Isolating adverse effects of glucocorticoids on the embryonic cardiovascular system.

TitleIsolating adverse effects of glucocorticoids on the embryonic cardiovascular system.
Publication TypeJournal Article
Year of Publication2020
AuthorsTeulings, NEWD, Garrud, TAC, Niu, Y, Skeffington, KL, Beck, C, Itani, N, Conlon, FG, Botting, KJ, Nicholas, LM, Ashmore, TJ, Blackmore, HL, Tong, W, Camm, EJ, Derks, JB, Logan, A, Murphy, MP, Ozanne, SE, Giussani, DA
JournalFASEB J
Date Published2020 Jun 05
ISSN1530-6860
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.

DOI10.1096/fj.202000697R
Alternate JournalFASEB J.
Citation Key10.1096/fj.202000697R
PubMed ID32502311
Grant ListPG/10/99/28656 / / British Heart Foundation (BHF) /
RG85891 / / Lister Institute of Preventive Medicine /
MC_U105663142 / / Medical Research Council (MRC) /
110159/A/15/Z / / Wellcome Trust Investigator /