We hypothesize that important mechanisms underlying the toxic effects of ethanol (E) on the developing brain are enhanced apoptosis and inhibition of key components of mitochondrial respiration. We propose that these effects are mediated by formation of two reactive aldehydes within the fetal/neonatal brain. These aldehydes fall into two categories. First is acetaldehyde AcHO), an oxidative product of ethanol catabolism, which is generated by developmentally elevated catalase activities. The second aldehyde is a toxic product of lipid peroxidation, 4-hydroxynonenal (HNE) which is formed by E-induced oxidative stress. The proposed studies are based on three new findings. These are: First, lipid peroxidation within the E exposed developing brain generates HNE; this compound directly inhibits mitochondrial respiratory components; and the mechanism underlying this inhibition may be adduct formation with subunits of cytochrome c oxidase (CO). Second, the developing brain possesses high activities of catalase which catalyzes the oxidation of E to AcHO. Third, we have evidence of strikingly amplified apoptotic cell death in neonatal brains under conditions where both aldehydes are increased. Both compounds can induce apoptosis. Animal models for short term and Chronic ethanol exposure will be used. There are 3 specific aims.
Specific Aim 1 will define the ethanol- related enhancement of apoptotic cell death and inhibition of key components of mitochondrial respiration in fetal rat brain following in utero ethanol exposure and in the neonatal brain during the third trimester brain growth spurt.
Specific Aim 2 will dissect the mechanisms underlying enhanced apoptosis and impaired mitochondrial respiration with respect to amplified production of the two toxic aldehydes in the developing brain and it will directly test the hypothesis that E- generated HNE inhibits a key component of the respiratory chain (CO). These studies will focus on the formation of HNE and AcHO protein adducts and inhibition of mitochondrial function, centering on events connected to the initiation of apoptosis.
Specific Aim 3 consists of the development of strategies for treatment regimens to prevent or mitigate ethanol-induced toxic aldehyde formation and cell death in the undeveloped brain. These studies are based on new/novel developments and should significantly add to our understanding of the toxic effects of E on fetal tissues.
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