SAT-204 Silencing of Maternal Hepatic Glucocorticoid Receptor Is Essential for Normal Fetal Development

Excessive or chronic stress can lead to a variety of diseases due to aberrant activation of the glucocorticoid receptor (GR), a ligand activated transcription factor. Pregnancy represents a particular window of sensitivity in which excessive stress can have adverse outcomes, particularly on the developing fetus. Models of maternal stress have historically relied on the use of psychosocial stressors or chronic administration of glucocorticoids leading to systemic increases in glucocorticoids, making it near impossible to understand the tissue-specific effects of stress during pregnancy in contributing to maternal and fetal diseases. We have previously demonstrated an antagonistic relationship between reproductive axis activity and hepatic glucocorticoid sensitivity in a mouse model of menopause. However, if stress/sex hormone crosstalk exists in the liver during pregnancy, and if so, what the physiological purpose it serves is completely unknown. We have discovered hepatic stress hormone responsiveness is diminished during pregnancy. Utilizing whole transcriptome array we profiled the maternal hepatic transcriptome and found a substantial overlap between the pregnancy-regulated transcriptome and glucocorticoid regulated transcriptome. Of the overlapping genes and pathways, we observed the direction of regulation to be largely opposite between the pregnancy-regulated transcriptome and stress hormone regulated transcriptome. Furthermore, we observed reduced basal expression of classical GR target genes in the pregnant liver and impaired induction of GR target genes in response to dexamethasone treatment in the liver of pregnant versus virgin mice. The reduced glucocorticoid sensitivity in the liver during pregnancy is due to impaired expression of GR, which is mediated via epigenetic silencing. Provocatively, we found reinstallation of GR to hepatocytes during pregnancy via adeno-associated viral transduction dysregulates genes involved in proliferation, ultimately culminating in impaired pregnancy-induced hepatomegaly. Furthermore. disruption of the maternal hepatic adaptation to pregnancy by GR reinstallation results in impaired in utero growth of the fetus. These data demonstrate the tissue-specific effects of stress hormone signaling in the maternal compartment is regulated in a dynamic fashion to ultimately support the healthy development of embryos.