Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology

Abstract

Excessive alcohol exposure has severe health consequences, and clinical and animal studies have demonstrated that disruptions in the epigenome of somatic cells, such as those in brain, are an important factor in the development of alcohol-related pathologies, such as alcohol-use disorders (AUDs) and fetal alcohol spectrum disorders (FASDs). It is also well known that alcohol-related health problems are passed down across generations in human populations, but the complete mechanisms for this phenomenon are currently unknown. Recent studies in animal models have suggested that epigenetic factors are also responsible for the transmission of alcohol-related pathologies across generations. Alcohol exposure has been shown to induce changes in the epigenome of sperm of exposed male animals, and these epimutations are inherited in the offspring. This paper reviews evidence for multigenerational and transgenerational epigenetic inheritance of alcohol-related pathology through the germline. We also review the literature on the epigenetic effects of alcohol exposure on somatic cells in brain, and its contribution to AUDs and FASDs. We note gaps in knowledge in this field, such as the lack of clinical studies in human populations and the lack of data on epigenetic inheritance via the female germline, and we suggest future research directions.

Keywords: Birth outcome; DNA methylation; Fetal alcohol; Germline transmission; Offspring anxiety behavior; Offspring stress response; Preconception alcohol.

Fig. 1

Role of epigenetic processes in the development of FASD. In vivo and in vitro studies have shown evidence that early developmental exposure to alcohol alters DNA methylation (Bekdash et al., 2013; Chen et al., 2013; Downing et al., 2011; Garro et al., 1991; Govorko et al., 2012; Kim et al., 2013; Liu et al., 2009; Marutha Ravindran & Ticku, 2004; Qiang et al., 2010; Zhang et al., 2014) histone modifications (Bekdash et al., 2013; Guo et al., 2011; Veazey et al., 2013), and miRNAs (Marjonen et al., 2015; Sathyan et al., 2007; Wang et al., 2009). The genes targeted by these modifications are regulators of development, metabolism, neural maturation, learning and memory, motor coordination, and stress. These studies provide evidence that these epigenetic modifications are involved in mediating the development of FASD symptoms.

Fig. 2

Mechanisms for transgenerational inheritance of fetal alcohol-induced epigenetic marks on the Pomc gene and relation to stress axis disruption. Fetal alcohol exposure induces epigenetic modifications on the Pomc gene and hyper-stress response in male and female F1 offspring. These epigenetic changes and functional defects are carried on to the F2 and F3 generations via the male, but not female, germline (Govorko et al., 2012). Specifically, fetal alcohol exposure leads to increased repressive epigenetic marks on histones in Pomc-producing hypothalamic neurons including increased de-acetylation by HDACs. Fetal alcohol exposure also leads to increased levels of DNMTs and increased methylation of the Pomc promotor, leading to reduced hypothalamic expression of Pomc, reduced hypothalamic production of the protein β-endorphin (β-EP), and increased stress response. Hypermethylation of the Pomc gene in the hypothalamus is accompanied by a similar hypermethylation of Pomc in sperm cells in the F1-F3 males.