title: Dose-dependent alcohol-induced alterations in chromatin structure persist beyond the window of exposure and correlate with fetal alcohol syndrome birth defects.
abstract: BACKGROUND
  In recent years, we have come to recognize that a multitude of in utero exposures have the capacity to induce the development of congenital and metabolic defects. As most of these encounters manifest their effects beyond the window of exposure, deciphering the mechanisms of teratogenesis is incredibly difficult. For many agents, altered epigenetic programming has become suspect in transmitting the lasting signature of exposure leading to dysgenesis. However, while several chemicals can perturb chromatin structure acutely, for many agents (particularly alcohol) it remains unclear if these modifications represent transient responses to exposure or heritable lesions leading to pathology.
  
  
  RESULTS
  Here, we report that mice encountering an acute exposure to alcohol on gestational Day-7 exhibit significant alterations in chromatin structure (histone 3 lysine 9 dimethylation, lysine 9 acetylation, and lysine 27 trimethylation) at Day-17, and that these changes strongly correlate with the development of craniofacial and central nervous system defects. Using a neural cortical stem cell model, we find that the epigenetic changes arising as a consequence of alcohol exposure are heavily dependent on the gene under investigation, the dose of alcohol encountered, and that the signatures arising acutely differ significantly from those observed after a 4-day recovery period. Importantly, the changes observed post-recovery are consistent with those modeled in vivo, and associate with alterations in transcripts encoding multiple homeobox genes directing neurogenesis. Unexpectedly, we do not observe a correlation between alcohol-induced changes in chromatin structure and alterations in transcription. Interestingly, the majority of epigenetic changes observed occur in marks associated with repressive chromatin structure, and we identify correlative disruptions in transcripts encoding Dnmt1, Eed, Ehmt2 (G9a), EzH2, Kdm1a, Kdm4c, Setdb1, Sod3, Tet1 and Uhrf1.
  
  
  CONCLUSIONS
  These observations suggest that the immediate and long-term impacts of alcohol exposure on chromatin structure are distinct, and hint at the existence of a possible coordinated epigenetic response to ethanol during development. Collectively, our results indicate that alcohol-induced modifications to chromatin structure persist beyond the window of exposure, and likely contribute to the development of fetal alcohol syndrome-associated congenital abnormalities.
authors.affiliation: Room 338 VMA, 4466 TAMU, Department of Veterinary Physiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4466 USA.
authors.forename: Kylee J
authors.initials: KJ
authors.lastname: Veazey
authors.affiliation: Bowles Center for Alcohol Studies and Department of Cell Biology and Physiology, School of Medicine, CB# 7178, University of North Carolina, Chapel Hill, NC 27599 USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Parnell
authors.affiliation: Texas A&M Health Sciences Center, Texas A&M University, 8441 State Highway 47, Clinical Building 1, Suite 3100, Bryan, TX 77807 USA.
authors.forename: Rajesh C
authors.initials: RC
authors.lastname: Miranda
authors.affiliation: Room 338 VMA, 4466 TAMU, Department of Veterinary Physiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4466 USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Golding
keywords: Chromatin; Developmental programming; Environmental epigenetics; Epigenetic inheritance; Epigenetics; Fetal alcohol syndrome; Neural stem cells; Neurodevelopmental programming; Teratogen