Sex-Determining Region Y Controls the Effects of Fetal Alcohol Exposure on Proopiomelanocortin Gene Expression.

Fetal alcohol exposure (FAE) causes various neurodevelopmental deficits in offspring, including reduced expression of the stress regulatory proopiomelanocortin () gene and an elevated stress response for multiple generations via the male germline. Male germline-specific effects of FAE on the gene raises the question if the sex-determining region Y (SRY) may have a role in regulating gene expression. Using a transgenerational model of FAE in Fischer 344 rats, we determined the role of SRY in the regulation of the gene. FAEs, like on the gene, reduced gene expression in sperm and the mediobasal hypothalamus (MBH) in male adult offspring. Fetal alcohol-induced inhibition of gene expression was associated with increased promoter DNA methylation. Additionally, fetal alcohol effects on the gene persisted for three generations in the male germline but not in the female germline. gene knockdown reduced the gene expression. recruitment onto the promoter was found to be reduced in the hypothalamus of fetal alcohol-exposed rats compared to control rats. promoter luciferase activity was increased following overexpression. A site-directed mutagenesis study revealed that binding sites are required for promoter transcription activity. Overall, these findings suggest that SRY plays a stimulatory role in the regulation of gene expression and may potentially contribute to the fetal alcohol-induced changes in the level of gene expression for multiple generations.