Abstract
Background: Foetal Alcohol Spectrum Disorders (FASD) diagnosis without maternal confirmation has led to difficulties in accurate diagnosis for healthcare professionals. Despite several studies on the effects of alcohol and its metabolites on the developing foetus, animal studies have failed to identify the exact neuronal mechanism of the damage responsible for deficits in cognitive function. A potential biomarker that can be rapidly obtained, cost-effective and non-invasive can be a steppingstone in identification of prenatal alcohol exposure (PAE) in all stages of life.Aim of the study: (1) To investigate Renin Angiotensin System (RAS) activities and expression in a mouse model of PAE. (2) To identify urinary and serum RAS aminopeptidases (IRAP, ApN, ApB and ApA) in a healthy population and in individuals with an independent FASD diagnosis. (3) To explore how confounding factors affect serum and urinary aminopeptidases.
Methods: RAS aminopeptidases activity and expression were measured in whole brain, heart, kidney and uteri of 33 C57BL/6J mice. Urine was collected from healthy participants and urine and serum were collected from children independently diagnosed with FASD. Enzyme assays, Western blot analysis and Immunohistochemical (IHC) detection by Immunofluorescence were used to measure the rate of activity, expression and localities of aminopeptidases.
Results: (1) PAE causes significant changes in aminopeptidases rate of activity and expression in a mouse model of PAE. (2) There are demonstrable differences in urinary and serum aminopeptidase activities between FASD and non-FASD children. (3) Aminopeptidases are altered by changes in hormonal status in humans.
Conclusion: Using a mouse model of PAE, this study has identified a potential mechanism, involving Angiotensin IV receptor binding, by which PAE causes defects in cognitive function. In animals, IRAP is known to be involved in learning, memory, cognition and emotional processing; drugs targeted at IRAP open-up possibilities of potential therapies for FASD. Knowledge of factors affecting aminopeptidases in human urine and serum can lead to their possible use as biomarkers to identify PAE. This would allow early and reliable diagnosis and early targeted therapeutic intervention for individuals with FASD.
| Date of Award | Oct 2023 |
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| Original language | English |
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| Supervisor | Nigel Brissett (Supervisor) & Raja Mukherjee (Supervisor) |