Alcohol consumption during pregnancy is a significant public health problem and may result in a wide range of adverse outcomes for the child. Many of these fetal alcohol exposed children show poor stress tolerance, immune system incompetence, and abnormalities in endocrine system functions. Using the rat as an animal model, our work during the previous funding period demonstrated that alcohol exposure during early life produces neurotoxicity of beta-endorphin neurons in the hypothalamus and causes a permanent defect in this neuronal control of stress axis and immune system functions. How ethanol exposure during early life produces a neurotoxic action on beta-endorphin neurons is not completely well understood. We hypothesize that ethanol's neurotoxic action on beta-endorphin neurons is caused by oxidative stress leading to microglia-mediated inflammation. To test this hypothesis we will determine whether highly reactive oxygen species and reactive nitrogen species generated extracellularly and intracellularly by various processes initiate and promote ethanol-induced apoptotic death of beta-endorphin neurons in the hypothalamus of newborn rats. Furthermore, we will evaluate whether ethanol induces reactive oxygen species generation and inflammatory response through activation of microglia. Additionally, we will study whether trophic factors that are known to regulate beta-endorphin functions inhibit the inflammatory response and correct the fundamental oxidant/antioxidant imbalance to prevent beta-endorphin neuronal death. We will use rats as an animal model in both in vivo and in vitro studies. We will employ standard histological methods to determine cell death by apoptosis or autophagy and use biochemical methods to determine the enzyme activities that cause oxidative stress and neuroinflammation. We will also employ state-of-the-art techniques like combined laser capture microdissection and quantitative real-time polymerase chain reaction to determine changes in gene expression in beta-endorphin cells in vivo. The proposed series of studies should continue to generate valuable data leading to better understanding of ethanol's neurotoxic action on developing beta-endorphin neurons. Additionally, the proposed research should identify compounds acting on novel targets to inhibit the release of a wide range of proinflammatory factors from overactivated microglia that might be critical for preventing of beta-endorphin neuronal death.

Public Health Relevance

Using the rat as an animal model, our work during the previous funding period demonstrated that alcohol exposure during early life produces neurotoxicity to beta-endorphin neurons in the hypothalamus and causes a permanent defect in this neuronal control of stress axis and immune system functions. The proposed series of studies in this proposal is aimed at improving our understanding of ethanol's neurotoxic action on beta-endorphin neurons as well as identifying compounds for preventing beta-endorphin neuronal death in order to develop pharmacotherapy for controlling poor stress tolerance and immune system incompetence in fetal alcohol exposed patients in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA008757-16
Application #
8212173
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Regunathan, Soundar
Project Start
1991-08-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
16
Fiscal Year
2012
Total Cost
$398,339
Indirect Cost
$139,186
Name
Rutgers University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Zhang, Changqing; Murugan, Sengottuvelan; Boyadjieva, Nadka et al. (2015) Beta-endorphin cell therapy for cancer prevention. Cancer Prev Res (Phila) 8:56-67
Chastain, Lucy G; Sarkar, Dipak K (2014) Role of microglia in regulation of ethanol neurotoxic action. Int Rev Neurobiol 118:81-103
Rachdaoui, Nadia; Sarkar, Dipak K (2014) Transgenerational epigenetics and brain disorders. Int Rev Neurobiol 115:51-73
Agapito, Maria A; Zhang, Changqing; Murugan, Sengottuvelan et al. (2014) Fetal alcohol exposure disrupts metabolic signaling in hypothalamic proopiomelanocortin neurons via a circadian mechanism in male mice. Endocrinology 155:2578-88
Bekdash, Rola; Zhang, Changqing; Sarkar, Dipak (2014) Fetal alcohol programming of hypothalamic proopiomelanocortin system by epigenetic mechanisms and later life vulnerability to stress. Alcohol Clin Exp Res 38:2323-30
Cermakian, Nicolas; Lange, Tanja; Golombek, Diego et al. (2013) Crosstalk between the circadian clock circuitry and the immune system. Chronobiol Int 30:870-88
Boyadjieva, Nadka I; Sarkar, Dipak K (2013) Cyclic adenosine monophosphate and brain-derived neurotrophic factor decreased oxidative stress and apoptosis in developing hypothalamic neuronal cells: role of microglia. Alcohol Clin Exp Res 37:1370-9
Bekdash, Rola A; Zhang, Changqing; Sarkar, Dipak K (2013) Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in *-endorphin-producing POMC neurons of the hypothalamus. Alcohol Clin Exp Res 37:1133-42
Rachdaoui, Nadia; Sarkar, Dipak K (2013) Effects of alcohol on the endocrine system. Endocrinol Metab Clin North Am 42:593-615
Murugan, Sengottuvelan; Zhang, Changqing; Mojtahedzadeh, Sepideh et al. (2013) Alcohol exposure in utero increases susceptibility to prostate tumorigenesis in rat offspring. Alcohol Clin Exp Res 37:1901-9

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