Background
Alcohol use during pregnancy is associated with a range of adverse consequences including miscarriage, still birth, low birth weight and Fetal Alcohol Spectrum Disorder (FASD). There are currently no lab tests that can assess the possibility that an individual has been affected by prenatal alcohol exposure (PAE), creating a diagnostic challenge for children in which developmental screening has identified concerns. Improvements in screening and diagnosis is now a National priority to facilitate surveillance, timely and appropriate intervention and ultimately raise awareness of FASD to prevent further exposure.
Objectives
To identify DNA methylation biomarkers of PAE in a controlled murine experiment, with replication in existing methylation data sets from a) human neonates with well characterized PAE exposure patters b) children diagnosed with FASD.
Study design
A cross-species investigation of the effects of PAE on the fetal epigenome. Using a previously validated model that recapitulates clinical features of FASD while being equivalent to a common pattern of exposure to moderate alcohol levels until recognition of pregnancy, pregnant dams will be exposed to ethanol in drinking water during the first 3-4 weeks of pregnancy. Whole-genome bisulphite sequencing will be carried out on newborn tissue from fetal brain and liver. Littermates will be reared to adulthood and undergo a series of neurodevelopmental assessments. We will identify changes at methylation sensitive genes caused by PAE that are detectable across multiple fetal tissues from exposed pups compared to un-exposed matched controls. Gene expression analysis will be used to assess the functional consequence of disrupted DNA methylation. Top candidates will be validated in human data sets where existing DNA methylation data from buccal cells are available through our partnership with the following studies: a) AQUA/Triple B cohorts (Australian based), internationally unique cohorts with well characterized prenatal alcohol exposure patterns including dose and timing. b) Canadian children with confirmed diagnosis of FASD as part of the Kids Brain Health Network. Through these unique partnerships we will examine the validity of PAE biomarkers identified in mice in human cohorts well characterized for dose and timing of PAE (AQUA/Triple B), and in adolescents with clinical FASD (Kids Brain Health).
Significance
This research will garner new knowledge into the epigenetic and early life origins of alcohol-induced neurodevelopmental disorders. We aim to develop innovative non-invasive testing for PAE that could enhance capacity for screening and diagnosis of FASD. Potentially the approach could be applied across a range of neurodevelopmental disorders driven by adverse prenatal exposures (e.g. drug and alcohol abuse), creating new avenues for detecting the risk of disability as early as possible.
Our Project Team
- Dr David Martino – Telethon Kids Institute
- Dr Martyn Symons – Telethon Kids Institute
- A/Prof Alexander Larcombe – Telethon Kids Institute
- Prof Ryan Lister – University of Western Australia & Harry Perkins Institute
- A/Prof. Delyse Hutchinson – Deakin University
- Ms Evelyne Muggli – Murdoch Children’s Research Institute
- A/Prof Jeff Craig – Deakin University Centre for Molecular and Medical Research
- Prof Jane Halliday – Murdoch Children’s Research Institute
- Dr James Fitzpatrick – PATCHES Paediatrics
- Prof James Reynolds – Queens University Canada & Kids Brain Health Network
- Dr Sam Buckberry – University of Western Australia
- Mitchell Bestry – Telethon Kids Institute
- Prof Elizabeth Elliott – University of Sydney
Project Funders: WA Child Research Fund, FASD Research Australia Centre of Research Excellence
Contact Us
08 6319 1672