title: Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations.
abstract: 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.
authors.affiliation: Rutgers Endocrine Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Govorko
authors.forename: Rola A
authors.initials: RA
authors.lastname: Bekdash
authors.forename: Changqing
authors.initials: C
authors.lastname: Zhang
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Sarkar
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects*; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics* / Q000378:metabolism; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D018095:Germ-Line Mutation; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D011333:Pro-Opiomelanocortin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000431:Ethanol; D011333:Pro-Opiomelanocortin