Fetal alcohol spectrum disorders and their transmission through genetic and epigenetic mechanisms

Abstract

Fetal alcohol spectrum disorders (FASD) are a group of related conditions that arise from prenatal exposure to maternal consumption of the teratogen, ethanol. It has been estimated that roughly 1% of children in the US suffer from FASD (Sampson etal., 1997), though in some world populations, such as inhabitants of some poorer regions of South Africa, the rate can climb to as high as 20% (May etal., 2013). FASD are the largest cause of mental retardation in U.S. neonates, and ironically, are entirely preventable. FASD have been linked to major changes in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in lifelong impairments through mental disorders, retardation, and sensitivity to stress. FASD are linked to an impaired immune system which consequently leads to an elevated risk of cancer and other diseases. FASD arise from a complex interplay of genetic and epigenetic factors. Here, we review current literature on the topic to tease apart what is known in these areas particularly emphasizing HPA axis dysfunction and how this ties into new studies of transgenerational inheritance in FASD.

Keywords: FASD; HPA axis; fetal alcohol; proopiomelanocortin; transgenerational epigenetic.

FIGURE 1

The impact of fetal alcohol exposure on the hypothalamic-pituitary-adrenal (HPA) axis. Fetal alcohol exposure increases DNA methyltransferase activity to methylate CpGs in the promoter of the POMC gene in the hypothalamus and activates histone deacetylases to remove acetyl groups from histones in the proximity of the POMC gene. Both methylation and deacetylation lead to the repression of POMC gene transcription. This results in reduced production of β-endorphin, a peptide derived from POMC gene, in the hypothalamus. Reduced β-endorphin production disrupts the normal feedback regulation of the HPA axis causing hyper-response of CRH following stress and subsequently, increased secretion of ACTH from the anterior pituitary and glucocorticoids (corticosterone in rats and cortisol in humans) from the adrenal gland. In fetal alcohol-exposed rats, the HPA axis is dysregulated resulting in hyperstress-response, mental dysfunction, and an impaired immune system. POMC gene hypermethylation and its subsequent impact on the HPA axis persist for a minimum of three generations of progeny, carried through the male germline.