Prof. Graham Burton

Brief CV

We have broad research interests in the regulation of placental development, but have focused in particular on the impact of oxygen and reactive oxygen species (ROS) in normal and complicated pregnancies (1, 2). In collaboration with Eric Jauniaux we have confirmed through a multidisciplinary approach that there is little, if any, maternal blood flow through the human placenta during the first three months of pregnancy (3). Instead, we have demonstrated that histiotrophic nutrition through secretions from the uterine glands may be an important pathway for materno-fetal exchange during the first trimester. The glands deliver their secretions into the intervillous space until at least 10 weeks of pregnancy, and we have observed that maternal glycoproteins are phagocytosed by the trophoblast where they enter the lysosomal pathway (4). Many nutrients appear to be transferred through the trophoblast into the fluid of the extraembryonic coelom, and our recent demonstration of specific transfer proteins on the outer surface of the yolk sac suggest that this structure, long considered vestigial in the human, may play an important role in materno-fetal exchange in early pregnancy (5). The glandular secretions are also rich in growth factors and cytokines, and so the endometrium may play a more important role in regulating placental differentiation post-implantation than previously appreciated (6).

Consequently, the human feto-placental unit initially develops in a low-oxygen environment, a situation that is common in many species and one which we suggest protects the embryo from free radical teratogenesis during the critical period of organogensis (7). Metabolism is heavily anaerobic, but may also involve phylogentically older pathways in order to maintain the redox balance (8). The placental tissues, in particular the syncytiotrophoblast, contain low concentrations and activities of the main antioxidant enzymes, and so are highly vulnerable to attack from ROS (9). The oxygen tension within the placenta rises three-fold between 10-12 weeks of gestation as the maternal circulation is established, and this is associated with a burst of oxidative stress in the trophoblast (3). More recently, we have demonstrated that the maternal circulation starts in the periphery of the placenta where trophoblast invasion is shallowest, and subsequently extends to the centre (10). Oxidative stress is greatest in the periphery, and results in localised degeneration of the syncytiotrophoblast and villous regression to form the chorion laeve. By contrast, in cases of missed miscarriage onset of the maternal circulation is premature and generalised throughout the placenta (10). Trophoblastic oxidative stress and degeneration is therefore severe and extensive, and undoubtedly contributes to the failure of these pregnancies (11).

We have recently applied our ideas that changes in oxygen tension are more important determinants of trophoblast function and well-being than absolute levels to the mature placenta. Subjecting term villous samples to hypoxia/reoxygenation in vitro has proved to be a potent stimulus for the generation of oxidative stress (12), and results in increased apoptosis in the trophoblast layer and secretion of pro-inflammatory cytokines (13, 14). We speculate that the placental oxidative stress that appears to be a key intermediary event in the generation of preeclampsia may be due to intermittent functioning of the utero-placental arteries secondary to incomplete trophoblast invasion. Current research involving the investigation of signalling pathways and microarray-analysis of gene expression is aimed at understanding the broader roles that ROS may play in regulating trophoblast differentiation and function.

Other work in our group relates to the quantitation of placental structure using stereological techniques (15). These have recently been applied to the mouse to provide the first quantitative database for placental development in this species (16). Comparisons between physiological and stereological data pertaining to the diffusing capacity reveal that this technique provides information that accurately reflects placental physiological performance (17). We are currently collaborating with Anne Ferguson-Smith to investigate the role that imprinted genes play in regulating placental development in the mouse and the human.

Colleagues

• Dr Tereza Cindrova-Davies (Research Associate)
• Dr Billy Yung (Research Associate)
• Dr Jemma Johns (Clinical Research Fellow)
• Ms Olivera Spasic-Boskovic (Research Technician)
• Ms Svitlana Korolchuk (Research Technician)
• Mr Philip Coan (Graduate Student)
• Principal collaborators
  • Professor Eric Jauniaux (University College Hospital, London)
  • Dr Stephen Charnock-Jones (University of Cambridge)
  • Dr Anne Ferguson-Smith (University of Cambridge)
  • Dr Jeremy Skepper (University of Cambridge)
  • Professor Lucilla Poston (St Thomas’s Hospital, London)

Main Sources of funding

Wellcome Trust, Tommy’s the Baby Charity, WellBeing

Selected publications

1.         Jauniaux E, Gulbis B, Burton GJ 2003 The human first trimester gestational sac limits rather than facilitates oxygen transfer to the fetus-a review. Placenta 24, Suppl. A:S86-93.

2.         Burton GJ, Jauniaux E 2004 Placental oxidative stress; from miscarriage to preeclampsia. Journal of Society for Gynecological Investigation 11:342-352.

3.         Jauniaux E, Watson AL, Hempstock J, Bao Y-P, Skepper JN, Burton GJ 2000 Onset of maternal arterial bloodflow and placental oxidative stress; a possible factor in human early pregnancy failure. American Journal of Pathology 157:2111-2122.

4.         Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E 2002 Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. Journal of Clinical Endocrinology and Metabolism 87:2954-2959.

5.         Jauniaux E, Cindrova-Davies T, Johns J, Dunster C, Hempstock J, Kelly FJ, Burton GJ 2004 Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestational sac. Journal of Clinical Endocrinology and Metabolism 89:1452-1459.

6.         Hempstock J, Cindrova-Davies T, Jauniaux E, Burton GJ 2004 Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy; a morphological and immunohistochemical study. Reproductive Biology and Endocrinology 2:58.

7.         Burton GJ, Hempstock J, Jauniaux E 2003 Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reproductive BioMedicine Online 6:84-96.

8.         Jauniaux E, Hempstock J, Teng C, Battaglia F, Burton GJ 2004 Polyol concentrations in the fluid compartments of the human conceptus during the first trimester of pregnancy; maintenance of redox potential in a low oxygen environment. Journal of Clinical Endocrinology and Metabolism Epub ahead of print

9.         Watson AL, Skepper JN, Jauniaux E, Burton GJ 1998 Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. Journal of Clinical Endocrinology and Metabolism 83:1697-1705.

10.       Jauniaux E, Hempstock J, Greenwold N, Burton GJ 2003 Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. American Journal of Pathology 162:115-125.

11.       Hempstock J, Jauniaux E, Greenwold N, Burton GJ 2003 The contribution of placental oxidative stress to early pregnancy failure. Human Pathology 34:1265-1275.

12.       Hung TH, Skepper JN, Burton GJ 2001 In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. American Journal of Pathology 159:1031-1043.

13.       Hung T-H, Skepper JN, Charnock-Jones DS, Burton GJ 2002 Hypoxia/reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circulation Research 90:1274-1281.

14.       Hung T-H, Charnock-Jones DS, Skepper JN, Burton GJ 2004 Secretion of tumour necrosis factor-a from human human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia. American Journal of Pathology 164:1049-1061.

15.       Mayhew TM, Burton GJ 1997 Stereology and its impact on our understanding of human placental functional morphology. Microscopy Research and Technique 38:195-205.

16.       Coan PM, Ferguson-Smith AC, Burton GJ 2004 Developmental dynamics of the definitive mouse placenta assessed by stereology. Biology of Reproduction 70:1806-1813.

17.       Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Constancia M 2004 Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. PNAS 101:8204-8208.