Research
Basic science: Obstetrics
Fetal alcohol syndrome: cardiac birth defects in mice and prevention with folate

Presented at the American Heart Association Scientific Sessions 2009, Orlando, FL, Nov. 18, 2009.
https://doi.org/10.1016/j.ajog.2010.03.017Get rights and content

Objective

Alcohol (ethanol) consumption during pregnancy is linked to congenital heart defects that are associated with fetal alcohol syndrome. Recent reports have associated ethanol exposure with the Wnt/β-catenin pathway. Therefore, we defined whether ethanol affects Wnt/β-catenin signaling during cardiac cell specification.

Study Design

Pregnant mice on embryonic day 6.75 during gastrulation were exposed by an intraperitoneal injection to a binge-drinking dose of ethanol. Folic acid supplementation of mouse diet was tested for the prevention of ethanol-induced cardiac birth defects.

Results

Acute ethanol exposure induced myocardial wall changes and atrioventricular and semilunar valve defects, which was determined by echocardiography on embryonic day 15.5. A high folate diet prevented the ethanol-induced cardiac defects. Ethanol exposure in avian embryos suppressed 2 key Wnt-modulated genes that are involved in cardiac induction; folic acid rescued normal gene expression.

Conclusion

Folic acid supplementation alone or with myoinositol prevented alcohol potentiation of Wnt/β-catenin signaling that allowed normal gene activation and cardiogenesis.

Section snippets

Avian model

White leghorn chick (Gallus gallus; Charles River Laboratories, Wilmington, MA) and quail (Coturnix coturnix; Strickland Farms, Lake Park, GA) embryos were used because of accessibility to determine precisely the embryonic stage. Heart development in the avian embryo is similar to that in the mouse and human. Stage 4 embryos10 were incubated on an agar-albumin medium for 8 or 24 hours at 38°C.11 The teratogenic ethanol dose was determined to be 25-30% ethanol. Control embryos were incubated on

Alcohol exposure of avian embryos during gastrulation

Avian embryos that were exposed to ethanol in vitro at Hamburger and Hamilton staging10 stage 4 displayed morphologic defects of delayed growth and severe cardiac malformations (Figure 1, A, control, and B-D, ethanol exposed; Figure 2). After 24 hours, the early cardiac malformations included (1) wide hearts at embryonic middle and cardia bifida (ie, bilateral heart fields not fusing, (2) cardiac tissue situated anterior to the head that signified a truncation of the neural tube because of an

Comment

The mouse and avian results, when taken together, suggest that acute ethanol exposure potentiates Wnt/β-catenin inhibition of early cardiogenesis by suppressing expression of 2 cardiac-inducing molecules, Hex and Islet 1.21, 22 These genes are activated when canonical Wnt signaling is inhibited by Wnt antagonists. We demonstrated that high dietary folate taken from the time of conception can prevent the alcohol-induced heart defects. These results support a recent Canadian epidemiologic human

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  • Cited by (0)

    Reprints not available from the authors.

    Supported in part by the Mason Chair Endowment (K.K.L.) from the Foundation of the University of South Florida College of Medicine and All Children's Hospital.

    Cite this article as: Serrano M, Han M, Brinez P, et al. Fetal alcohol syndrome: cardiac birth defects in mice and prevention with folate. Am J Obstet Gynecol 2010;203:75.e7-15.

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