Academic journal article Alcohol Research: Current Reviews

Dysregulation of microRNA Expression and Function Contributes to the Etiology of Fetal Alcohol Spectrum Disorders

Academic journal article Alcohol Research: Current Reviews

Dysregulation of microRNA Expression and Function Contributes to the Etiology of Fetal Alcohol Spectrum Disorders

Article excerpt

MicroRNAs (miRNAs) are members of a vast, evolutionarily ancient, but poorly understood class of regulatory RNA molecules, termed non-protein-coding RNAs (ncRNAs). This means that in contrast to RNA molecules generated during gene expression (i.e., messenger RNA [mRNA] molecules), they are not used as templates for the synthesis of proteins. ncRNAs are encoded within the genomes of both eukaryotic and prokaryotic organisms and represent a novel layer of cell regulation and function that rivals the diversity and function of protein-coding mRNAs (for review, see Mattick 2007).

In recent years, researchers have investigated whether, and how, miRNAs interact with beverage alcohol (i.e., ethanol) and/or mediate its effects. Initial studies (Sathyan et al. 2007) explored the ethanol-miRNA interactions in fetal neural stem cells. Since then, increasing evidence has indicated that miRNAs play a role in the etiology of alcoholism (Pietrzykowski et al. 2008) and potentially alcohol withdrawal (Guo et al. 2011), as well as in ethanol's effects on brain development (Guo et al. 2011; Tal et al. 2012; Wang et al. 2009), brain damage associated with adult alcoholism (Lewohl et al. 2011), and liver damage (i.e., hepatotoxicity) (Dolganiuc et al. 2009; Tang et al. 2008). Other drugs of abuse such as nicotine are also known to influence miRNA expression (Huang 2009); furthermore, ethanol and nicotine collaborate to regulate the expression of miRNAs in neural tissues (Balaraman et al. 2012). These data collectively suggest that miRNAs are an important, but as yet poorly understood, component of alcoholism and ethanol-associated toxicology and damage to the developing fetus (i.e., teratology). This review specifically focuses on the association between miRNAs and the developmental effects of ethanol exposure, examining both the current data and future potential for research in this field of ncRNA biology to promote a coherent understanding of teratology associated with alcohol exposure.

Fetal Alcohol Spectrum Disorders

Maternal alcohol consumption during pregnancy can lead to a constellation of brain, face, cardiovascular, and skeletal defects of varying severity that collectively have been termed fetal alcohol spectrum disorders (FASD). At the extreme end of the spectrum of severity is fetal alcohol syndrome (FAS) (Clarren 1986), which is characterized by craniofacial abnormalities (e.g., small openings of the eyes, thin upper lip, flattened area above the upper lip), motor dysfunction, impaired coordination of muscle movements (i.e., ataxia), behavioral disturbances, and cognitive deficits as well as growth retardation (Jones et al. 1973). According to the Centers for Disease Control and Prevention, the incidence of FAS is 1 to 3 per 1,000 live births, and these rates increase to 10 to 15 per 1,000 in at-risk groups, such as the foster care population (May and Gossage 2001). More recent estimates suggest that the prevalence of FASD in school-aged children in the United States is between 2 and 5 percent (May et al. 2009). FASD imposes significant socioeconomic costs on families and society. The lifetime cost of caring for a child with FASD was estimated at about $2 million, and the total annual cost of FASD in the United States was estimated at $4 billion in 2004 (Lupton et al. 2004); these costs may be significantly higher today.

Although the facial characteristics seen in patients with FASD are the most obvious signs of fetal alcohol exposure, the most devastating consequences of prenatal alcohol exposure are brain defects that result in cognitive, affective, and motor deficits (Sampson et al. 2000). Therefore, understanding the diverse effects of alcohol on the developing brain during pregnancy may provide researchers with the key to developing therapies for managing both fetal and adult effects of alcohol exposure during pregnancy. This review focuses on an emerging body of data from animal and cell-culture studies that implicates miRNA dysregulation in the etiology of FASD. …

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