Increasing evidence indicates that the majority of children adversely affected by prenatal alcohol exposure (PAE) do not present with the physical features characteristic of Fetal Alcohol Syndrome (FAS). In the absence of these features, a confirmation of maternal drinking is required both for diagnosing Fetal Alcohol Spectrum Disorder (FASD) and initiating interventions. However, maternal self-report of drinking can be unreliable and conventional ethanol biomarkers are not sensitive enough for a diagnosis of drinking in many pregnant women, especially those who are moderate drinkers. The advent of high-throughput screening technologies for assessing the expression of genes, proteins and other metabolites in biological fluids has created new opportunities for developing more sensitive and specific biomarkers. MicroRNAs (miRNAs) are particularly appealing in this respect as they are very stable in plasma and serum and have shown great promise as biomarkers of a variety of disease conditions from cancer to myocardial infarction. Thus far, the utility of miRNAs as biomarkers for diagnosis of FASD has not been explored in detail. Our preliminary data suggest that alterations in the levels of at least two serum miRNAs could be used to reliably detect alcohol consumption during pregnancy. Furthermore, given that one of these miRNAs is expressed in the maternal reproductive system and the other in the fetal brain, these miRNAs could also serve as biomarkers of alcohol-induced tissue damage. The establishment of a panel of miRNAs as a clinically useful diagnostic tool will require replication of these findings in a larger clinical sample as well as a systematic evaluation of various factors that could affect the levels of circulating miRNAs during pregnancy. Thus, the goals of this translational research proposal are twofold.
Aim 1 : To identify a panel of serum miRNAs that predicts maternal alcohol consumption in pregnant women with higher specificity and sensitivity than conventional biomarkers, even in the presence of co-exposures with other drugs such as nicotine and opioids. The tissue origin and targets of these miRNAs will also be evaluated to assess potential mechanisms of alcohol-induced teratogenicity.
In Aim 2. we will use a rodent model of prenatal alcohol exposure to further examine the specificity of these novel biomarkers in relationship to co-exposure with either methadone (Aim 2A) or nicotine (Aim 2B), the """"""""window of detectability"""""""" after the last drinking episode (Aim 2C) and the impact of ethanol dose (Aim 2D). It is expected that this highly translational project will advance the field of FASD by providing novel biomarkers for an earlier and more accurate diagnosis of affected children.
Most children adversely affected by prenatal alcohol exposure do not present with the physical features characteristic of Fetal Alcohol Syndrome making diagnosis difficult. This project will investigate the potential utility of microRNAs as a novel laboratory indicator to ascertain if drinking occurred during pregnancy.
|Rodriguez, Carlos I; Davies, Suzy; Calhoun, Vince et al. (2016) Moderate Prenatal Alcohol Exposure Alters Functional Connectivity in the Adult Rat Brain. Alcohol Clin Exp Res 40:2134-2146|
|Marquardt, Kristin; Brigman, Jonathan L (2016) The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: Insights from rodent models. Alcohol 51:1-15|
|Morton, Russell A; Valenzuela, C Fernando (2016) Further characterization of the effect of ethanol on voltage-gated Ca(2+) channel function in developing CA3 hippocampal pyramidal neurons. Brain Res 1633:19-26|
|Kajimoto, Kenta; Valenzuela, C Fernando; Allan, Andrea M et al. (2016) Prenatal alcohol exposure alters synaptic activity of adult hippocampal dentate granule cells under conditions of enriched environment. Hippocampus 26:1078-87|
|Morton, Russell A; Valenzuela, C Fernando (2016) Third Trimester Equivalent Alcohol Exposure Reduces Modulation of Glutamatergic Synaptic Transmission by 5-HT1A Receptors in the Rat Hippocampal CA3 Region. Front Neurosci 10:266|
|Welch, J H; Mayfield, J J; Leibowitz, A L et al. (2016) Third trimester-equivalent ethanol exposure causes micro-hemorrhages in the rat brain. Neuroscience 324:107-18|
|Nirgudkar, Pranita; Taylor, Devin H; Yanagawa, Yuchio et al. (2016) Ethanol exposure during development reduces GABAergic/glycinergic neuron numbers and lobule volumes in the mouse cerebellar vermis. Neurosci Lett 632:86-91|
|Weick, Jason P (2016) Functional Properties of Human Stem Cell-Derived Neurons in Health and Disease. Stem Cells Int 2016:4190438|
|Izquierdo, A; Brigman, J L; Radke, A K et al. (2016) The neural basis of reversal learning: An updated perspective. Neuroscience :|
|Topper, Lauren A; Baculis, Brian C; Valenzuela, C Fernando (2015) Exposure of neonatal rats to alcohol has differential effects on neuroinflammation and neuronal survival in the cerebellum and hippocampus. J Neuroinflammation 12:160|
Showing the most recent 10 out of 18 publications