We propose to study the genetic mechanisms mediating differential susceptibility to the teratogenic effects of ethanol. Previous research has identified a maternal effect mediating different teratogenic outcomes following prenatal ethanol exposure. In this proposal, we will examine genomic imprinting as a mechanism for the effect. We first propose to further characterize the genetic architecture underlying ethanol teratogenesis in populations of mice derived from C57BL/6J and DBA/2J mice and perform quantitative trait locus (QTL) mapping for imprinted QTLs mediating teratogenesis. We will examine DMA methylation, histone modifications and changes in gene expression, in embryos and placentae, following prenatal ethanol exposure, of several imprinted genes known to play a role in growth and development. In addition, we will examine global gene expression changes in fetuses exposed to alcohol in utero. We also will examine the effects of providing dams with a methyl-enriched diet on teratogenesis. Given that, in the US, an estimated 130,000 per year women expose their fetuses to high levels of alcohol, and the estimated associated costs are $4-$11 billion, the relevance of our proposal to public health is paramount. If we identify epigenetic modifications and/or gene expression changes in imprinted genes following prenatal alcohol exposure in mice, they become targets for human studies. If we find that methyl-supplementation of dams diets' ameliorates some of the teratogenic effects of ethanol, it suggests an effective strategy that may be applicable to human pregnancy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016676-03
Application #
7475823
Study Section
Special Emphasis Panel (ZAA1-DD (72))
Program Officer
Hereld, Dale
Project Start
2006-09-30
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$483,423
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Downing, Chris; Balderrama-Durbin, Christina; Kimball, Alexi et al. (2012) Quantitative trait locus mapping for ethanol teratogenesis in BXD recombinant inbred mice. Alcohol Clin Exp Res 36:1340-54
Downing, Chris; Flink, Stephen; Florez-McClure, Maria L et al. (2012) Gene expression changes in C57BL/6J and DBA/2J mice following prenatal alcohol exposure. Alcohol Clin Exp Res 36:1519-29
Downing, Chris; Johnson, Thomas E; Larson, Colin et al. (2011) Subtle decreases in DNA methylation and gene expression at the mouse Igf2 locus following prenatal alcohol exposure: effects of a methyl-supplemented diet. Alcohol 45:65-71
Downing, Chris; Biers, Jami; Larson, Colin et al. (2010) Genetic and maternal effects on valproic acid teratogenesis in C57BL/6J and DBA/2J mice. Toxicol Sci 116:632-9
Downing, Chris; Marks, Michael J; Larson, Colin et al. (2010) The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol. Pharmacogenet Genomics 20:553-64
Downing, Chris; Balderrama-Durbin, Christina; Hayes, Jonathan et al. (2009) No effect of prenatal alcohol exposure on activity in three inbred strains of mice. Alcohol Alcohol 44:25-33
Downing, Chris; Balderrama-Durbin, Christina; Broncucia, Hali et al. (2009) Ethanol teratogenesis in five inbred strains of mice. Alcohol Clin Exp Res 33:1238-45
Leakey, Tatiana I; Zielinski, Jerzy; Siegfried, Rachel N et al. (2008) A simple algorithm for quantifying DNA methylation levels on multiple independent CpG sites in bisulfite genomic sequencing electropherograms. Nucleic Acids Res 36:e64