Alcohol use disorders (AUDs) are pervasive in society. Collectively, they incur enormous socioeconomic costs and contribute to tens of thousands of deaths each year. Therefore, it is of critical importance to develop new strategies for identifying people at increased risk for developing AUDs, which will likely improve prevention and treatment initiatives. Our proposal presents a novel approach to study transmission of alcohol drinking behaviors that contribute to risk for AUDs. About half of the risk for alcohol dependence (alcoholism) is transmitted from parents to offspring. While past research has focused on genes that modify risk for alcoholism, recent evidence suggests that acquired, epigenetic factors can be transmitted to offspring and affect their behavior. These epigenetic factors include DNA methylation and histone modifications, which are involved in regulating gene transcription. There is also strong evidence that preconception alcohol consumption by both mothers and fathers leads to behavioral deficits in offspring;moreover, a recent study showed that maternal preconception alcohol exposure induces changes in DNA methylation of offspring. However, no studies have examined the effect of paternal preconception alcohol consumption on alcohol drinking behaviors and the epigenetic landscape of offspring. To study the effects of paternal preconception alcohol exposure, we will expose male mice to alcohol for 5 weeks (one cycle of spermatogenesis) and mate them to alcohol-naive females. After mating, we will measure changes in DNA methylation in paternal germ cells. Offspring from these matings will be tested for changes in expression of enzymes that methylate DNA and modify histones in a key brain region for alcohol response. We will also use a comprehensive set of behavioral assays to test offspring for alcohol drinking behaviors and alcohol-induced behaviors during adulthood. Successful completion of the aims in our proposal will establish the effects of paternal preconception alcohol exposure on offspring behavior and uncover epigenetic changes that are likely mediators of these effects. These findings will be important for studying transgenerational inheritance of behaviors in the following generation. Our findings may also reveal new epigenetic targets for the treatment of alcoholism and fetal alcohol syndrome (FAS).
Our research proposal aims to study the effects of paternal alcohol exposure on alcohol drinking and alcohol- induced behaviors of offspring;moreover, we aim to identify epigenetic targets that may be mediating inheritance of these behaviors. This proposal is important because of the tremendous socioeconomic costs associated with alcoholism and its high degree of heritability. Given that few genes have been discovered that account for the heritability of alcoholism, studying epigenetic factors is an innovative approach for identifying how risk for alcoholism is transmitted from parents to offspring.
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|Rompala, Gregory R; Finegersh, Andrey; Homanics, Gregg E (2016) Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice. Alcohol 53:19-25|
|Finegersh, Andrey; Homanics, Gregg E (2016) Chromatin immunoprecipitation and gene expression analysis of neuronal subtypes after fluorescence activated cell sorting. J Neurosci Methods 263:81-8|
|Finegersh, Andrey; Rompala, Gregory R; Martin, David I K et al. (2015) Drinking beyond a lifetime: New and emerging insights into paternal alcohol exposure on subsequent generations. Alcohol 49:461-70|
|Finegersh, Andrey; Homanics, Gregg E (2014) Acute ethanol alters multiple histone modifications at model gene promoters in the cerebral cortex. Alcohol Clin Exp Res 38:1865-73|
|Finegersh, Andrey; Homanics, Gregg E (2014) Paternal alcohol exposure reduces alcohol drinking and increases behavioral sensitivity to alcohol selectively in male offspring. PLoS One 9:e99078|