ALCOHOL TERATOGENESIS--APOPTOSIS AND TOXIC ALDEHYDES

我们假设毒物效应背后的重要机制 酒精(E)对发育中的大脑的作用是促进细胞凋亡和 抑制线粒体呼吸的关键成分。我们建议 这些效应是通过两种反应性醛的形成而起作用的 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)，它是乙醛的氧化产物 酒精分解代谢，这是由发育升高产生的 过氧化氢酶活性。二醛是脂类的有毒产物 E诱导产生的过氧化，4-羟基壬烯醛(HNE) 氧化应激。 这项拟议的研究基于三项新发现。这些是：第一， 暴露于E的发育中的大脑中的脂质过氧化反应会产生HNE； 该化合物直接抑制线粒体呼吸成分； 这种抑制作用的机制可能是加合物的形成。 含有细胞色素C氧化酶(CO)亚基。二、发展中的 大脑具有高活性的过氧化氢酶，催化 将E氧化成Acho。第三，我们有明显放大的证据 在两种情况下新生儿大脑中的凋亡细胞死亡 醛增加了。这两种化合物都能诱导细胞凋亡。 将使用短期和长期酒精暴露的动物模型。 有三个具体目标。具体目标1将定义乙醇- 促进细胞凋亡与抑制KEY的相关研究 胎鼠脑线粒体呼吸成分的研究 宫内酒精暴露和第三个月期间新生儿脑内 怀孕三个月的大脑快速生长。《特定目标2》将剖析这些机制。 潜在的细胞凋亡增强和线粒体呼吸受损 关于放大生产中的两种有毒醛 它将直接检验E-E- 产生的HNE抑制呼吸链(CO)的一个关键成分。 这些研究将集中在HNE和Acho蛋白的形成上。 以事件为中心的加合物和线粒体功能抑制 与启动细胞凋亡有关。具体目标3包括 制定治疗方案的战略，以预防或 减轻乙醇诱导的乙醛生成和细胞死亡 未发育的大脑。 这些研究是基于新的/新的发展，应该 大大增加了我们对E对人体的毒性影响的了解 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.