Early life corticosteroid overexposure: Epigenetic and fetal origins of adult diseases

Abstract

The relationship between events occurring during intrauterine development and later‐life predisposition to long‐term disease, has been described. The fetus responds to excess intrauterine exposure to high levels of corticosteroids, modifying their physiological development and stopping their growth. Fetal exposure to elevated levels of either endogenous (alterations in fetal hypothalamic‐pituitary‐adrenal axis) or synthetic corticosteroids, is one model of early‐life adversity; to developing adult disease. At the molecular level, there are transcriptional changes in metabolic and growth pathways. Epigenetic mechanisms participate in transgenerational inheritance, not genomic. Exposures that change 11β‐hydroxysteroid dehydrogenase type 2 enzyme methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol. More precise diagnosis and management of antenatal corticosteroids for preterm birth, would potentially decrease the risk of long‐term adverse outcomes. More studies are needed to understand the potential roles of factors to alter fetal corticosteroid exposure. Long‐term infant follow‐up is required to determine whether methylation changes in placenta may represent useful biomarkers of later disease risk. This review, summarize recent advances in the programming of fetal effects of corticosteroid exposure, the role of corticosteroids in epigenetic gene regulation of placental 11β‐hydroxysteroid dehydrogenase type 2 enzyme expression and transgenerational effects.

Placental Cortisol Dysregulation in Mothers with Experiences of Childhood Adversity: Potential Mechanisms and Clinical Implications

“…ACE exposure may act according to a similar mechanism. That is, 11β-HSD2 methylation resulting in transcriptional gene repression may result in decreased amounts of protective placental 11β-HSD2 enzyme, causing the fetus to be exposed to higher cortisol levels throughout pregnancy [22]. These changes may be subsequently transferred to future generations.…”