Abstract
Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off-target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the chicken embryo, a model system in which the effects on the developing heart and circulation of therapy can be investigated, independent of effects on the mother and/or the placenta. Fertilized chicken eggs were incubated and divided randomly into control (C) or dexamethasone (Dex) treatment at day 14 out of the 21-day incubation period. Combining functional experiments at the isolated organ, cellular and molecular levels, embryos were then studied close to term. Chicken embryos exposed to dexamethasone were growth restricted and showed systolic and diastolic dysfunction, with an increase in cardiomyocyte volume but decreased cardiomyocyte nuclear density in the left ventricle. Underlying mechanisms included a premature switch from tissue accretion to differentiation, increased oxidative stress, and activated signaling of cellular senescence. These findings, therefore, demonstrate that dexamethasone treatment can have direct detrimental off-target effects on the cardiovascular system in the developing embryo, which are independent of effects on the mother and/or placenta.
Highlights
Antenatal Corticosteroid Therapy (ACT) given to women threatened with preterm birth is one of the best examples of the successful translation of basic experimental science into human clinical practice, as it diminishes neonatal morbidity and mortality by accelerating fetal lung maturation.[1,2] Toward term, the fetal plasma glucocorticoid concentration rises, triggering maturation of vital organ systems in preparation for postnatal life.[3]
We show that direct treatment of the chicken embryo with dexamethasone at a developmental stage equivalent to the 27-week-old human fetus promotes asymmetric growth restriction and adversely affects cardiovascular structure and function
We propose that enhanced protein carbonylation in the heart and activation of cardiomyocyte senescence signaling pathways provides a molecular link between dexamethasone treatment and adverse cardiovascular changes in the chicken embryo (Figure 7)
Summary
KEYWORDS antenatal glucocorticoid therapy, cardiac function, cellular senescence, oxidative stress
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