New Study Provides First Linkage Of Fetal Alcohol Exposure
And Enlarged Heart

Groundbreaking experiments with lab animals support the hypothesis that adaptations to the fetal environment, which result in low birth weight, also “program” physiological and harmful changes in the adult

August 1, 2003 – (Bethesda, MD) -- Cardiac malformations exist in children with fetal alcohol syndrome and animal models of prenatal alcohol exposure, and an enlarged heart (cardiac hypertrophy) has been found in children with fetal alcohol syndrome. The high incidence of heart defects indicates that alcoholism during pregnancy has to be considered as a serious and preventable cause of congenital heart disease. 

Moreover, low birth weight is linked to a later emergence of cardiovascular and metabolic medical disorders, including ischemic heart disease, hypertension, insulin resistance, and non-insulin-dependent diabetes. Accordingly, many scientists have suspected that changes in the fetal environment produce physiological adaptations by the fetus that lead to small birth weight. Such adaptations, known as fetal programming, may be beneficial before birth but may also produce adverse outcomes for years to come.

One consistent feature found in animal research models is that low birth weight is associated with prenatal exposure to glucocorticoid steroids (any compound capable of significantly influencing intermediary metabolism, such as promotion of hepatic glycogen deposition, and of exerting a clinically useful anti-inflammatory effect).  Even brief prenatal exposure to elevated glucocorticoids can result in permanent adverse changes in the adult offspring’s cardiovascular system. Glucocorticoids are important in normal development, but excessive exposure through the mother leads to reduced birth weight.

Scientists have also found that very low levels of steroids produced by the adrenal glands (corticosterone or (Cort)) are sufficient to normalize birth weight and increase fetal Cort levels. However, removal of one or both adrenal glands in the mother will cause reduced birth weight and decreased levels of maternal plasma Cort. 

As fetal adrenals start functioning during the last week of gestation, maternal Cort may  affect fetal development indirectly through regulating fetal adrenal function. Normally, fetuses are protected from any large excursions in maternal glucocorticoids by placental enzymes that inactivate cortisol and Cort. The expression and activity of the enzyme 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2), however, are developmentally regulated and also subject to external influence.

Maternal alcohol ingestion is also associated with elevated glucocorticoid levels and low birth weight in the fetus. Previous rat studies have shown that maternal ethanol ingestion over the last two weeks of gestation causes consistently and significantly elevated maternal plasma Cort levels from gestational day 18 to birth.  In contrast, fetal Cort levels are decreased suggesting a highly significant inverse relationship between maternal and fetal glucocorticoid levels exists during the last week of gestation.

An inverse relationship in the opposite direction exists between fetal and maternal Cort after maternal adrenalectomy such that increased the former Cort during the last week of gestation. However, alcohol exposure in adrenalectomized dams still leads to significantly decreased fetal Cort levels in both sexes, suggesting that ethanol inhibits fetal Cort production directly. Because glucocorticoids in the fetus play a key role in the regulation of growth and maturation of many organ systems, as well as the programming of the postnatal hypothalamic-pituitary-adrenal axis itself, decreased fetal Cort levels, resulting from increased maternal Cort levels and/or ethanol, have the potential to permanently alter the physiology of the offspring.

A New Study

A team of researchers hypothesized that developmental exposure to high, followed by low, levels of fetal glucocorticoids leads to cardiovascular vulnerability of the fetal alcohol-exposed (FAE) offspring.  Accordingly, removal of the maternal adrenal glands, and the ensuing low levels of maternal Cort, should eliminate cardiovascular problems found in adult offspring.

The authors of “Sexually Dimorphic Effects of Maternal Alcohol Intake and Adrenalectomy on Left Ventricular Hypertrophy in Rat Offspring” are Jennifer Slone Wilcoxon, Fraser Aird, and Eva E. Redei, from the Department of Psychiatry and Behavioral Sciences, Northwestern University Medical School, The Asher Center, Chicago, IL; and Jeff Schwartz, at the Department of Physiology, University of Adelaide, Adelaide, Australia.  Their findings appear in the July 2003 edition of the American Journal of Physiology –– Endocrinology and Metabolism. The journal is one of 14 published monthly by the American Physiological Society (APS) (www.the-aps.org).

Methodology

The study’s objective was to systematically measure in a rat model the effects of maternal ethanol consumption and maternal adrenalectomy on fetal body weight, placental weight, placental 11β-HSD-2 expression, and left ventricular weight in the adult.  The methodology consisted of four experiments that involved the mating of adult male and female Sprague-Dawley rats (56-68 days of age).

Experiment 1a. Because low birth weight and increased placental weight are associated with prenatal exposure to increased glucocorticoids, plasma Cort levels of alcohol-consuming dams and fetal body weight and placental weight were measured in the offspring.

Experiment 1b. Low birth weight and increased placental weight (found in experiment 1a) were predisposing factors to cardiovascular vulnerability later in life. The heart weight, specifically left ventricular weight, was measured in adult FAE and control offspring. The left ventricle was normalized to body weight.

Experiment 2a. If the cause of decreased body weight and increased placental weight is alcohol-induced elevated plasma Cort in the female, the elevated maternal Cort needs to have access to the fetus via decreased protection by 11β-HSD-2. Removing the elevated maternal Cort in the alcohol-consuming dams by adrenalectomy would eliminate the increased placental weight and decreased 11β-HSD-2 expression.

Experiment 2b. Because maternal adrenalectomy eliminated the increased placental weight and decreased 11β-HSD-2 expression in the female placenta in response to alcohol, the researchers measured heart weight in the adult offspring of females (with the adrenal glands removed) in order to determine if the ventricular hypertrophy found in female offspring of alcohol-consuming mothers (experiment 1b) was also abolished.

Results 

Key findings from the experiments showed that:

Alcohol exposure of dams during the last two weeks of gestation resulted in significantly decreased fetal weight and increased placental weight on gestational day 21.

Adult female (but not male) offspring of alcohol-consuming mothers exhibited left ventricular hypertrophy. Placental (11β-HSD-2) mRNA levels were decreased in females but not males.

Adrenalectomy of alcohol-consuming dams reversed the increase in placental weight and the decrease in female placental 11β-HSD-2 expression and eliminated the left ventricular hypertrophy of adult female offspring.

Conclusions

These data suggest that alcohol-induced changes in placental 11β-HSD-2 mRNA levels and left ventricular weight are coupled in female offspring only (an influence of testosterone in the male offspring, confirmed in previous studies) and depend on maternal adrenal status.

The research results suggest that maternal adrenal hormones might contribute to the cardiovascular changes found in adult female offspring exposed to ethanol in utero. In this study, maternal ethanol ingestion increased the bulk of the left ventricle in the adult FAE female offspring, which was normalized by maternal adrenalectomy.  Maternal adrenalectomy also normalized the increased placental weight found in fetuses of both sexes in response to fetal alcohol exposure.

This information garnered from this research could suggest a potential mechanism of alcohol-induced fetal programming of the cardiovascular system. Therefore, these groundbreaking experiments support the hypothesis that adaptations to the fetal environment, which result in low birth weight, also “program” physiological and harmful changes in the adult.

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Source: July 2003 edition of the American Journal of Physiology –– Endocrinology and Metabolism

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: A copy of the research article is available in pdf format to the press. Members of the press are invited to obtain a pdf copy of the study and to interview members of the research team. To do so, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.