037. Impact of glucocorticoids on fetal-placental growth and the postnatal phenotype
B. J. Waddell A , C. S. Wyrwoll A , D. P. Hewitt A and P. J. Mark ASchool of Anatomy and Human Biology, The University of Western Australia, Nedlands, WA, Australia
Reproduction, Fertility and Development 17(9) 72-72 https://doi.org/10.1071/SRB05Abs037
Submitted: 26 July 2005 Accepted: 26 July 2005 Published: 5 September 2005
Abstract
Glucocorticoids are recognised as a key fetal programming signal, with excess glucocorticoid exposure in utero linked to various adverse outcomes in offspring including delayed puberty onset, hyperleptinemia and hypertension. Fetal glucocorticoid exposure is controlled by the placental glucocorticoid barrier, whereby two 11β-hydroxysteroid dehydrogenase enzymes regulate transplacental passage of active glucocorticoids (cortisol and corticosterone). Fetal programming by glucocorticoids is likely due to their actions in several fetal tissues, but may also be mediated via effects exerted within the placenta. Indeed, in our model of fetal programming, treatment of pregnant rats with dexamethasone inhibits both fetal and placental growth, and dose–response experiments suggest that the placenta is more susceptible than the fetus to this growth inhibition. Moreover, glucocorticoid treatment stimulates placental apoptosis and reduces expression of several placental gene products, including PPARγ, Muc1 and VEGF. This down-regulation of gene expression occurs specifically within the labyrinth zone, the region of maternal–fetal exchange, and is associated with a marked reduction in placental vascularity. These data indicate that excess placental glucocorticoid exposure is likely to compromise fetal nutrient supply, which in turn could result in adverse fetal programming effects. Subsequent, long-term effects of fetal programming in offspring can either be amplified or attenuated by the postnatal environment. Thus, while programmed hyperphagia and adiposity are exacerbated by a high-energy diet in postnatal life, we have demonstrated that programmed hyperleptinemia and hypertension are prevented by a postnatal diet enriched with omega-3 fatty acids. These effects are mediated, in part, by changes in the adipocyte phenotype, most notably in relation to leptin mRNA expression. In conclusion, fetal programming by glucocorticoids is likely to be mediated, in part, by their detrimental effects on placental growth and vascularity. Postnatally, adverse outcomes of glucocorticoid-induced fetal programming can be prevented by dietary manipulations, thus raising the possibility of preventative, therapeutic interventions.
