Mary Marshall and Arthur Walton Professor of the Physiology of Reproduction
Director of Centre for Trophoblast Research
Graham Burton is accepting applications for PhD students.
Our focus is on human placental development, and the involvement of the placenta in complications of pregnancy such as miscarriage, fetal growth restriction and pre-eclampsia. In particular, we are interested in the effects of oxygen, hypoxia, and oxidative and endoplasmic reticulum stress on trophoblast differentiation and function. This interest stems from our finding, in collaboration with Professor Eric Jauniaux, that the maternal arterial circulation to the placenta is not fully established until towards the end of the first trimester of pregnancy. We demonstrated that prior to this time the conceptus is supported by secretions from the endometrial glands, histotrophic nutrition, that are delivered into the intervillous space through the developing basal plate. Consequently early development takes place in a physiologically low oxygen environment, and there is a threefold increase in the intraplacental oxygen concentration at the start of the second trimester, the oxygen transition. Currently, we are investigating how the placenta may stimulate its own development during early pregnancy by signalling to the endometrial glands and upregulating their secretion of growth factors and nutrients.
Our research has shown that fluctuations in oxygenation are particularly damaging to the trophoblast, leading us to propose ischaemia-reperfusion as the primary placental insult when trophoblast invasion and spiral artery remodeling are deficient. Recent work has elucidated the signalling pathways activated by that stress, leading to changes in gene transcript profiles and cytokine secretion that may stimulate the development of pre-eclampsia. We have also provided the first evidence that the syncytiotrophoblast is vulnerable to endoplasmic reticulum stress, describing a spectrum of changes from homeostatic adaptations to low oxygen in healthy high-altitude pregnancies to frank pathology in cases of fetal growth restriction. Most recently, we have shown that the placental molecular pathology is strikingly different in cases of early-onset pre-eclampsia compared to late-onset cases, demonstrating that the syndrome is heterogeneous and has different aetiologies.
Key advances of the group since 2005
2005: Identified that phylogenetically old carbohydrate metabolic (polyol) pathways are highly active during the first trimester when the intraplacental oxygen concentration is low.
2006: Demonstrated that fetal cell-free DNA is released from the placenta through apoptotic pathways
2007: Demonstrated that labour induces oxidative stress and transcriptional changes in the placenta that mimic those seen in pre-eclampsia
2008: First identification that endoplasmic reticulum stress contributes to the placental pathophysiology of intrauterine growth restriction
2009: First demonstration that a proportion of the nuclei within the syncytiotrophoblast are transcriptionally active
2010: Identified a transcriptional network that may define a trophoblast stem cell population within the placenta
2011: Identified that soluble FLT1 sensitises endothelial cells to pro-inflammatory cytokines, a potential mechanism in pre-eclampsia
2012: First demonstration that endoplasmic reticulum stress compromises mitochondrial function through inhibition of synthesis of MTC complexes
2013: First demonstration that hydrogen sulphide is a potent placental vasodilator, and that production is impaired in pathological placentas with increased vascular resistance
2014: First demonstration of the heterogeneity of placental molecular pathology in pre-eclampsia
2015: Identified that different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast
Funding: MRC, Wellcome Trust Programme grants, Anatomical Society, Action Medical Research, Evelyn Trust
Fogarty NME, Burton GJ, Ferguson-Smith AC, (2015), Different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast of the human placenta, Placenta, 36, 796-802
Burton GJ, Fowden AL, (2015), The placenta; a multifaceted, transient organ, Philosophical Transactions of the Royal Society B, 370, 21040066
Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ, (2014), Differential activation of placental Unfolded Protein Response pathways implies heterogeneity of causation of early- and late-onset pre-eclampsia, Journal of Pathology, 234, 262-276
Cindrova-Davies T, Herrera EA, Niu Y, Kingdom J, Giussani DA, Burton GJ, (2013), Reduced cystathionine g-lyase and increased miR-21 are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator, American Journal of Pathology, 182, 1448-1458
Benirschke K, Burton GJ, Baergen R, (2012), Pathology of the Human Placenta, 6th edition, Springer, Berlin, pp. 941