BACKGROUND: Neurons containing proopiomelanocortin (POMC)-derived peptides, 
known to control stress axis, metabolic, and immune functions, have a lower 
function in patients with a family history of alcoholism, raising the 
possibility that alcohol effects on the POMC system may transmit through 
generations. Here we describe epigenetic modifications of Pomc gene that 
transmit through generation via male germline and may be critically involved in 
alcoholism-inherited diseases.
METHODS: Whether an epigenetic mechanism is involved in causing a Pomc 
expression deficit in fetal alcohol-exposed rats is studied by determining Pomc 
gene methylation, expression, and functional abnormalities and their 
normalization following suppression of DNA methylation or histone acetylation. 
Additionally, transgenerational studies were conducted to evaluate the 
germline-transmitted effect of alcohol.
RESULTS: Fetal alcohol-exposed male and female rat offspring showed a 
significant deficit in POMC neuronal functions. Associated with this was an 
increased methylation status of several CpG dinucleotides in the proximal part 
of the Pomc promoter region and altered level of histone-modifying proteins and 
DNA methyltransferases levels in POMC neurons. Suppression of histone 
deacetylation and DNA methylation normalized Pomc expression and functional 
abnormalities. Fetal alcohol-induced Pomc gene methylation, expression, and 
functional defects persisted in the F2 and F3 male but not in female germline. 
Additionally, the hypermethylated Pomc gene was detected in sperm of fetal 
alcohol-exposed F1 offspring that was transmitted through F3 generation via male 
germline.
CONCLUSIONS: Trangenerational epigenetic studies should spur new insight into 
the biological mechanisms that influence the sex-dependent difference in genetic 
risk of alcoholism-inherited diseases.