Chronic Binge Alcohol Exposure During Pregnancy Impairs Rat Maternal Uterine Vascular Function

Abstract

Background Alcohol exposure during pregnancy results in an array of structural and functional abnormalities called Fetal Alcohol Spectrum Disorders (FASD). Alcohol dysregulates the exquisite coordination and regulation of gestational adaptations at the level of the uterine vasculature. We herein hypothesized that chronic binge-like alcohol impairs maternal uterine artery reactivity to vasoconstrictors and dilators and that alcohol-induced vascular dysfunction is dependent on the endothelium. Methods We utilized a once-daily binge alcohol (4.5 g/kg body weight) exposure paradigm (gestational day (GD) 7-17) in a pregnant rat model system and investigated primary uterine artery function in response to vasoconstrictors and vasodilators utilizing wire myography. Results Alcohol (peak blood alcohol concentration, 216 mg/dl) produced uterine vascular dysfunction in the absence of grossly observable growth deficits in maternal and fetal body weights, fetal crown-rump length and placental weight. Alcohol did not produce altered uterine vascular reactivity to α1 adrenergic agonist phenylephrine or the prostanoid thromboxane. However, alcohol specifically impaired endothelium-dependent acetylcholine (Ach)-mediated uterine artery vasodilation but exogenous endothelium-independent vasodilators like sodium nitroprusside exhibited no alcohol effect; Ach significantly decreased vessel relaxation (P=0.003; ↓pD2 (negative log molar Ach concentration producing the half maximum response), −7.004±0.215 vs. −6.310±0.208; EMax (maximal Ach response), 92% vs. 75%). Conclusion We conclude that moderate alcohol exposure impairs uterine vascular function in pregnant mothers. Alcohol specifically impairs endothelium-dependent agonist-induced uterine artery vasodilation. In summary, the maternal uterine compartment may play a significant role in the pathogenesis of FASD. Thus, the mechanistic targets of alcohol at the level of both the mother and the fetus need to be considered in order to develop effective therapeutic treatment strategies for FASD.

Dose effect of gestational ethanol exposure on placentation and fetal growth

“…For example, prenatal alcohol exposure could alter fetal programming and induce epigenetic effect, but information along these lines is lacking. Furthermore, evidence suggests that the manner of ethanol exposure impacts placental development and function since repeated binge exposures adversely affect maternal uterine vasculature [33], whereas moderate exposures impair agonist-induced uterine artery vasodilation [34]. Further studies are needed to determine if maternal binge drinking increases susceptibility or alters duration of alcohol-induced vasoconstriction in placental bed vessels.…”

Chronic Binge Alcohol Exposure During Pregnancy Alters mTOR System in Rat Fetal Hippocampus

“…Animals were assigned to either a pair‐fed control (PF‐Cont) group ( n = 5 dams) or a binge alcohol treatment (Alcohol) group ( n = 5 dams) on gestational day (GD) 4. Alcohol group animals were acclimatized via a once‐daily orogastric gavage of 4.5 g/kg (22.5% wt/v) ethanol [peak blood alcohol concentration (BAC), 216 mg/dl] from GD 5–10, and progressed to 6.0 g/kg (28.5% wt/v) ethanol (peak BAC, 289 mg/dl) from GD 11–21 (Davis‐Anderson et al, 2018; Subramanian et al, 2014). The exposure paradigm utilized in this study is modeled after alcohol consumption patterns in pregnant women and is commonly utilized to study FASD phenotypes in animal models (Caetano et al, 2006; Church and Gerkin, 1988; Cudd et al, 2002; Thomas et al, 2010; Thomas et al, 2008).…”

Fetal regional brain protein signature in FASD rat model

“…The prenatal model of binge alcohol exposure used in this study is based on previously established rodent models of FASD (29, 30). The alcohol group animals were acclimatized via a dosing regimen of 22.5% (wt/v) ethanol (4.5 g/kg) between GD 5–10 (31), followed by 28.5% ethanol (6 g/kg) on GD 11–20. In a separate set of dams, blood from the tail vein was collected for BAC measurement following the 6 g/kg alcohol dose on GD 11.…”