UBC Theses and Dissertations
Epigenetic signatures of prenatal alcohol exposure Lussier, Alexandre André
Prenatal alcohol exposure (PAE) can alter the development, function, and regulation of neurobiological and physiological systems, causing lasting cognitive alterations, behavioral deficits, immune dysfunction, and increased vulnerability to mental health problems. In humans, the spectrum of these deficits is known as fetal alcohol spectrum disorder (FASD). Although the molecular underpinnings are not fully elucidated, epigenetic mechanisms are a prime candidate for the programming of physiological systems by PAE, as they may bridge environmental stimuli and neurodevelopmental outcomes. DNA methylation is also emerging as a potential biomarker of early-life events, which may aid in earlier FASD diagnoses. Thus, my overarching aim was to identify epigenetic mechanisms that may contribute to the deficits associated with FASD and act as biosignatures of PAE. Specifically, I used genome-wide approaches to assess underlying gene expression programs and epigenomic profiles in a rat model of PAE and clinical cohorts of individuals with FASD. In the rat model, I identified alterations to gene expression programs in the brain of adult PAE females under steady-state and immune challenge conditions. Building on these long-term alterations to transcriptomic programs, I identified altered DNA methylation patterns persisting from birth to weaning in the hypothalamus PAE animals, suggestive of early reprogramming of neurobiological systems. In parallel, I found concordant alterations to DNA methylation profiles in the hypothalamus and white blood cells of PAE animals, which may reflect systemic effects and potential biomarkers of PAE. To complement the animal model, I also investigated DNA methylation patterns in two clinical cohorts of FASD, where I identified an epigenetic signature of FASD in buccal epithelial cells. As these results raised the possibility of an epigenetic biomarker, I investigated the relevance of DNA methylation as a diagnostic method for PAE, and successfully generated a predictive algorithm that could classify individuals with FASD versus controls. Overall, these findings provide evidence for the biological embedding of PAE’s effects through changes in gene expression and DNA methylation, while setting the stage for the development of novel biomarkers. Ultimately, these may aid in the development of targeted interventions and early screening tools to mitigate the deficits associated with FASD.
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