Perinatal and Early Life Exposures

Periconceptional alcohol exposure: Programming long-term health in offspring

Approximately 80% of Australian women drink alcohol around the time of conception. Whilst many cease or reduce alcohol consumption once pregnancy is confirmed, the long term consequences of exposure around conception are largely unknown. We have developed a pre-clinical rat model of periconceptional alcohol exposure (PCE) and demonstrated that exposure results in fetal growth restriction, impairments in placental development and metabolic, renal and cardiac dysfunction in offspring in adult life. Given that many women drink prior to recognition of pregnancy, the urgent challenge is to understand the mechanisms contributing to disease and design effective intervention strategies.

We currently have projects involving our rat model that are further characterising the impact of PCE on neonatal and long-term offspring health. These include projects involving the development and function of the kidneys (nephron/tubule number and structure; measures of renal function), the heart (vessel morphology/structure; measures of cardiovascular function), the brain and circadian systems (behaviour and circadian rhythms) and the ovary (ovarian reserve, follicle development and fertility).

In addition to describing the offspring phenotypes produced from this periconceptional insult, our lab is currently focused on determining molecular mechanisms underlying the programming of disease outcomes in offspring. We are examining impacts on uterine-embryo interactions at the time of implantation which impact on trophoblast cell invasion and subsequent placental structure. We are also testing the hypothesis that there is altered activity and methylation of the glucocorticoid receptor (GR), which is central to the activity of the hypothalamic-pituitary-adrenal (HPA) axis in both the mother and offspring in response to a stressor. Given that our perturbation is occurring during pregnancy prior to fetal organ and placental formation, epigenetic changes or alterations to maternal physiology are likely mechanisms driving the observed offspring phenotypes.

We are also focusing on testing a safe and feasible intervention during pregnancy. Choline is an essential nutrient and methyl donor and thus can influence DNA methylation. Supplementation with choline has been shown to be safe in human pregnancies. We are currently testing the potential for choline to ameliorate the impacts of PCE placental development and offspring organ function in our preclinical rodent model of periconceptional alcohol exposure.

Co-supervision: Dr David Simmons, Dr Lisa Akison, Prof Vicki Clifton, Dr Oliver Rawashdeh

Emerging therapies for diabetes and complications: Effects on metabolic, cardiovascular and renal function

Diabetes mellitus affects more than 415 million people worldwide and many will experience premature mortality due to cardiovascular and/or kidney disease. Blood glucose control is the primary strategy to prevent vascular complications in diabetes. However, there is no guarantee that achieving near-normal blood glucose levels, particularly in patients with long-standing type 2 diabetes, will prevent the onset and progression of micro- and/or macrovascular diseases. This research program aims to refine preventative and interventional treatments for cardiovascular and kidney diseases in diabetes.

At present, we are studying the therapeutic potential of a new anti-diabetic agent, SGLT2 inhibitor, for the treatment of cardiovascular and kidney disease in diabetes. This agent targets the kidney to prevent glucose reabsorption, thereby promoting urinary glucose excretion and lowering blood glucose levels. In a recent clinical trial, this agent reduced cardiovascular mortality and the progression of kidney disease in patients with type 2 diabetes. However, the mechanisms underlying these benefits are unknown and we aim to identify what they are to design more specific treatments. We use whole-animal physiological techniques to study metabolic, cardiovascular, and kidney disease. Molecular approaches are utilised to gain a better understanding of the mechanisms involved.

Co-supervision: Dr Linda Gallo

Effect of prenatal insults on the developing placenta

Normal placental function is essential for optimal fetal growth. Thus, many adverse perinatal outcomes including miscarriage, intra-uterine growth restriction (IUGR) and even some fetal defects can be attributed to poor placental function. These can often occur in pregnancies complicated by conditions such as gestational diabetes, asthma/hypoxia, stress or preeclampsia. Our lab, in conjunction with clinical collaborators, is interested in examining placental development, morphology and function in compromised pregnancies.

Transport of glucose from mother to fetus is particularly critical to meet fetal nutrient demands and is controlled by a number of specific placental glucose transporters. In both humans and rodents, glucose can also be stored in the placenta in the form of glycogen, however the function of this glycogen deposition remains a matter of debate. Some evidence suggests placental glycogen provides a source of fuel for the placenta itself, while other studies suggest placental glycogen is stored for later use by the fetus in times of need. While the significance of placental glycogen deposition remains elusive, mounting evidence from both human and animal studies indicates that altered glycogen deposition accompanies many pregnancy complications that adversely affect fetal development. Our lab is interested in determining the circumstances under which glycogen is stored and/or released in the placenta and what role altered placental glycogen deposition may play in inappropriate fetal growth.

Maternal insults during pregnancy also typically result in activation of the hypothalamus-pituitary-adrenal (HPA) axis in both the mother and offspring resulting in elevated glucocorticoids (GC) (cortisol in humans and corticosterone in rodents). GCs exert their action predominantly through binding to the glucocorticoid receptor (GR) which is expressed in many tissues including the placenta. However, activity of the GR is dependent upon the specific isoforms present which in turn is dependent upon DNA methylation of GR tissue-specific promoters. We hypothesise that changes in specific GR isoforms may contribute to altered GR signaling pathways involved in metabolism, growth and inflammation in the placenta.

Co-supervision: Prof Vicki Clifton, Dr Marloes Nitert Dekker, Dr James Cuffe, Dr David Simmons

Effect of prenatal insults on the developing kidney and implications for adult disease

In Australia, around 1.7 million people have clinical evidence of chronic kidney disease (CKD) and 3.7 million people are affected by cardiovascular disease. Abnormal kidney development, in particular, a low nephron endowment, directly correlates with an increased risk of these diseases in adulthood. A reduced nephron number, resulting in impaired glomerular filtration rate (GFR) can occur as a result of low birth weight or premature delivery. However, reduced nephron number alone cannot fully explain the increased prevalence of CKD and hypertension. Unlike nephrogenesis, which ceases around 36 weeks of gestation in humans, the development of the renal tubular system, particularly within the papilla, starts during embryogenesis and continues after birth, not reaching functional maturation until 12-18 months of age. Impairments in papillary tubule development are associated with reduced renal function in children. However, the association between abnormal development of the renal papilla and increased risk of kidney disease in the adult has never been studied. This project will use both clinical and preclinical studies to determine if impaired development of the renal papilla contributes to CKD in adults. Papilla development in normal and premature babies will be examined by ultrasound images and adult kidneys examined using archival kidney samples. Preclinical animal models will evaluate how papilla development and functional maturation is affected by common perturbations including prenatal hypoxia, birth asphyxia and preterm birth. Our ultimate goal is to develop a clinically relevant postnatal intervention that can improve kidney outcomes following an early life perturbation. This project involves clinical collaborators from the Lady Cilento Children’s Hospital in Brisbane and Townsville Hospital.

Co-supervision: Dr Peter Trnka

Impact of maternal cannabis and alcohol around conception on development and long-term health of offspring

In Australia, ~80% of women of reproductive age are consuming alcohol and ~10% report using cannabis in the previous year. Of those that used cannabis, more than a third reported using at least once a week. Many women are using both these substances in early pregnancy, but although we know that alcohol in this period can have harmful consequences, we know much less about cannabis use during this sensitive developmental window. Recent legalisation in some countries is increasing the perception that cannabis is safe to use during pregnancy. However, concentrations of Δ9-tetrahydrocannabinol (THC), the psychoactive cannabinoid in cannabis, have dramatically increased (3 to 5-fold) in recent decades; and while cannabidiol (CBD), another prominent cannabinoid, is widely consumed in extracted forms for its potential therapeutic benefits, reports have also indicated CBD use in pregnancy can have negative consequences on fetal growth. However, few studies have looked at co-exposure with alcohol and cannabis and no studies have focussed on exposure exclusively around conception. Therefore, this project aims to determine the impacts of using cannabis and/or its active constituents during early pregnancy, either alone or in combination with alcohol, on fetal and placental growth and offspring health.

This project will utilise our current rat model of periconceptional alcohol exposure but will include additional treatment groups that focus on looking at THC and/or CBD exposure during the periconceptional window. We will look at these cannabinoids alone or in combination with alcohol. The project will examine fetal and placental outcomes, as well as more long-term consequences on metabolic and behavioural outcomes in adult offspring. Detailed analysis of placental formation/implantation will be performed during gestation, assessing the extent of decidualisation and depth of trophoblast invasion using histology/stereology. We also plan to examine trophoblast and uterine stromal cell differentiation via in situ hybridisation.

Co-supervision: Dr David Simmons and Dr Lisa Akison