Ethanol is a known human teratogen of immense public health impact. Heavy drinking during pregnancy is the leading known cause of mental retardation, while more subtle effects particularly on the developing brain occur in 1% of all liveborns. Recent evidence has shown that many of the known protein targets for ethanol's toxic effects on the developing central nervous system are associated with lipid rafts. Lipid rafts are specialized microdomains of the plasma membrane and serve as platforms for protein-protein interactions. Our prior work has shown that the ability of L1 cell adhesion molecule (L1), a protein critical for the proper development of the nervous system, to promote neurite outgrowth is exquisitely sensitive to ethanol. Localized disruption of lipid rafts reduces L1 mediated neurite outgrowth. Our preliminary data show that ethanol alters the distribution of L1 in lipid rafts, and that cholesterol depletion abolishes ethanol sensitivity. Further, our preliminary data suggests that other protein targets of ethanol change their lipid raft distribution in the presence of ethanol. We hypothesize that a major mechanism of ethanol toxicity is through alteration of lipid raft-protein interactions, and that interventions which reduce toxicity prevent this disruption. These hypotheses will be tested using cerebellar granule neurons (CGN) from rat pups and from mice, both wild type and lacking L1, and a rat in vivo entubation model.
In Aim 1, we will confirm that lipid raft-L1 interactions underlie ethanol sensitivity of neurite outgrowth by transfecting CGN lacking L1 with mutant constructs of L1 lacking a signal to colocalize with lipid rafts. Neurite outgrowth in transfected cells is expected to be ethanol insensitive.
In Aim 2, we will determine whether L1 or the lipid raft is the site of the ethanol action, and the effect of ethanol on the kinetics of L1 trafficking to and out of the lipid raft compartment.
In Aim 3, we will use four nutrients shown to be protective in other experimental systems, to prevent the changes in protein distribution secondary to ethanol. The most effective combination of these nutrients will be determined with L1 in CGN and in the in vivo model. The relevance of this research is that simple dietary manipulations with these nutrients may prevent some aspects of ethanol neurotoxicity much like folic acid supplementation and reduction of neural tube defects. ? ? ?
| Akinmboni, T O; Davis, N L; Falck, A J et al. (2018) Excipient exposure in very low birth weight preterm neonates. J Perinatol 38:169-174 |
| Shah, Shetal; Wong, Shale; Bearer, Cynthia et al. (2017) Environmental health reform in a synthetic world. Pediatr Res 82:373-375 |
| White, Kimberly M R; Sabatino, Julia A; He, Min et al. (2016) Toluene disruption of the functions of L1 cell adhesion molecule at concentrations associated with occupational exposures. Pediatr Res 80:145-50 |
| Bearer, Cynthia F; Wellmann, Kristen A; Tang, Ningfeng et al. (2015) Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure. Cerebellum 14:413-20 |
| Tang, Ningfeng; Bamford, Penny; Jones, Jace et al. (2014) Choline partially prevents the impact of ethanol on the lipid raft dependent functions of l1 cell adhesion molecule. Alcohol Clin Exp Res 38:2722-30 |
| Milstone, Aaron M; Bamford, Penny; Aucott, Susan W et al. (2014) Chlorhexidine inhibits L1 cell adhesion molecule-mediated neurite outgrowth in vitro. Pediatr Res 75:8-13 |
| Littner, Yoav; Tang, Ningfeng; He, Min et al. (2013) L1 cell adhesion molecule signaling is inhibited by ethanol in vivo. Alcohol Clin Exp Res 37:383-9 |
| Tang, Ningfeng; Farah, Benjamin; He, Min et al. (2011) Ethanol causes the redistribution of L1 cell adhesion molecule in lipid rafts. J Neurochem 119:859-67 |
| Bearer, Cynthia F; Bailey, Shannon M; Hoek, Jan B (2010) Advancing alcohol biomarkers research. Alcohol Clin Exp Res 34:941-5 |
| Gifford, Anne E; Farkas, Kathleen J; Jackson, Leila W et al. (2010) Assessment of benefits of a universal screen for maternal alcohol use during pregnancy. Birth Defects Res A Clin Mol Teratol 88:838-46 |
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