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 #
5R37AA008757-17
Application #
8401175
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Regunathan, Soundar
Project Start
1991-08-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
17
Fiscal Year
2013
Total Cost
$344,778
Indirect Cost
$121,069
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; Franklin, Tina; Sarkar, Dipak K (2016) Inhibition of Mammary Cancer Progression in Fetal Alcohol Exposed Rats by β-Endorphin Neurons. Alcohol Clin Exp Res 40:134-40
Sarkar, Dipak K (2016) Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review. Addict Biol 21:23-34
Logan, Ryan W; Wynne, Olivia; Maglakelidze, George et al. (2015) β-endorphin neuronal transplantation into the hypothalamus alters anxiety-like behaviors in prenatal alcohol-exposed rats and alcohol-non-preferring and alcohol-preferring rats. Alcohol Clin Exp Res 39:146-57
Zhang, Changqing; Murugan, Sengottuvelan; Boyadjieva, Nadka et al. (2015) Beta-endorphin cell therapy for cancer prevention. Cancer Prev Res (Phila) 8:56-67
Sarkar, Dipak K (2015) Fetal alcohol exposure increases susceptibility to carcinogenesis and promotes tumor progression in prostate gland. Adv Exp Med Biol 815:389-402
Murugan, Sengottuvelan; Boyadjieva, Nadka; Sarkar, Dipak K (2014) Protective effects of hypothalamic beta-endorphin neurons against alcohol-induced liver injuries and liver cancers in rat animal models. Alcohol Clin Exp Res 38:2988-97
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
Gangisetty, Omkaram; Bekdash, Rola; Maglakelidze, George et al. (2014) Fetal alcohol exposure alters proopiomelanocortin gene expression and hypothalamic-pituitary-adrenal axis function via increasing MeCP2 expression in the hypothalamus. PLoS One 9:e113228

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