Abstract
BackgroundFetal alcohol exposure causes in the offspring a collection of permanent physiological and neuropsychological deficits collectively termed Fetal Alcohol Spectrum Disorder (FASD). The timing and amount of exposure cannot fully explain the substantial variability among affected individuals, pointing to genetic influences that mediate fetal vulnerability. However, the aspects of vulnerability that depend on the mother, the father, or both, are not known.Methodology/Principal FindingsUsing the outbred Sprague-Dawley (SD) and inbred Brown Norway (BN) rat strains as well as their reciprocal crosses, we administered ethanol (E), pair-fed (PF), or control (C) diets to the pregnant dams. The dams' plasma levels of free thyroxine (fT4), triiodothyronine (T3), free T3 (fT3), and thyroid stimulating hormone (TSH) were measured to elucidate potential differences in maternal thyroid hormonal environment, which affects specific aspects of FASD. We then compared alcohol-exposed, pair fed, and control offspring of each fetal strain on gestational day 21 (G21) to identify maternal and paternal genetic effects on bodyweight and placental weight of male and female fetuses.ConclusionsSD and BN dams exhibited different baseline hypothalamic-pituitary-thyroid function. Moreover, the thyroid function of SD dams was more severely affected by alcohol consumption while that of BN dams was relatively resistant. This novel finding suggests that genetic differences in maternal thyroid function are one source of maternal genetic effects on fetal vulnerability to FASD. The fetal vulnerability to decreased bodyweight after alcohol exposure depended on the genetic contribution of both parents, not only maternal contribution as previously thought. In contrast, the effect of maternal alcohol consumption on placental weight was consistent and not strain-dependent. Interestingly, placental weight in fetuses with different paternal genetic contributions exhibited opposite responses to caloric restriction (pair feeding). In summary, these novel findings demonstrate both maternal and paternal genetic contributions to in utero vulnerability to alcohol, refining our understanding of the genetically-based heterogeneity seen in human FASD.
Highlights
Alcohol consumption during pregnancy can result in fetal alcohol spectrum disorder (FASD), a constellation of disabilities including deficient pre- and postnatal growth, morphological malformations of the face and/or brain, and cognitive and behavioral deficits [1]
The thyroid function of SD dams was more severely affected by alcohol consumption while that of Brown Norway (BN) dams was relatively resistant
This novel finding suggests that genetic differences in maternal thyroid function are one source of maternal genetic effects on fetal vulnerability to Fetal Alcohol Spectrum Disorder (FASD)
Summary
Alcohol consumption during pregnancy can result in fetal alcohol spectrum disorder (FASD), a constellation of disabilities including deficient pre- and postnatal growth, morphological malformations of the face and/or brain, and cognitive and behavioral deficits [1] These teratological outcomes vary significantly among individuals with respect to range and severity even after allowing for the effects of timing, duration, and amount of alcohol exposure, suggesting that genetic vulnerability may contribute to the etiology of FASD [2]. Animal studies using a single dosage of ethanol during pregnancy show that different mouse strains exhibit different severities of morphological and fetal weight deficits after alcohol exposure, which the authors attributed primarily to maternal genetic effects [8,9,10] These data together with the observations in human alcohol-exposed twins suggest that paternal genetic influences may directly impact fetal susceptibility to alcohol. The aspects of vulnerability that depend on the mother, the father, or both, are not known
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