New Study Provides First Linkage Of Fetal Alcohol
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
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
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).
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
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
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.
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.
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
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
- end -
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.
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 firstname.lastname@example.org.