4–Hydroxynonenal Levels Are Enhanced in Fetal Liver Mitochondria By In Utero Ethanol Exposure

Abstract

Studies in many laboratories show that ethanol can induce Lipid peroxidation has been implicated in ethanol-inoxidative stress in adult tissues and that this may be associduced liver injury and observed in fetal liver and brain ated with subsequent ethanol-related damage. 3,4 Likewise, after maternal ethanol consumption with mitochondria lipid peroxidation resulting from oxidative stress has been being the target organelles. This process generates a shown to increase in tissues/cells after in vivo and in vitro highly reactive and toxic product, 4-hydroxynonenal ethanol exposure and could be an important factor in the (HNE). In the present study, HNE levels and metabolism pathogenesis of alcoholic liver disease. 5,6 There is compelling were assessed in mitochondria of fetal and maternal evidence that a key target organelle for ethanol-related oxidaliver after in vivo ethanol exposure. Female Spraguetive stress is the mitochondrion. 3,7 Long-term administration Dawley rats received five doses of ethanol (4 g/kg orally at 12-hour intervals) and were killed on day 19 of gesta-of ethanol to rats has been shown to increase production of tion. The results showed that HNE levels were enhanced malondialdehyde, conjugated dienes, and 4-hydroxynonenal in hepatic mitochondria of fetal rats exposed to ethanol, (HNE) in mitochondria.8 Moreover, ethanol may selectively far in excess of that in adult liver mitochondria. Mea-deplete hepatic mitochondrial glutathione, and this may be surement of HNE metabolism showed that fetal mito-connected to its impairment of key mitochondrial functions. chondria had a lower capacity for HNE catabolism thanThe role of oxidative stress in the fetotoxicity of ethanol is adult mitochondria. In adult mitochondria, HNE could much less studied and is under investigation in our laborabe metabolized by nicotine adenine dinucleotide-tory. We have recently documented ethanol-associated oxidadependent oxidation, reduced glutathione conjugation, tive stress in fetal brain and liver after in utero ethanol expoand reduced nicotine adenine dinucleotide-dependent sure and in cultured fetal hepatocytes, neonatal astrocytes, reduction, whereas in fetal liver only the former two and cardiac myocytes. 10,11 In both settings, ethanol increased pathways were active, but to a lesser degree than in membrane lipid peroxidation. The ethanol-mediated blockadult mitochondria. On the other hand, mitochondria ade of fetal hepatocyte replication could be reversed by augfrom fetal liver showed a higher production of HNE mentation of cellular antioxidant defenses, as could inhibiwhen oxidative stress was induced with t-butyl hydro-tory effects of ethanol on mitochondrial respiration.10,11 Thus, peroxide. Prior in vivo ethanol exposure further potenti-oxidative stress may play an important mechanistic role in ated HNE formation in t-butyl hydroperoxide-stimu-the fetotoxic effects of ethanol, yet the specific means by lated fetal liver mitochondria, but not in adult which this occurs remain unclear. mitochondria. These findi...

Oxidative Stress, Unfolded Protein Response, and Apoptosis in Developmental Toxicity

“…Fetal alcohol exposure has been shown to lead to an increase in lipid peroxidation in the brain and liver (Chen et al, 1997). There have been several studies documenting the use of antioxidants or ROS-clearing enzymes to decrease the rates of alcohol-induced malformations (Chen et al, 2004; Shirpoor et al, 2009; Patten et al, 2013; Parnell et al, 2010).…”

Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation

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Developmental Ethanol Exposure Leads to Dysregulation of Lipid Metabolism and Oxidative Stress in Drosophila

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