Paternal Genetic Contribution Influences Fetal Vulnerability to Maternal Alcohol Consumption in a Rat Model of Fetal Alcohol Spectrum Disorder

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.

Candidate Placental Biomarkers for Intrauterine Alcohol Exposure

“…As reported previously, males had higher birth weight than females (Sittig and Redei, 2010; Wilcoxon and Redei, 2004) (Table 1, F[1, 22]= 4.48, p<0.05).…”

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System

“…Pregnant dams were sacrificed by decapitation on GD21 between 0900h and 1100h as previously described (Sittig and Redei, 2010). The uterine horns were quickly removed and placed on ice.…”

Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats

“…Sprague-Dawley (S, Harlan - Indianapolis, IN) and Brown Norway (B, Charles River – Wilmington, MA) rats were housed in a climate-controlled environment with a 14:10 hour light/dark cycle (lights on at 6am) with water provided ad libitum throughout the duration of the study. We chose these strains with the knowledge that B is the most phylogenetically divergent inbred rat strain from all others, and S is the most commonly utilized outbred strain (Swerdlow et al, 2008) that has also been employed in all our previous studies (Sittig and Redei, 2010; Wilcoxon et al, 2005). The B and S genomes have been sequenced by the Rat Genome Project and Celera respectively, and therefore, allele-specific expression in imprinted genes can be explored in these crosses as we have done previously (Sittig et al, 2011b).…”

“…Plasma was collected from trunk blood was used for measurements of free T3 (fT3). fT3 levels were measured by RIA as described previously (Sittig and Redei, 2010). Assay was manufactured by MP Biomedicals, LLC (Irvine, CA, USA) and the assay sensitivity and coefficient of variation were 0.6 pg/ml and 8%, respectively.…”