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

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