Long-term genomic and epigenomic dysregulation as a consequence of prenatal alcohol exposure: a model for fetal alcohol spectrum disorders

Abstract

There is abundant evidence that prenatal alcohol exposure leads to a range of behavioral and cognitive impairments, categorized under the term fetal alcohol spectrum disorders (FASDs). These disorders are pervasive in Western cultures and represent the most common preventable source of neurodevelopmental disabilities. The genetic and epigenetic etiology of these phenotypes, including those factors that may maintain these phenotypes throughout the lifetime of an affected individual, has become a recent topic of investigation. This review integrates recent data that has progressed our understanding FASD as a continuum of molecular events, beginning with cellular stress response and ending with a long-term “footprint” of epigenetic dysregulation across the genome. It reports on data from multiple ethanol-treatment paradigms in mouse models that identify changes in gene expression that occur with respect to neurodevelopmental timing of exposure and ethanol dose. These studies have identified patterns of genomic alteration that are dependent on the biological processes occurring at the time of ethanol exposure. This review also adds to evidence that epigenetic processes such as DNA methylation, histone modifications, and non-coding RNA regulation may underlie long-term changes to gene expression patterns. These may be initiated by ethanol-induced alterations to DNA and histone methylation, particularly in imprinted regions of the genome, affecting transcription which is further fine-tuned by altered microRNA expression. These processes are likely complex, genome-wide, and interrelated. The proposed model suggests a potential for intervention, given that epigenetic changes are malleable and may be altered by postnatal environment. This review accentuates the value of mouse models in deciphering the molecular etiology of FASD, including those processes that may provide a target for the ammelioration of this common yet entirely preventable disorder.

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Therefore, it is important to understand the variables that may increase or decrease the probability that PAE will produce deleterious effects on fetal development. These factors include the gestational timing, duration, and dose of alcohol (Astley et al 1999), amount consumed per drinking session (Khoale et al 2004), genetic and epigenetic factors (Kaminen-Ahola et al 2010 a ; Kleiber et al 2014; Lussier et al 2015), maternal and fetal stress (Glavas et al 2007; Uban et al 2013; Raineki et al 2014), nutritional status (Weinberg 1984, 1985; Keen et al 2010), and the mother’s ability to metabolize alcohol, which are all known to be critically involved in alcohol teratogenicity (Ramchandani et al 2001; Riley et al 2011). …”

“…Mouse models of PAE are being used to study global methylation patterns and identify specific genes implicated in the brain abnormalities reported in FASD (Kaminen-Ahola et al 2010 a ; Kleiber et al 2012, 2013, 2014; Hill et al 2014). Many of these studies have used robust acute and chronic dosage paradigms discussed in this review.…”

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

“…Alcohol is a toxic substance during pregnancy, particularly due to its teratogenicity [334,335,336,337,338]. There are no safe limits for alcohol consumption in pregnancy [339].…”

Associative DNA Methylation Changes in Children with Prenatal Alcohol Exposure

“…This effect of PAE in rodent models has been reported from a number of independent laboratories [9][10][11][12][13][14][15] over the last decade. They are now viewed as a milestone in FASD research [16,17]. The genes affected participate in the critical neural processes of synaptogenesis, apoptosis, cellular identity, cell-cell adhesion, and signaling [7,8].…”