Behavioral and Epigenetic Consequences of Paternal Alcohol Exposure



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Familial transmission of alcohol use disorders reflects genetic and environmental factors. For decades, studies in rodents demonstrated that paternal alcohol exposure produces cognitive and physiological abnormalities in offspring. The mechanisms of these effects may reflect epigenetic modifications transmitted through the male germ line. While mouse studies show that paternal alcohol exposure alters sensitivity to alcohol in offspring, no studies have examined whether paternal alcohol exposure impacts sensitivity to unconditioned and reinforcing effects of alcohol using genetically diverse rat strains. We exposed male Wistar rats to a chronic intermittent ethanol procedure (CIE) in alcohol vapor chambers (16 h/day; 5 days/week; 6 weeks) or to air. Eight weeks later, rats were mated with alcohol-naive females and separate groups of adult offspring (F1) were assessed on a range of alcohol-induced behaviors and operant alcohol self-administration. In Experiment 1, separate groups of alcohol- and control-sired offspring were intragastrically administered alcohol (1.5 g/kg) or water 30 min prior to testing for general locomotor activity (open field), anxiety-like behaviors (elevated plus maze [EPM]), and motor coordination (rotarod). We found that alcohol reduced locomotor activity in alcohol-sired male offspring but not alcohol-sired female or control-sired offspring. Alcohol-sired males showed less anxiety-like behavior on the EPM regardless of treatment. Alcohol-sired males were resistant but alcohol-sired females were more sensitive to alcohol-induced impairments in motor coordination relative to their respective controls. In Experiment 2, alcohol- and control-sired offspring were trained to lever press for increasing alcohol concentrations (2.5%, 5%, & 10%, v/v). Tests were conducted under a progressive ratio (PR) schedule of reinforcement at 5% and 10% alcohol. Extinction training was followed by reinstatement tests and reinitiation procedures. During acquisition training sessions, alcohol-sired offspring self-administered less alcohol (5% & 10%) relative to control-sired offspring. Under progressive ratio tests, alcohol-sired offspring self-administered less alcohol (5% & 10%) relative to control-sired offspring. Alcohol-sired offspring displayed lower responding during extinction training and blunted relapse-like behavior during reinstatement. During reinitiation, alcohol-sired offspring self-administered less alcohol relative to control-sired offspring. In Experiment 3, global and brain-derived neurotrophic factor (Bdnf) DNA methylation levels were measured in sperm, the medial prefrontal cortex, and the nucleus accumbens of sires and adult offspring. Global methylation levels varied by tissue in alcohol sires compared to controls, but no changes were seen in offspring. Alcohol sires had lower Bdnf DNA methylation levels in the nucleus accumbens but higher methylation levels in the medial prefrontal cortex relative to control sires. Alcohol-sired offspring also had aberrant Bdnf DNA methylation levels in the nucleus accumbens that varied as a function of sex and CpG site. Overall, results indicate that paternal alcohol exposure prior to conception induces long-lasting behavioral and epigenetic effects that reflect an alcohol resistant phenotype in offspring.



Alcohol, Epigenetics, Operant self-administration, DNA methylation


Portions of this document appear in: Nieto, Steven J., and Therese A. Kosten. "Who’s your daddy? Behavioral and epigenetic consequences of paternal drug exposure." International Journal of Developmental Neuroscience (2019).