Paternal alcohol exposure has task‐ and sex‐dependent behavioral effect in offspring

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2022-12, Vol.46 (12), p.2191-2202
• Main Authors: Nieto, Steven J., Harding, Mark J., Nielsen, David A., Kosten, Therese A.
• Format: Article
• Language: English
• Subjects: Alcohol; Alcohol Drinking; Alcohol use; Animals; anxiety; Anxiety - genetics; Behavior; DNA methylation; Epigenetics; Ethanol; Fathers; Female; Females; Gender differences; Humans; Locomotor activity; Male; Males; motor coordination; Nucleus accumbens; Offspring; Operant conditioning; Paternal Exposure - adverse effects; Prefrontal cortex; Rats; Reinforcement; Semen; Sex; sex differences; Sperm
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14964

Background Endophenotypes for alcohol use disorder are well known and may reflect paternal exposure effects passed down to offspring via epigenetic mechanisms. Previously, we showed that paternal alcohol exposure prior to conception attenuates the acquisition of operant alcohol self‐administration. We now test whether paternal alcohol exposure alters their offsprings' behavioral responses to alcohol (endophenotypes) and global DNA methylation levels in reward‐related brain regions. Methods Adult male rats were exposed to alcohol vapors or air for 6 weeks and mated with alcohol‐naïve females 8 weeks later. Adult male and female offspring of the alcohol‐ and control‐sired litters were tested on three behaviors 30 m after gavage with water or alcohol (1.5 g/kg): open field, elevated plus maze, and accelerating rotarod. Global DNA methylation levels in sperm, nucleus accumbens, and prefrontal cortex were examined in male sires and in another group of offspring. Results Alcohol‐sired males showed less anxiety‐like behavior in the elevated plus maze that was not affected by alcohol administration. By contrast, alcohol had anxiolytic effects in the open field in male offspring only with no paternal alcohol effect. Neither paternal alcohol exposure nor alcohol administration altered locomotor activity in either sex. Sex‐specific effects of paternal alcohol exposure were seen in the rotarod test. Alcohol‐sired male offspring showed blunted sensitivity to the alcohol's motor‐impairing effects, whereas alcohol‐sired female offspring showed enhanced sensitivity. Global DNA methylation was altered in the sperm of alcohol‐exposed males, but no changes were seen in their offspring. Conclusions Paternal alcohol exposure prior to conception has sex‐ and task‐dependent effects on unconditioned behaviors in their offspring. This study demonstrates that paternal alcohol exposure in outbred rats alters some behaviors in the offspring either in response to alcohol administration or under basal conditions. In some cases (e.g., motor coordination), the effect occurs in a sex‐dependent manner. While we find altered global DNA methylation in sperm of alcohol‐exposed sires, no changes are seen in offspring. These results contribute to growing literature showing alcohol or drug exposure in males prior to conception has enduring effects in the offspring.