Diagnosis of fetal alcohol spectrum disorders (FASD) is difficult in infancy and in the many affected nonsyndromal children, who do not manifest facial stigmata. Promising meconium- and blood-based metabolic biomarkers have been developed. However, these markers of exposure are only moderately predictive of adverse effects and are measured in biological substrates that can be obtained only during limited developmental windows. We will assess the biomarker potential of circulating plasma microRNAs (cirmiRNAs), small non-protein-coding RNAs that are secreted into the blood stream, can be acquired at different postnatal ages, and may serve as endocrine factors. PI Miranda and colleagues have found that in utero maternal alcohol exposure leads to an altered expression pattern of cirmiRNAs in newborn sheep, including a previously identified ethanol-sensitive miRNA, miR-9, the ablation of which leads to a zebra fish phenotype similar to that seen in prenatal alcohol exposure. Based on these pre-clinical data, we hypothesize that prenatal alcohol exposure leads to an altered expression pattern of cirmiRNAs in humans that may serve as a biomarker for exposure and that specific cirmiRNAs altered by prenatal alcohol exposure will also serve as biomarkers for fetal alcohol-related deficits in neurodevelopment and/or growth. To test this hypothesis, we propose to screen for cirmiRNA biomarkers in a unique cohort of alcohol-exposed infants from the Cape Colored (mixed ancestry) population in Cape Town, South Africa, which has among the highest worldwide incidence of fetal alcohol syndrome. PI Jacobson and colleagues are currently conducting a study of infants from this population, which includes detailed maternal alcohol consumption interviews obtained prospectively during pregnancy, FASD diagnosis by expert dysmorphologists, neonatal structural MRI data, physical growth measurements, and cognitive assessments at 6.5 and 12 mo. postpartum. Plasma samples will be obtained for miRNA profiling from 30-35 heavily exposed and 30-35 control infants from this cohort at 2 wk. and 6.5 mo. postpartum. Using real-time PCR arrays, we will attempt to identify a profile of cirmiRNAs that distinguish alcohol-exposed infants from controls. We will then determine whether the cirmiRNAs that are altered by alcohol exposure predict fetal alcohol-related developmental outcomes, including smaller birth size, structural brain anomalies, poorer cognitive function, and FASD diagnosis. This proposal addresses a critical need for developing diagnostic biomarkers for both prenatal alcohol exposure and effect from samples acquired during and beyond the neonatal period. It is responsive to PA-13-197, The Role of Extracellular RNA in Mediating the Health Effects of Alcohol, with its specific focus on biomarker development. Evidence of distinctive cirmiRNAs profiles in FASD has potential to uncover novel endocrine mechanisms mediating effects of fetal alcohol exposure that may provide the basis for development of novel therapies.
Despite four decades of research on fetal alcohol spectrum disorders (FASD), maternal alcohol consumption during pregnancy continues to be a major worldwide public health problem in the U.S. and worldwide and diagnosis of FASD during infancy, when early interventions can be most effective, remains difficult. There is, therefore, a strong, currently unmet need for biologic tests that can be easily performed in infancy to identify which children were prenatally exposed to alcohol and which of these children will go on to exhibit adverse effects on cognitive and behavioral function and growth. Based on new evidence from a sheep model, we plan to identify patterns of circulating microRNAs in the infant's blood that can be used as tests in clinical practice to meet this need and that may advance our understanding of how prenatal alcohol exposure harms the fetus, ultimately leading to development of novel therapies.
