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.
Highlights
Alcohol Use Disorder (AUD) is prevalent and contributes to substantial costs to both individuals and society
To determine if paternal EtOH exposure leads to lasting changes in brain gene expression in offspring, we examined Bdnf and Dlk1 expression in offspring ventral tegmental area (VTA) and medial profrontal cortex (mPFC)
We demonstrate in mice, where genotype effects can be rigorously controlled, that exposure of sires to EtOH prior to mating induces increased sensitivity to the anxiolytic and motor effects of EtOH and reduces EtOH preference and consumption exclusively in male offspring
Summary
Alcohol Use Disorder (AUD) is prevalent and contributes to substantial costs to both individuals and society. In rodent studies in which genetics and environment can be rigorously controlled, it is established that environmental perturbations can produce phenotypic (without genotypic) alterations in the subsequent 1–3+ generations that were themselves never exposed. In isogenic rodents, exposure to stress [7], endocrine disruptors [8], high fat diet [9], low protein diet [10], and olfactory fear conditioning [11] all can result in phenotypic changes in subsequent generations. Male offspring of cocaine-exposed sires surprisingly displayed a cocaine-resistance phenotype [13]. Prenatal exposure to ethanol (EtOH) was associated with transgenerational effects on POMC expression that was inherited through the male germ line [14]
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