Ethanol, oxidative stress, reactive aldehydes, and the fetus
Ethanol, oxidative stress, reactive aldehydes, and the fetus
复制标题
DOI：
10.2741/henderson
复制
发表时间：
1999-06-15
期刊：
影响因子：
--
通讯作者：
Schenker, Steven
中科院分区：
文献类型：
--
作者：
Henderson, George I.;Chen, JuanJuan;Schenker, Steven
20多年来，孕妇摄入乙醇(E)对胎儿的毒性作用已经被记录在案，但这种毁灭性现象背后的机制仍然不确定。E对胎儿组织的各种细胞/生化效应本身就是一个谜，并强烈表明对E的胎儿毒性反应反映了一个多因素的环境。这些反应中的许多在概念上可以与对膜结构和功能的影响有关。具有代表性的是我们实验室的研究，记录了E对胎儿细胞复制、膜转运系统、膜流动性、Na+-K+泵表达和EGF受体表达的影响。最近的研究表明，氧化应激可能是E产生这些膜相关事件的机制之一。我们最初在培养的胎鼠肝细胞中观察到E诱导的氧化应激，后者表现出线粒体损伤的形态和生化迹象。E增加了H_2O_2、O_2~-、脂质过氧化产物，并伴有膜损伤的迹象。补充抗氧化剂或促进谷胱甘肽储存的试剂可以逆转这些影响。E被发现抑制线粒体呼吸链成分的活性(H_2O_2和O_2-水平升高的一个潜在来源)，这种作用可以被抗氧化剂逆转。随后的研究记录了孕妇摄入两天E后胎儿大脑和肝脏(妊娠第19天)的氧化应激和膜脂过氧化反应，以及在怀孕第14天和第17天给怀孕母猪一次性服用E后立即出现的“胚胎”。E诱导胎儿细胞氧化应激的方式正在研究中。我们检测了E对关键抗氧化酶活性的影响，没有发现抑制反应。然而，胎儿组织中低水平的抗氧化剂，以及体外胎儿线粒体对促氧化剂刺激的夸大反应，表明胎儿细胞对氧化应激具有很强的易感性。此外，最近的研究表明，胎儿组织同样容易形成和随后积累至少一种有毒的脂质过氧化产物--4-羟基壬烯醛。我们的结论是，母亲摄入E会导致胎儿组织中的氧化应激，这与E的某些毒性反应有关。此外，胎儿组织中的低抗氧化防御系统和脂质过氧化的有毒醛产物的积累使胎儿容易受到氧化损伤。
The fetotoxic effects of maternal ethanol (E) consumption have been documented for over two decades, yet the mechanisms underlying this devastating phenomenon remain uncertain. The wide variety of cellular/biochemical effects of E on fetal tissues is itself a puzzle and strongly suggests that fetotoxic responses to E reflect a multifactorial setting. Many of these responses can be conceptually connected to effects on membrane structure and function. Representative of this, are studies in our laboratory documenting E effects on fetal cell replication, membrane transport systems, membrane fluidity, Na+-K+ pump expression, and EGF receptor expression. Recent studies have provided evidence that oxidative stress may be one mechanism by which E produces these membrane-related events. We initially observed E-induced oxidative stress in cultured fetal rat hepatocytes, the latter exhibiting morphological and biochemical signs of mitochondrial damage. E increased H2O2, O2-, lipid peroxidation products, along with signs of membrane damage. Supplementation with antioxidants or agents that enhance glutathione stores reversed these effects. E was found to inhibit activities of mitochondrial respiratory chain components (a potential source of the enhanced levels of H2O2, and O2-) and this could be reversed by antioxidant treatment. Subsequent studies have documented oxidative stress and membrane lipid peroxidation in fetal brain and liver (gestation day 19) following a two day maternal E consumption and in gestation day 14 and 17 "embryos" immediately following a single dose of E to the pregnant dam. The means by which E can induce oxidative stress in fetal cells is under investigation. We have examined effects of E on activities of key antioxidant enzymes and found no depressant responses. However, the low levels of antioxidants in fetal tissues and an exaggerated response of fetal mitochondria to prooxidant stimulation in vitro, suggest that fetal cells are strongly predisposed to oxidative stress. Additionally, recent studies have suggested that fetal tissues are likewise prone to the formation and subsequent accumulation of at least one toxic lipid peroxidation product, 4-hydroxynonenal. We conclude that maternal E consumption induces oxidative stress in fetal tissues and that this is responsible for some toxic responses to E. Additionally, the low antioxidant defenses in fetal tissues and accumulation of toxic aldehyde products of lipid peroxidation predispose the fetus to oxidative damage.