Pregnancy, placenta and parturition

This research group focuses on fetal and placental growth and development, implantation of the embryo, pregnancy and parturition (birth). Studies include

• epigenetic regulation of parturition
• epigenetic regulation of embryo implantation 
• the mechanisms of major complications of pregnancy such as preterm birth, gestational diabetes, preeclampsia and spontaneous recurrent miscarriage
• the effect of endocrine disruptors on the fetus and subsequent generations
• the role of myostatin in the placenta
• gene expression and regulation in the human endometrium during the menstrual cycle.

Preterm birth
Preterm birth is one of the leading causes of death and illness in the period before and after birth. We are investigating the role of intrauterine infection in precipitating the onset of premature labour.

Embryo implantation
Over half of all conceptions fail during the first half of pregnancy – mainly due to failure of implantation. Our research focuses on understanding how the embryo is recognized and the molecular regulation of embryo implantation.

Endocrine disruptors
Endocrine disruptors are widely distributed compounds that interfere with hormone physiology. Studies in animals suggest there is an association between developmental abnormalities and prenatal exposure to these compounds. The human placenta is designed to minimise the effects of toxic compounds in the maternal circulation on the fetus. We are trying to understand how endocrine disruptors affect the fetus.

The role of placental myostatin in the maternal-fetal metabolic dialogue
Myostatin, a member of the TGF-β super family, was initially identified as a negative regulator of muscle growth. Myostatin has also been shown to have a role in regulating adipogenesis, fat deposition, insulin secretion and glucose uptake.

We have recently shown that myostatin is present in the placenta and that it regulates glucose uptake in placental explants in vitro. In addition, our initial studies in rats show that maternal under-nutrition affects placental myostatin expression not only in the current gestation, but also in the pregnancies of the F1 (daughter) generation.

Maternal under-nutrition during early gestation is known to affect fetal growth and endocrinology, and consequently to predispose the offspring to metabolic disorders such as Type II diabetes in adult life.

We hypothesize that the link between maternal under-nutrition and increased susceptibility to adult-onset metabolic disorders in the offspring may be due to changes in myostatin expression.

Developmental origins of health and disease
The endocrine disruptor hypothesis
Epigenetics

Dr Anna Ponnampalam 
Professor Murray Mitchell
 

Associates within Liggins Institute
Professor Peter Lobie
Dr Jo Perry
Dr Deborah Sloboda
Dr Mark Vickers
Professor Wayne Cutfield
Dr Mark Green

Associates at other organisations
New Zealand
AgResearch: Dr Chris McMahon,

Australia
University of Western Australia: Associate Professor Jeff Keelan

• Placental perfusion
  The placenta is the only conduit for the transfer of materials from the maternal circulation to fetus. Since ex vivo perfusion of human placental tissue mimics the in vivo conditions for drugs and other xenobiotic transfer, it forms a good method to study the placental transfer of materials. The transfer kinetics can be studied by using a known standard compound which diffuses freely across the placenta (eg, antipyrine). The transfer of the chemicals due to leakage can be ruled out using a standard compound which minimally crosses the placenta (eg, FITC dextran). The viability of the perfused cotyledon at various stages can be detected by measuring the metabolites and human chorionic gonadotropin level.
• Real-time PCR
• Western blotting
• Tissue culture
• Immunohistochemistry (IHC)
• Enzyme-linked immunosorbent assay (ELISA)
• Radio-immuno assay (RIA)
• Liquid Chromatography/Mass Spectrometry (LC/MS)
• High Performance Liquid Chromatography (HPLC)

• Epigenetic regulation of implantation of the embryo
• Epigenetic regulation of parturition
• The role of myostatin on placental nutrient transport
• The transgenerational effects of myostatin in regulating glucose homeostasis and the role of placental myostatin in the maternal and fetal metabolic dialogue
• Adverse effects of endocrine disruptors in human reproductive health

Zoe Vincent
Sheryl Munro
Philip Logan
Biju Balakrishnan
Noha Ahmed Nasef
 

• Transgenerational effects of endocrine disruptors
• Transfer and actions of endocrine disruptors in the human placenta using placental perfusion methods
• Role of the endometrial epithelium in embryo implantation 

Mitchell, M.D., Simpson, K.L. and Keelan, J.A. Paradoxical proinflammatory actions of interleukin 10: potential roles in term and preterm labour. J Clin Endocrinol Metabol 89: 4149-4152, 2004.

Helliwell, R. J., L. W. Chamley, Blake-Palmer, K., Mitchell, M.D., Wu, J., Kearn, C.S., Glass, M. Characterization of the endocannabinoid system in early human pregnancy. J Clin Endocrinol & Metabol 89(10): 5168-74, 2004.

Berry, E.B.E., Keelan,J.A., Helliwell, R.J.A., Gilmour, R.S. and Mitchell, M.D. Nanomolar and micromolar effects of15-deoxyΔ12,14-prostaglandin J2 on amnion-derived WISH epithelial cells: differential roles of PPAR-γ, -δ and NFκB. Mol Pharmacol 68: 169-178, 2005.

Glass, M., Hung, J., Sato, T., and Mitchell, M.D. Misidentification of prostamides as prostaglandins. J Lipid Res 46: 1364-1368, 2005.

Blumenstein, M., Keelan, J.A., Bowen-Shauver, J.M. and Mitchell, M.D. Suppressors of Cytokine Signaling (SOCS) proteins in human preterm placental tissues. J Mol Endocrinol 35: 165-175, 2005.

Helliwell, R.J., Keelan, J.A., Marvin, K.W., Adams, A., Chang, M.C., Anand, A., Sato, T., O’Carroll, S., Chaiworapongsa, T., Romero, R.J., and Mitchell, M.D. Gestational age-dependent up-regulation of prostaglandin D synthase (PGDS) and production of PGDS-derived anti-inflammatory prostaglandins in human placenta. J Clin Endocrinol Metabol 91: 2, 597-606, 2006.

Mitchell, M.D. Unique suppression of prostaglandin H synthase-2 expression by inhibition of histone deacetylation and DNA methylation specifically in human amnion and not in adjacent choriodecidua. Mol Biol Cell 17: 1, 549-553, 2006.

Sato, T.A. and Mitchell, M.D. Molecular inhibition of histone deacetylation results in a major enhancement of the production of interleukin-1 beta in response to LPS. Am J Physiol (Endocrinology & Metabolism) 290: E490-E493, 2006.

Mitchell, M.D., McMahon, C. Osepchook, C.C., Leung, K. and Bass, J.J. Myostatin is a human placental product that regulates glucose uptake. J Clin Endocrinol Metabol 91:1434-1437, 2006.

Rahnama, F., Shafiei, F., Gluckman, P.D., Mitchell, M.D. and Lobie, P.E. Epigenetic regulation of human trophoblastic cell migration and invasion. Endocrinology 147: 5275-5283, 2006.

Cutfield, W.S, Hofman, P., Mitchell, M.D, and Morison, I. Could epigenetics play a role in the developmental origins of health and disease? Ped Res 61: 68R-75R, 2007.

Keelan, J.A. and Mitchell, M.D. Placental cytokines and preeclampsia. Front Biosci 12: 2706-27, 2007.

Mitchell, M. D. Epigenetics of preterm labour. Proc 8th World Congress of Perinatal Medicine, Medimond S R L: 187-191, 2007.

Shafiei, F., Rahnama, F., Pawella, L., Mitchell, M.D., Gluckman, P.D., and Lobie, P.E. DNMT-3a and -3b mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells. Oncogene 27 : 2602-2612, 2008.

Rahnama, F., Thompson, B., Steiner, M. , Shafiei, F., Lobie, P. and Mitchell, M.D. Epigenetic regulation of e cadherin controls endometrial receptivity. Endocrinology 150: 1466-1472, 2009.

Foundation for Research Science and Technology
National Research Centre for Growth and Development
Faculty Research Development Fund