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New Lambton, Australia

Mitchell C.,Hunter Medical Research Institute | Mitchell C.,University of Newcastle | Johnson R.,Northumbria University | Bisits A.,Hunter Medical Research Institute | And 5 more authors.
Endocrinology | Year: 2011

The in vivo role of glucocorticoids in controlling prostaglandin endoperoxide synthase-2 (PTGS2) expression in the human amnion is unclear despite extensive studies using in vitro models. We addressed this issue by determining PTGS2 mRNA levels and gene transcriptional activity, RNA polymerase-II (pol-II) binding, pol-II C-terminal domain (CTD) phosphorylation, histoneacetylation, and histonemethylation at the PTGS2 gene in fresh amnion and in amnion explants incubated with dexamethasone for 24 h after delivery, when adaptation from in vivo to in vitro conditions occurred. PTGS2 mRNAturnover changed during incubation involving the initial rapid decrease and subsequent rebound of the transcription rate and stabilization of mRNA. pol-II accumulated in the 5′-region of the gene, which indicated postinitiation pausing. pol-II binding, 5′-accumulation, C-terminal domain Ser-5and Ser-2 phosphorylation, and histoneacetylation decreased rapidly and did not reverse during the transcriptional rebound, suggesting that the transcriptional mechanism altered in vitro. Dexamethasone decreased PTGS2 gene activity and mRNA levels. Glucocorticoid receptor-α (GRα) was bound to the PTGS2 promoter but did not affect pol-II recruitment, pausing, orthe epigenetic marks. GRα binding, however, decreased initiating (Ser-5) and elongating (Ser-2) pol-II phosphorylation. The ability of the PTGS2 promoter to bind GRα in response to dexamethasone diminished during incubation. We conclude that PTGS2 mRNA turnover is accelerated in vivo, but the underlying mechanisms are not sustained beyond 24 h in explants. Glucocorticoids chronically transrepress PTGS2 gene activity in vivo in part by interfering with transcription initiation and elongation. Glucocorticoid transrepression of PTGS2 may be important for pregnancy maintenance and the timing of parturition. Copyright © 2011 by The Endocrine Society. Source

Blumfield M.L.,University of Newcastle | Blumfield M.L.,Mothers and Babies Research Center | Hure A.J.,Mothers and Babies Research Center | Hure A.J.,University of Newcastle | And 4 more authors.
Nutrition Reviews | Year: 2013

Micronutrient status during pregnancy influences maternal and fetal health, birth outcomes, and the risk of chronic disease in offspring. Research reporting dietary intake during pregnancy in nationally representative population samples, however, is limited. This review summarizes the micronutrient intakes of pregnant women from developed countries and compares them with relevant national recommendations. A systematic search without date limits was conducted. All studies reporting the micronutrient intakes of pregnant women were considered, irrespective of design. Two authors independently identified studies for inclusion and assessed methodological quality. Nutritional adequacy was summarized, with confounding factors considered. Meta-analysis data are reported for developed countries collectively, by geographical region, and by dietary methodology. Pregnant women in developed countries are at risk of suboptimal micronutrient intakes. Folate, iron, and vitamin D intakes were consistently below nutrient recommendations in each geographical region, and calcium intakes in Japan were below the Japanese recommendations and the average intake levels in other developed countries. Research examining the implications of potential nutrient insufficiency on maternal and offspring health outcomes is needed along with improvements in the quality of dietary intake reporting. © 2013 International Life Sciences Institute. Source

Welsh T.N.,John Hunter Hospital | Welsh T.N.,University of Newcastle | Welsh T.N.,Mothers and Babies Research Center | Hirst J.J.,University of Newcastle | And 9 more authors.
PLoS ONE | Year: 2014

Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote estrogen dominance and foster myometrial contractions. © 2014 Welsh et al. Source

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