Children and young adults who were exposed to alcohol during fetal life often show fetal alcohol spectrumdisorders (FASD) consisting of learning disabilities, emotional disturbances, stress abnormalities and immuneincompetence. Furthermore, some grandparents who had alcohol-related medical problems often hadgrandchildren with a higher rate of fetal alcohol syndrome than those grandparents without alcohol-relatedmedical problems. Epidemiological studies also have shown association of paternal alcohol consumption withdeficiencies in offspring—effects which are typically found with maternal alcohol exposure. However, theprocess underlying the heritability of alcohol-induced health issues is not clearly understood. Our recentstudies identified an epigenetic mechanism in the heritable effect of fetal alcohol on stress response abnormalities and immune dysfunctions. These studies showed that the proopiomelanocortin (Pomc) gene,which negatively controls the functions of the stress axis and stimulates the functions of the immune systems,is hypermethylated while the response of stress axis hormones and the production of the cytokine interferon-γ(IFN-γ) is dysregulated in fetal alcohol exposed offspring for three generations via the male germline. However,the process by which these epigenetic variants induced by fetal alcohol are transmitted from parents tooffspring through multiple generations has not been established. We hypothesize that a transcription factor like sex-determining region Y (SRY), which has significant control over Pomc gene expression, undergoesheritable epigenetic modifications by fetal alcohol exposures that in turn modify the expression of the Pomcgene and its endophenotypes. The objective of this proposal is to determine the heritable epigenetic effects ofalcohol exposure during the prenatal period on SRY-mediated Pomc gene expression and its endophenotypes,i.e., the stress hormone response and IFN-γ production to an immune challenge, in isogenic Fischer 344 rats.This research aim will be achieved by determining the relationship between the fetal alcohol epigenetic markson Pomc and its endophenotypes with the epigenetic marks on the Sry gene in the isogenic rat population inthree generations of offspring, studying the interaction between SRY and Pomc at the molecular level, andevaluating whether increased methylation affects SRY interaction with the Pomc promoter and contributes tofetal alcohol effects on Pomc and its endophenotypes. Various state of the art techniques will be employed involving promoter methylation, promoter demethylation, promoter activity, mutational analysis, gene knockdown, in vivo electroporation for gene overexpression, and stress and immune response studies. These studies will establish the process by which developmental alcohol exposure induces gene expression variantsin the offspring and how they are transmitted to next generations. Knowledge on the process involved in theheritability of alcohol-induced epigenetic variants may help in establishing new biomarkers and novelepigenetic-based therapies for many alcohol-related disorders.
|Effective start/end date||8/1/17 → 6/30/22|
- National Institutes of Health (NIH)
Fetal Alcohol Spectrum Disorders