Maternal ethanol (E) consumption often has a devastating and lasting effect on fetal growth and development, both in humans and in animal models. Yet, the mechanism(s) for this remaining uncertain and no treatment, either preventative or postinsult for the fetal damage has evolved. Previous studies in our laboratory have documented a variety of fetotoxic responses to E using rat models for in vivo exposure and primary cultures of fetal cells in vitro. Recently we reported that in cultured fetal rat hepatocytes (FRH), E blocked replication, induced total and mitochondrial membrane damage, increased production of reactive oxygen species [O2 and H2O2 (ROS)] and membrane lipid peroxidation products in whole cell and mitochondria (M), and reduced GSH pools and ATP synthesis. Importantly, normalizing cell antioxidant status could reverse these measures and restore cell replicative capacity. Preliminary studies included here illustrate similar responses in vivo after a maternal binge exposure as well as in cultured neonatal astrocytes (A) and cardiac myocytes (CM), and documented an E-related inhibition of M respiratory complexes I and IV. Also, administration of allopurinol (AL) to dams concomitant with E, normalized H2O2 production and GSH in fetal brain (but not liver), indicating a xanthine oxidase interaction. Thus, we hypothesize, first, that the underlying mechanism for the toxic effects of E on fetal cells is E-induced generation of ROS, second, that many of these fetotoxic effects can be prevented or mitigated by treatments that optimize oxidant defense systems in fetal tissues, and third, that E damage of M plays an important role in these processes. The models will be Sprague Dawley rats exposed to E from gestation days (GD) 3-20 (chronic) or on GD days 11-13, 14-17, 18-20 (binge). We will focus on fetal brain, heart and liver as known targets fore, and on key cells of these tissues, cultured RFH, A, and CM.
Specific Aim 1 is to define the oxidative stress with respect to ROS production, oxidative products in membrane lipids (MDA, dienes, 4-hydroxynonenal), proteins (thiol oxidation, aldehyde adducts), DNA (8-hydroxydeoxyguanosine), antioxidant status (GSH, vitamin E, ascorbate), and activities of SOD, catalase, and glutathione peroxidase. We will determine the rate of onset; duration, degree, and gestational timing of E exposure needed to elicit effects; and the reversibility of these parameters.
Specific Aim 2 will develop treatment regimens to prevent or reduce this oxidative stress and its consequences. To this end, we will optimize oxidative defenses in E-exposed fetal tissues by maintaining GSH stores (with N- acetylcysteine, S-adenosylmethionine) and other antioxidants (vitamin E, ascorbate), and by administration of a xanthine oxidase inhibitor (AL). These treatments will be tested individually and in combination to be tailored to specific E exposure patterns and tissue requirements.
Specific Aim 3 will test the hypothesis that there are close connections between E-related oxidative stress and M damage and that this is an important factor in the fetotoxicity of E. We will define effects of E on M integrity and function (especially respiratory chain) with respect to onset, exposure pattern, and reversal by antioxidant treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010114-04
Application #
2457477
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1994-08-01
Project End
1999-03-31
Budget Start
1997-08-01
Budget End
1999-03-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Patel, Dhyanesh; Rathinam, Marylatha; Jarvis, Courtney et al. (2018) Role for Cystathionine ? Lyase (CSE) in an Ethanol (E)-Induced Lesion in Fetal Brain GSH Homeostasis. Int J Mol Sci 19:
Patel, Dhyanesh; Mahimainathan, Lenin; Narasimhan, Madhusudhanan et al. (2017) Ethanol (E) Impairs Fetal Brain GSH Homeostasis by Inhibiting Excitatory Amino-Acid Carrier 1 (EAAC1)-Mediated Cysteine Transport. Int J Mol Sci 18:
Riar, Amanjot Kaur; Narasimhan, Madhusudhanan; Rathinam, Mary Latha et al. (2016) Ethanol induces cytostasis of cortical basal progenitors. J Biomed Sci 23:6
Riar, Amanjot Kaur; Narasimhan, Madhusudhanan; Rathinam, Mary Latha et al. (2014) Ethanol-induced transcriptional activation of programmed cell death 4 (Pdcd4) is mediated by GSK-3? signaling in rat cortical neuroblasts. PLoS One 9:e98080
Narasimhan, Madhusudhanan; Riar, Amanjot Kaur; Rathinam, Mary Latha et al. (2014) Hydrogen peroxide responsive miR153 targets Nrf2/ARE cytoprotection in paraquat induced dopaminergic neurotoxicity. Toxicol Lett 228:179-91
Narasimhan, Madhusudhanan; Rathinam, Marylatha; Riar, Amanjot et al. (2013) Programmed cell death 4 (PDCD4): a novel player in ethanol-mediated suppression of protein translation in primary cortical neurons and developing cerebral cortex. Alcohol Clin Exp Res 37:96-109
Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G et al. (2012) Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain. J Biol Chem 287:43533-42
Narasimhan, Madhusudhanan; Rathinam, Marylatha; Patel, Dhyanesh et al. (2012) Astrocytes Prevent Ethanol Induced Apoptosis of Nrf2 Depleted Neurons by Maintaining GSH Homeostasis. Open J Apoptosis 1:
Kruman, Inna I; Henderson, George I; Bergeson, Susan E (2012) DNA damage and neurotoxicity of chronic alcohol abuse. Exp Biol Med (Maywood) 237:740-7
Narasimhan, Madhusudhanan; Patel, Dhyanesh; Vedpathak, Dhanashree et al. (2012) Identification of novel microRNAs in post-transcriptional control of Nrf2 expression and redox homeostasis in neuronal, SH-SY5Y cells. PLoS One 7:e51111

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