Effects of Acute Prenatal Ethanol Administration in a Reciprocal Cross of C57BL/6J and Short‐Sleep Mice: Maternal Effects and Nonmaternal Factors

Abstract

An animal model was used to see if maternal genetic factors contribute to ethanol-induced fetal malformations. Susceptible C57BL/6J (B6) and resistant Short-Sleep (SS) mice were used in a reciprocal cross-breeding design. This design produced four fetal genotypes: true-bred B6B6 and SSSS liters and hybrid B6SS and SSB6 litters. Dams were intubated with either 5.8 g/kg of ethanol or an isocaloric amount of maltose-dextrin on day 9 of pregnancy. Fetuses were removed on day 18 of pregnancy and assessed for soft tissue and gross malformations. Results show different prenatal treatment effects on malformations depending on the fetal genotype. Mean percentage of total malformations in ethanol-treated groups were 61% (B6B6), 28% (B6SS), 3% (SSB6), and 16% (SSSS), respectively. Litters exposed to maltose-dextrin showed low (< or = 4%) malformation rates regardless of fetal genotype. The difference in teratogenic response between genetically identical hybrid litters (B6SS and SSB6) suggests a maternal genetic contribution to susceptibility. Of the two major types of malformations, forelimb but not kidney malformations showed a pattern characteristic of a maternal genetic effect. It was concluded that maternal genetic effects can be distinguished from fetal genetic effects responsible for ethanol teratogenesis. Genetically based physiological responses to alcohol in the mother may confer varying degrees of risk for prenatal alcohol effects in the child.

Alcohol dehydrogenase 1B genotype and fetal alcohol syndrome: a HuGE minireview

“…These distinctions were observed for the hybrid, genetically similar progeny, consistent with maternal genetic factors contributing to susceptibility. Gilliam et al 23 had similar findings, except that fetal, not maternal, genotype conferred susceptibility to fetal weight deficits. Gilliam and Irtenkauf 22 and Gilliam et al 23 found that ethanol-exposed progeny with different genotypes that were carried by the same maternal strain showed distinct rates of malformation, indicating that fetal genotype also plays a role in susceptibility.…”

“…Gilliam et al 23 had similar findings, except that fetal, not maternal, genotype conferred susceptibility to fetal weight deficits. Gilliam and Irtenkauf 22 and Gilliam et al 23 found that ethanol-exposed progeny with different genotypes that were carried by the same maternal strain showed distinct rates of malformation, indicating that fetal genotype also plays a role in susceptibility. However, in both cases, the effect was only significant when progeny were carried by the more susceptible maternal strain, indicating that maternal genotype had a greater influence than fetal genotype on susceptibility to ethanol teratogenesis.…”

“…[21][22][23][24] Those studies, which could distinguish between maternal and fetal genotypic effects, found that both maternal and fetal genetic factors contributed significantly to susceptibility to ethanol teratogenesis. 22,23 For example, Gilliam and Irtenkauf 22 found a greater litter weight deficit and increased malformation rate in ethanol-exposed litters carried by the C57BL/6J strain of mice compared with those carried by the LS strain when the 2 strains were crossed. These distinctions were observed for the hybrid, genetically similar progeny, consistent with maternal genetic factors contributing to susceptibility.…”

Subtle decreases in DNA methylation and gene expression at the mouse Igf2 locus following prenatal alcohol exposure: effects of a methyl-supplemented diet

“…Animal models, particularly mice, have proven to be an invaluable resource for investigating genetic influences on many phenotypes, including several prenatal alcohol traits. Both inbred and selectively bred mice can differ in susceptibility to many of the detrimental effects of in utero ethanol exposure, which provides additional support for the importance of genetics in the development of FASD (Boehm et al, 1997; Downing et al, 2009; Giknis et al, 1980; Gilliam et al, 1989, 1997; Webster et al, 1980). …”

Genetic Influences on Craniofacial Outcome in an Avian Model of Prenatal Alcohol Exposure

“…Allelic differences in alcohol dehydrogenases affect maternal blood alcohol levels, the dose that reaches the embryo, and thus FAS risk (Chernoff, 1980;Giknis et al, 1980;McCarver et al, 1997). Gilliam and colleagues documented mouse strains that exhibit distinct ethanol-induced dysmorphologies in response to equivalent maternal blood alcohol levels and exposure windows; they reported differential sensitivities to limb and urogenital defects, learning deficits, postnatal growth, and brain reductions (Boehm et al, 1997;Gilliam and Kotch, 1996;Gilliam et al, 1987Gilliam et al, , 1997Goodlett et al, 1989). Chick strains also exhibit differential sensitivity with respect to mortality, growth, cardiac deficits, and ethanol-induced cell death (Becker and Shibley, 1998;Bruyere and Stith, 1993;Debelak and Smith, 2000).…”