Synthetic glucocorticoid dexamethasone inhibits branching morphogenesis in the Spiny Mouse Placenta

O'Connell, Bree A., Moritz, Karen M., Walker, David W. and Dickinson, Hayley (2013) Synthetic glucocorticoid dexamethasone inhibits branching morphogenesis in the Spiny Mouse Placenta. Biology of Reproduction, 88 1: 26.1-26.8. doi:10.1095/biolreprod.112.100644

Author O'Connell, Bree A.
Moritz, Karen M.
Walker, David W.
Dickinson, Hayley
Title Synthetic glucocorticoid dexamethasone inhibits branching morphogenesis in the Spiny Mouse Placenta
Journal name Biology of Reproduction   Check publisher's open access policy
ISSN 0006-3363
Publication date 2013-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1095/biolreprod.112.100644
Open Access Status Not Open Access
Volume 88
Issue 1
Start page 26.1
End page 26.8
Total pages 8
Place of publication Madison, WI., United States
Publisher Society for the Study of Reproduction
Language eng
Abstract Maternal dexamethasone exposure in the mouse impairs placental development and programs adult disease in a sexually dimorphic manner. Glucocorticoids bind to different glucocorticoid receptor (GR) isoforms to regulate gene transcription and cellular signaling. We hypothesized that sexually dimorphic placental responses to glucocorticoids are due to differences in GR isoforms present in the placenta. Pregnant C57Bl6 mice were exposed to saline or dexamethasone from E12.5 until E14.5 (1 µg/kg/h) before the collection of placentae. Cytoplasmic and nuclear protein fractions were extracted from placentae of male and female fetuses for Western blot analysis of GR isoforms. Eight known isoforms of the GR were detected in the mouse placenta including the translational isoforms GRα-A, B, C and D1-3 and the splice variants GRA and GRP. The expression of GRA, GRP and each of the GRα isoforms were altered by dexamethasone in relation to fetal sex and cellular location. Placentae of female fetuses had higher GRα-A and GRP expression in the cytoplasm than males, and GRα-C was more highly expressed in the nucleus of females than that in males. Dexamethasone significantly increased the cytoplasmic expression of GRα-A, but reduced the expression of GRα-C in placentae of males. Dexamethasone increased the expression of the GRα-C-regulated genes Sgk1 and Bcl2l11, particularly in females. The cleaved caspase-3 staining in placental sections indicated GRα-C may mediate sex differences in dexamethasone-induced apoptosis. These findings may underlie the sex-specific placental adaptations that regulate different growth profiles in males and females and different risks for programmed disease outcomes in offspring.
Formatted abstract
High levels of maternal glucocorticoids during pregnancy can alter the developmental trajectory of some fetal organs. These perturbations are often more profound for the male fetus and have been attributed to passage of glucocorticoids through the
placenta. However, the effect of excess glucocorticoids on the placenta itself is less well understood and, particularly, whether this is affected by fetal sex. Expression of genes involved in placental patterning, apoptosis, and nutrient transfer, along with
their response to maternal administration of dexamethasone (DEX), has previously been shown to be dependent on fetal sex in the spiny mouse. Here we describe the placental spatiotemporal expression of genes important for branching morphogenesis (WNT4, BMP4, GREM1, TGFB1, KDR, VEGFA).  Furthermore, we report that compared to TGFB1 expression in the female labyrinth, expression of TGFB1 in the male labyrinth was higher, and earlier peaks in expression levels of VEGFA (Day 19 placenta [male] vs. Day 37 labyrinth [female]) and KDR (Day
19 placenta [male] vs. Day 20 labyrinth [female]) were observed.  Administration of DEX to pregnant dams for 60 h commencing at mid-gestation caused significantly different, sex-related changes in expression of genes that were constitutively different before DEX treatment (e.g., KDR, TGFB1) and those that were not (i.e., VEGFA, WNT4). Similarly, some genes which displayed similar expression profiles across gestation for both sexes also showed similar responses to DEX (e.g., BMP4), while others did not (i.e., GREM1). These results showed that constitutive and glucocorticoid-
induced changes in expression of genes involved in branching morphogenesis may be influenced by fetal/placental sex and that fundamental differences exist between a male and female placenta.
Keyword Developmental origins of health and disease
Glucorticoid receptor
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Biomedical Sciences Publications
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