ALCOHOL TERATOGENESIS--APOPTOSIS AND TOXIC ALDEHYDES

我们推测，毒性作用的重要机制 乙醇（E）对发育中的大脑的作用增强了细胞凋亡， 抑制线粒体呼吸的关键成分。 我们提出 这些作用是由两种反应性醛的形成介导的， 在胎儿/新生儿的大脑中。 这些醛分为两种 类别 第一种是乙醛（AcHO），它是一种氧化产物， 乙醇催化剂，这是由发育升高产生的 过氧化氢酶活性 第二种醛是脂类的有毒产物 过氧化反应，4-羟基壬烯醛（HNE），它是由E-诱导形成的 氧化应激 这些研究基于三个新发现。 这些是：第一， 暴露于E的发育中的脑内的脂质过氧化产生HNE; 该化合物直接抑制线粒体呼吸成分; 这种抑制作用的机理可能是加合物的形成 与细胞色素c氧化酶（CO）的亚基。 第二，发展中 大脑具有高活性的过氧化氢酶， E氧化成AcHO。 第三，我们有证据表明， 在新生儿脑中的凋亡细胞死亡， 醛增加。 两种化合物均能诱导细胞凋亡。 将使用短期和慢性乙醇暴露的动物模型。 有三个具体目标。 具体目标1将定义乙醇- 凋亡细胞死亡的相关增强和关键的抑制 胎鼠脑线粒体呼吸成分的变化 子宫内乙醇暴露和新生儿大脑中的第三个 三个月的大脑快速发育期具体目标2将剖析机制 潜在的细胞凋亡增强和线粒体呼吸受损 关于放大生产的两种有毒醛在 它将直接检验E- 所产生的HNE抑制呼吸链（CO）的关键组分。 这些研究将集中在HNE和AcHO蛋白的形成上 加合物和抑制线粒体功能，以事件为中心 与细胞凋亡的启动有关。 具体目标3包括 制定治疗方案的战略， 减轻乙醇诱导的毒性醛形成和细胞死亡 未开发的大脑 这些研究基于新的/新颖的发展，应 这大大增加了我们对E的毒性作用的理解， 胎儿组织

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.