Front Genet. 2014 Aug 05;5:261. doi: 10.3389/fgene.2014.00261. eCollection 2014.

Hypothesis: genetic and epigenetic risk factors interact to modulate vulnerability and resilience to FASD.

Frontiers in genetics

Elif Tunc-Ozcan, Laura J Sittig, Kathryn M Harper, Evan N Graf, Eva E Redei

PMID: 25140173 PMCID: PMC4122175 DOI: 10.3389/fgene.2014.00261

Abstract

Fetal alcohol spectrum disorder (FASD) presents a collection of symptoms representing physiological and behavioral phenotypes caused by maternal alcohol consumption. Symptom severity is modified by genetic differences in fetal susceptibility and resistance as well as maternal genetic factors such as maternal alcohol sensitivity. Animal models demonstrate that both maternal and paternal genetics contribute to the variation in the fetus' vulnerability to alcohol exposure. Maternal and paternal genetics define the variations in these phenotypes even without the effect of alcohol in utero, as most of these traits are polygenic, non-Mendelian, in their inheritance. In addition, the epigenetic alterations that instigate the alcohol induced neurodevelopmental deficits can interact with the polygenic inheritance of respective traits. Here, based on specific examples, we present the hypothesis that the principles of non-Mendelian inheritance, or "exceptions" to Mendelian genetics, can be the driving force behind the severity of the prenatal alcohol-exposed individual's symptomology. One such exception is when maternal alleles lead to an altered intrauterine hormonal environment and, therefore, produce variations in the long-term consequences on the development of the alcohol-exposed fetus. Another exception is when epigenetic regulation of allele-specific gene expression generates disequilibrium between the maternal vs. paternal genetic contributions, and thereby, modifies the effect of prenatal alcohol exposure on the fetus. We propose that these situations in which one parent has an exaggerated influence over the offspring's vulnerability to prenatal alcohol are major contributing mechanisms responsible for the variations in the symptomology of FASD in the exposed generation and beyond.

Keywords: allele specific expression; prenatal ethanol; rat; second generation; strain differences; thyroid hormones

References

1. Neurosci Biobehav Rev. 2010 May;34(6):791-807 - PubMed
2. Endocrinology. 1997 Jan;138(1):389-96 - PubMed
3. Biol Psychiatry. 2012 Sep 1;72(5):378-88 - PubMed
4. Mol Psychiatry. 2011 Aug;16(8):786-7 - PubMed
5. Curr Opin Genet Dev. 2004 Apr;14(2):188-95 - PubMed
6. Epigenetics. 2012 Feb;7(2):119-30 - PubMed
7. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17046-9 - PubMed
8. Alcohol Clin Exp Res. 2002 Jan;26(1):53-8 - PubMed
9. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jul 1;35(5):1178-91 - PubMed
10. Lancet. 1989 Sep 9;2(8663):577-80 - PubMed
11. Matern Child Health J. 2008 Nov;12(6):760-5 - PubMed
12. Alcohol Clin Exp Res. 2011 Jul;35(7):1293-304 - PubMed
13. Alcohol Clin Exp Res. 2012 Aug;36(8):1340-54 - PubMed
14. Alcohol. 2010 Nov-Dec;44(7-8):659-71 - PubMed
15. Alcohol Clin Exp Res. 2009 Jul;33(7):1238-45 - PubMed
16. Neurosci Biobehav Rev. 2007;31(2):230-8 - PubMed
17. Front Genet. 2012 Dec 14;3:296 - PubMed
18. PLoS One. 2013 Jul 15;8(7):e66318 - PubMed
19. Alcohol Clin Exp Res. 2000 Jan;24(1):17-23 - PubMed
20. Alcohol Clin Exp Res. 1991 Jun;15(3):395-8 - PubMed
21. Acta Paediatr Suppl. 2004 Dec;93(446):26-33 - PubMed
22. Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E31-9 - PubMed
23. Front Genet. 2014 Jun 02;5:154 - PubMed
24. Physiol Genomics. 2014 Mar 1;46(5):159-68 - PubMed
25. BMC Genomics. 2013 Oct 22;14:725 - PubMed
26. Reprod Toxicol. 2011 May;31(4):507-12 - PubMed
27. Alcohol. 2011 Feb;45(1):65-71 - PubMed
28. Neurotoxicol Teratol. 2002 Mar-Apr;24(2):173-8 - PubMed
29. Science. 2010 Aug 6;329(5992):643-8 - PubMed
30. Alcohol Clin Exp Res. 2007 Sep;31(9):1598-610 - PubMed
31. Dis Model Mech. 2013 Jul;6(4):977-92 - PubMed
32. Nat Rev Genet. 2011 Jul 12;12(8):529-41 - PubMed
33. ISRN Pediatr. 2012;2012:975685 - PubMed
34. Biol Reprod. 2009 Oct;81(4):607-17 - PubMed
35. Nat Rev Genet. 2012 Jan 04;13(2):97-109 - PubMed
36. Alcohol Res. 2013;35(1):18-24 - PubMed
37. Am J Physiol Endocrinol Metab. 2004 Aug;287(2):E318-26 - PubMed
38. In Vivo. 2006 Mar-Apr;20(2):293-300 - PubMed
39. BMJ. 1990 Aug 4;301(6746):259-62 - PubMed
40. Philos Trans R Soc Lond B Biol Sci. 2013 Jan 5;368(1609):20110330 - PubMed
41. PLoS Genet. 2010 Jan 15;6(1):e1000811 - PubMed
42. Science. 2001 Aug 10;293(5532):1089-93 - PubMed
43. Alcohol Clin Exp Res. 2013 Nov;37(11):1986-95 - PubMed
44. Physiol Behav. 1994 Jun;55(6):1147-50 - PubMed
45. Exp Toxicol Pathol. 2011 Nov;63(7-8):607-11 - PubMed
46. Mol Psychiatry. 2005 Oct;10(10):961-71 - PubMed
47. Diabetologia. 1993 Jan;36(1):62-7 - PubMed
48. Acta Psychiatr Scand. 1996 Jun;93(6):470-6 - PubMed
49. Alcohol Clin Exp Res. 2011 Mar;35(3):559-65 - PubMed
50. Front Genet. 2012 Feb 22;3:10 - PubMed
51. Alcohol Clin Exp Res. 1997 Feb;21(1):28-34 - PubMed
52. FASEB J. 2011 Jul;25(7):2313-24 - PubMed
53. Nat Biotechnol. 2013 Feb;31(2):142-7 - PubMed
54. Alcohol Clin Exp Res. 1990 Aug;14(4):539-45 - PubMed
55. PLoS One. 2010 Apr 07;5(4):e10058 - PubMed

Publication Types

• Journal Article

Grant support

• F31 AA018251/AA/NIAAA NIH HHS/United States
• R01 AA017978/AA/NIAAA NIH HHS/United States