AUTHOR=Gangisetty Omkaram , Mead Edward A. , Sarkar Dipak K. 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.608102

DOI=10.3389/fnins.2021.608102

ISSN=1662-453X

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