One of the major causes of birth defects in North America is maternal ethanol consumption. Maternal alcohol consumption during critical windows of embryonic development can result in offspring with a number of predictable defects known as Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE). The effects of ethanol on normal development is very costly to society since FAS and FAE children suffer from impaired development, cognitive deficits and behavior problems. In order to reduce the cost of the devastating effects of ethanol on human health, we must understand the mechanism of ethanol action. It is also essential that we determine the genetic factors involved. A greater understanding of underlying mechanisms) of ethanol action on developing embryos should lead to new ideas about prevention and intervention of FAS and FAE. Although several hypotheses have been proposed to explain the molecular mechanism of ethanol-mediated fetal injury, the cause remains uncertain. The long-range goal of this project is to establish zebrafish as a vertebrate model to understand the molecular mechanisms) of ethanol-induced fetal injury. Zebrafish embryos share many cellular, anatomical, and physiological characteristics with higher vertebrates including humans and they offer many practical advantages making them an excellent research model for teratogenic studies. We specifically propose to: (I) Investigate the potential involvement of ethanol metabolism by completely characterizing the metabolizing pathways in developing embryos. (II) Determine the critical developmental window for embryonic CNS injury. (III) Identify the impact of ethanol exposure on zebrafish nervous system development and test the hypothesis that cell death contributes significantly to the teratogenic actions of ethanol. Completion of this project will result in a powerful model system that will allow for a greater understanding of the molecular mechanisms underlying ethanol-mediated fetal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA012783-01A1
Application #
6325416
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Foudin, Laurie L
Project Start
2001-06-01
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$151,000
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Reimers, Mark J; La Du, Jane K; Periera, Cliff B et al. (2006) Ethanol-dependent toxicity in zebrafish is partially attenuated by antioxidants. Neurotoxicol Teratol 28:497-508
Lassen, Natalie; Estey, Tia; Tanguay, Robert L et al. (2005) Molecular cloning, baculovirus expression, and tissue distribution of the zebrafish aldehyde dehydrogenase 2. Drug Metab Dispos 33:649-56
Reimers, Mark J; Flockton, Amanda R; Tanguay, Robert L (2004) Ethanol- and acetaldehyde-mediated developmental toxicity in zebrafish. Neurotoxicol Teratol 26:769-81
Reimers, Mark J; Hahn, Mark E; Tanguay, Robert L (2004) Two zebrafish alcohol dehydrogenases share common ancestry with mammalian class I, II, IV, and V alcohol dehydrogenase genes but have distinct functional characteristics. J Biol Chem 279:38303-12
Svoboda, Kurt R; Vijayaraghavan, Sukumar; Tanguay, Robert L (2002) Nicotinic receptors mediate changes in spinal motoneuron development and axonal pathfinding in embryonic zebrafish exposed to nicotine. J Neurosci 22:10731-41