Paternal Alcohol Exposure Reduces Alcohol Drinking and Increases Behavioral Sensitivity to Alcohol Selectively in Male Offspring

Abstract

Alcohol use disorder (AUD) is heritable, but the genetic basis for this disease remains poorly understood. Although numerous gene variants have been associated with AUD, these variants account for only a small fraction of the total risk. The idea of inheritance of acquired characteristics, i.e. “epigenetic inheritance,” is re-emerging as a proven adjunct to traditional modes of genetic inheritance. We hypothesized that alcohol drinking and neurobiological sensitivity to alcohol are influenced by ancestral alcohol exposure. To test this hypothesis, we exposed male mice to chronic vapor ethanol or control conditions, mated them to ethanol-naïve females, and tested adult offspring for ethanol drinking, ethanol-induced behaviors, gene expression, and DNA methylation. We found that ethanol-sired male offspring had reduced ethanol preference and consumption, enhanced sensitivity to the anxiolytic and motor-enhancing effects of ethanol, and increased Bdnf expression in the ventral tegmental area (VTA) compared to control-sired male offspring. There were no differences among ethanol- and control-sired female offspring on these assays. Ethanol exposure also decreased DNA methylation at the BdnfÆpromoter of sire's germ cells and hypomethylation was maintained in the VTA of both male and female ethanol-sired offspring. Our findings show that paternal alcohol exposure is a previously unrecognized regulator of alcohol drinking and behavioral sensitivity to alcohol in male, but not female, offspring. Paternal alcohol exposure also induces epigenetic alterations (DNA hypomethylation) and gene expression changes that persist in the VTA of offspring. These results provide new insight into the inheritance and development of alcohol drinking behaviors.

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

“…In the first, paternal consumption in mice related to decreased DNAm of Bdnf-implicated in stress response and neural development-in paternal sperm cells and offspring ventral tegmental area [12]. In the second, paternal alcohol consumption in rats was associated with increased Pomc methylation (another gene relevant in stress response) within both parental sperm and offspring hypothalamus, although findings were specific to the male germline [13].…”

“…However, the studies reviewed did provide preliminary support for the relevance of timing of substance exposure on DNAm. For example, evidence from animal models demonstrated that substance exposure can influence DNAm even prior to conception, supporting the existence of transgenerational effects [12][13][14]. Studies also pointed to the prenatal period as a particularly sensitive developmental window.…”

“…Findings from candidate gene studies further indicated that alcohol exposure in adulthood is associated with increased DNAm in multiple genes, including the serotonin receptor Htr3a in blood and hippocampal tissue [23], the sodium transporter Slc5a6 gene in pancreatic tissue [24], and immune function TLR-pathway genes in the liver [25]. Decreased DNAm was instead observed for the glutamate gene Nr2b in the prefrontal cortex [26] and Bdnf gene in motile sperm [12]. Tissue-and gene-specific DNAm alterations were identified by one study in folate-regulating genes [27].…”

Epigenetics of Addiction: Current Knowledge, Challenges, and Future Directions

“…Animal studies have also provided some tentative evidence for intergenerational transmission of DNAm patterns implicated in addiction risk (e.g., Finegersh & Homanics, 2014) as well as normalization of drug-induced DNAm changes by chemical intervention (e.g., Bekdash et al, 2013). In humans, studies have also supported a link between DNAm and addiction, reporting methylomic differences (e.g., in neurotransmitter genes) between substance users and drug-free controls across a number of tissue types and substances (Cecil et al, 2015;Harlaar & Hutchison, 2013).…”

Cross-Generational Effects of Alcohol Dependence in Humans on HRAS and TP53 Methylation in Offspring

“…Cross generational effects have been reported with famine experienced by parents affecting medical conditions and longevity in offspring [13,14]. Although not previously reported in humans, animal studies have shown that ethanol administration can influence DNA methylation through the germline in offspring exposed either through fetal exposure [15] or as a result of paternal exposure [16,17]; changes with the potential to alter every somatic cell in the body across generations. Determining if alcohol consumption in the preconception period in parents influences genes involved in cancer risk in offspring is critical to improvement in prevention initiatives.…”