Neurodevelopmental Epigenetic Etiologies: Insights from Studies on Mouse Models of Fetal Alcohol Spectrum Disorders

Abstract

time points [4,11–13]. These changes result in a long-lasting epigenetic footprint that can lead to changes in gene expression and behaviors characteristic of FASD. The results of our research and that of other groups suggest that prenatal alcohol exposure during any stage of pregnancy can result in the development of FASD [14]. Our group has been interested in the molecular basis of FASD for some time. We began by creating a mouse model of the behavioral abnormalities associated with FASD [4,11]. We then began to explore the molecular mechanisms underlying associated endophenotypes [3,12]. We have used four treatment protocols to examine the effects of binge drinking (intraperitoneal injection) during the first, second or third trimester of pregnancy, as well as moderate voluntary alcohol consumption throughout pregnancy. We found that all four exposure paradigms produced long-lasting (up to 70 days of age) changes in miRNA and gene expression [3]. Interestingly, changes in some miRNAs matched specific dysregulated target genes that are involved in a number of neurodevelopmental processes and adult brain functions. Interestingly, none of the identified transcripts were seen in all four paradigms that represented alcohol exposure at different stages of neurodevelopment. The exception was H/MBII-52, a snoRNA with a role in the etiology of numerous neurological disorders. We also examined DNA methylation in the voluntary alcohol consumption paradigm and found long-lasting changes in >6500 gene promoters. The affected genes are involved in neurodevelopment and adult brain processes. The methylation changes also included a number of CTCF binding sites that are known to bind to differentially methylated regions of imprinted genes, among others [15]. These changes are relatively stable during The development of an organism from a single cell (ontogeny) is an intricate and enigmatic process. It is initiated by maternal and paternal nuclear contributions that are complementary but not identical. The phenotypic outcome of the child is not only dependent on traditional genetic inheritance, but also on the prenatal environment, including the various exogenous and endogenous signals. Environmental factors affect various preand post-natal developmental processes via epigenetic regulation of gene expression. As such, many genetically complex disorders are studied at the epigenetic level. This approach has led to a much deeper understanding of a host of diseases and disorders from cancer to schizophrenia. A small but growing number of fetal alcohol spectrum disorder (FASD) researchers have similarly hypothesized that alcohol may exert its effects on fetal development through epigenetic mechanisms. Individuals aff licted with FASD exhibit impairments in cognition, learning, executive function, judgment, attention and social adaptation [1,2]. The extent to which an individual exhibits such impairments depends on their genetic background, as well as the timing and dose of alcohol exposure [3,4]. FASD affects 2–5% of pregnancies in North America, and has an annual cost in the tens of billions of dollars, making it a key public health concern [5,6]. Using various animal models and treatment regimes, a variety of the effects of alcohol on the brain epigenome have been studied, including genome-wide hypomethylation [7], and genespecific hyperand hypo-methylation [8–10], some of which are coincident with changes in gene expression and persist into adulthood. Furthermore, epigenetic and gene expression changes are associated with FASD-related endophenotypes at multiple developmental