Specifically, maternal genes influence risk more than fetal genes for some teratogenic outcomes. No evidence supported synergistic genetic effects on ethanol teratogenesis. This research supports the conclusion that uterine environment contributes to determining risk of Fetal Alcohol Spectrum Disorder. (C) 2011 Elsevier Inc. All rights reserved.