Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However, there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Sulforaphane (SFN) is a chemical that is abundant in broccoli sprouts. Compelling evidence indicates that SFN or SFN-rich broccoli sprouts trigger the induction of antioxidant enzymes through activation of Nrf2 signaling and prevent cancer and other diseases. It was recently discovered that SFN can regulate gene expression through epigenetic mechanisms. We have recently demonstrated that SFN can significantly diminish ethanol- induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to elucidate the epigenetic mechanisms by which SFN epigenetically regulates the anti-apoptotic gene expression and prevent ethanol-induced apoptosis, and to develop a safe and effective regimen to diminish the incidence and severity of FASD using SFN, a safe ?nutraceutical?. The central hypothesis of this project is that ethanol-induced epigenetic alterations lead to aberrant expression of the anti-apoptotic genes, resulting in excessive apoptosis and malformations in embryos, which can be prevented by epigenetic modulation elicited by SFN or SFN-rich broccoli sprout extract. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis, the following specific aims will be addressed:
Aim 1 : To identify the anti-apoptotic genes that are epigenetically silenced by ethanol and derepressed by SNF in ethanol-exposed NCCs and mouse embryos.
Aim 2 : To elucidate the mechanisms by which SFN epigenetically modulates the expression of the anti-apoptotic genes and apoptosis in ethanol- exposed NCCs and mouse embryos.
Aim 3 : To test the hypothesis that epigenetic modulation of the anti- apoptotic genes by maternal dietary SFN-rich broccoli sprout extract (BSE) represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. The proposed work is innovative, because it focuses on a novel approach, epigenetic modulation of the anti-apoptotic genes, to preventing ethanol-induced teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent FASD through the use of bioactive compounds derived from a vegetable. The results from this study will be significant, because they are expected to illustrate the potential of a practical nutraceutical-based therapeutic strategy for FASD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
1P50AA024337-01
Application #
8978014
Study Section
Special Emphasis Panel (ZAA1)
Project Start
2016-05-15
Project End
2021-04-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40208
Hardesty, Josiah E; Al-Eryani, Laila; Wahlang, Banrida et al. (2018) Epidermal Growth Factor Receptor Signaling Disruption by Endocrine and Metabolic Disrupting Chemicals. Toxicol Sci 162:622-634
Yuan, Fuqiang; Chen, Xiaopan; Liu, Jie et al. (2018) Sulforaphane restores acetyl-histone H3 binding to Bcl-2 promoter and prevents apoptosis in ethanol-exposed neural crest cells and mouse embryos. Exp Neurol 300:60-66
Zheng, Yuxuan; Ritzenthaler, Jeffrey D; Burke, Tom J et al. (2018) Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression. Free Radic Biol Med 118:13-22
Wang, Keling; Chen, Xiaopan; Liu, Jie et al. (2018) Embryonic exposure to ethanol increases the susceptibility of larval zebrafish to chemically induced seizures. Sci Rep 8:1845
Yuan, Fuqiang; Chen, Shao-Yu (2018) Manipulation of MicroRNAs in Cultured Mouse Embryos: Applications for Developmental Toxicology. Methods Mol Biol 1797:205-214
Liang, Yaqin; Lang, Anna L; Zhang, Jian et al. (2018) Exposure to Vinyl Chloride and Its Influence on Western Diet-Induced Cardiac Remodeling. Chem Res Toxicol 31:482-493
Kharbanda, Kusum K; Ronis, Martin J J; Shearn, Colin T et al. (2018) Role of Nutrition in Alcoholic Liver Disease: Summary of the Symposium at the ESBRA 2017 Congress. Biomolecules 8:
Ghosh Dastidar, Shubha; Warner, Jeffrey B; Warner, Dennis R et al. (2018) Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration. Biomolecules 8:
Gosney, Julie A; Wilkey, Daniel W; Merchant, Michael L et al. (2018) Proteomics reveals novel protein associations with early endosomes in an epidermal growth factor-dependent manner. J Biol Chem 293:5895-5908
Schuster, Susanne; Johnson, Casey D; Hennebelle, Marie et al. (2018) Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice. J Lipid Res 59:1597-1609

Showing the most recent 10 out of 50 publications