Alcohol consumption during pregnancy is a significant public health problem in the United States. Moreover, it is the leading preventable cause of mental retardation and birth defects. Alcohol consumption by pregnant women is frequently under-reported. Therefore, detection of alcohol use amongst pregnant women is crucial for decreasing alcohol-related birth defects. Although several existing biomarkers for identifying alcohol consumption during pregnancy have been able to detect varying degrees of alcohol exposure, further research is still needed to discover new biomarkers which have higher sensitivity and specificity for maternal and prenatal alcohol exposure. Work from our group has begun to suggest a novel mechanism for the teratogenic effects of ? alcohol via alterations in cholesterol metabolism. Even at very low dose of alcohol exposure, we ? observe consistent and dramatic decreases in cholesterol ester levels as well as decreases in the ? ratio of cholesterol ester-to-free cholesterol in zebra fish embryos. Furthermore, we also find impaired ? signaling in the Hedgehog pathway which plays a key role in the embryonic development of organs ? and structures that are vulnerable to prenatal alcohol exposure. This altered signaling appears to be ? due to defects in the cholesterol modification of Hedgehog ligand. ? ? To confirm our findings in a mammalian system, we have chronically fed mice an alcohol diet and have also found aberrations in cholesterol homeostasis. Based upon our preliminary data, the goal of this proposal will focus on identifying a biomarker signature for Fetal Alcohol Syndrome by fingerprinting metabolic intermediates, related key enzymes and genes in our zebra fish and mouse models.
Aim 1 will execute a high throughput metabolomics analysis using mass spectrometry techniques correlating with Raman spectroscopy to screen for a metabolic profile related to maternal and prenatal alcohol exposure. In particular, we will focus on the metabolic profiles of free fatty acid and cholesterol.
Aim 2 will validate key positive metabolic biomarkers in maternal alcohol use and will investigate the detailed chemical characteristics of these biomarkers for their sensitivity and specificity in determining alcohol exposure. Gene expression and enzyme activities related to this metabolic biomarker will also be investigated. In addition to providing a novel diagnostic tool, this unique signature will help to direct future research about the molecular pathogenesis of alcohol-related developmental defects. ? ? ?
|Mao, Hua; Diehl, Anna Mae; Li, Yin-Xiong (2009) Sonic hedgehog ligand partners with caveolin-1 for intracellular transport. Lab Invest 89:290-300|