Developmental Programming and the Placenta: Focusing in on Glucocorticoids

Fetal glucocorticoid exposure is a key mechanism involved in adverse programming outcomes in the adult. Impairment of fetal growth has predominantly been attributed to direct effects of glucocorticoids on the fetus, prematurely shifting tissue development from a proliferative to a more functionally mature state. However, fetal growth is dependent on a complex interplay of maternal, placental, and fetal endocrine signals, and glucocorticoid-mediated fetal growth retardation is likely also to relate to disturbances in placental growth and function. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid barrier, which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Overexposure to glucocorticoids or depletion of 11β-HSD2 has a dramatic effect on placental development and function, with a reduction in capillary networks and alterations in nutrient transport. This work highlights the finding that adverse programming effects of glucocorticoids are not exclusively due to direct actions on the fetus but are also a consequence of changes in placental development and function. Developmental Programming Low birth-weight and other indicators of reduced fetal growth are associated with adult cardio-metabolic and psychiatric disease. This association is the result of “developmental programming,” whereby a stimulus during a sensitive period of early development exerts permanent effects on structure, physiology or metabolism (Cottrell and Seckl 2009). The environmental mechanisms of developmental C.S. Wyrwoll (*) The School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, WA 6009, Australia e-mail: [email protected] J.R. Seckl and Y. Christen (eds.), Hormones, Intrauterine Health and Programming, Research and Perspectives in Endocrine Interactions 12, DOI 10.1007/978-3-319-02591-9_2, © Springer International Publishing Switzerland 2014 17 programming identified so far can be simplified into two major groups: fetal stress exposure and maternal nutrition, although changes in glucocorticoids appear to underpin the programming effects of both (Langley-Evans et al. 1996; Gardner et al. 2007; Harris and Seckl 2010). In many animals, including mice and humans, there is an increased exposure of the developing fetus to glucocorticoids late in pregnancy, as they have a crucial role in the structural development and functional maturation of fetal organs. However, glucocorticoid overexposure of the fetus can be detrimental, as glucocorticoids cause a shift from cell proliferation to differentiation. Therefore, exposure to excess glucocorticoids in utero alters fetal organ growth and maturation patterns, which can result in adverse consequences in later life. In humans, the actions of glucocorticoids are exploited for preterm births to advance fetal lung maturation (Roberts and Dalziel 2006), although this may set the stage for adverse effects in later life (Benediktsson et al. 1993; Brown et al. 1996a; Levitt et al. 1996; Lindsay et al. 1996; Dodic et al. 1998, 1999, 2002a, b; Gatford et al. 2000; Langdown and Sugden 2001; Jensen et al. 2002). The Feto-Placental Glucocorticoid Barrier: 11β-HSD2 As glucocorticoids are highly lipophilic, they readily diffuse across biological membranes and, therefore, control of intracellular levels of bioactive glucocorticoid is critical. This control arises from the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD), which interconverts the active glucocorticoids cortisol and corticosterone with their biologically inactive forms, cortisone and 11-dehydrocorticosterone (DHC), respectively. There are two distinct forms of 11β-HSD: 11β-HSD1, which is a low affinity, NADP(H)-dependent bidirectional enzyme, although in vivo it appears to act predominantly as an 11β-oxoreductase to enhance glucocorticoid activity; and 11β-HSD2, which is a high affinity NAD-dependent enzyme that exhibits exclusive 11β-dehydrogenase activity (conversion of corticosterone to DHC) to reduce glucocorticoid potency. 11β-HSD2 is highly expressed in aldosterone-selective target tissues such as the distal nephron (Roland et al. 1995), colon (Whorwood et al. 1994), salivary glands (Roland and Funder 1996) and skin (Kenouch et al. 1994), thus serving to confer aldosterone specificity on the mineralocorticoid receptor (MR) to which both corticosterone and aldosterone can bind. Importantly, 11β-HSD2 does not always colocalize with MR, such as within placental and fetal tissues, and so its function has expanded beyond involvement in electrolyte transport to include regulation of corticosteroid action. During much of normal pregnancy, circulating levels of glucocorticoids in the fetus are substantially lower than in the mother. This difference arises in part from the high expression of 11β-HSD2 in both the placenta and fetus, and this 11β-HSD2 expression serves as a “glucocorticoid barrier,” enabling tight regulation of materno-fetal glucocorticoid transfer. Within the placenta, 11β-HSD2 is highly expressed at the interface between maternal and fetal circulations, in the syncytiotrophoblast in humans (Brown et al. 1996a,b) and the labyrinthine zone in rodents 18 C.S. Wyrwoll