Cocaine-Induced Changes in Sperm Cdkn1a Methylation Are Associated with Cocaine Resistance in Male Offspring

• Published in: The Journal of neuroscience 2022-04, Vol.42 (14), p.2905-2916
• Main Authors: Swinford-Jackson, Sarah E, Fant, Bruno, Wimmer, Mathieu E, Chan, Donovan, Knouse, Melissa C, Sarmiento, Mateo, Thomas, Arthur S, Huffman, Phillip J, Mankame, Sharvari, Worobey, Samantha J, Pierce, R Christopher
• Format: Article
• Language: English
• Subjects: Animals; Cocaine; Cocaine - pharmacology; Cyclin-dependent kinase; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - pharmacology; Cyclin-dependent kinases; DNA methylation; DNA Methylation - drug effects; Drug self-administration; Enzyme inhibitors; Epigenesis, Genetic; Epigenetics; Females; Gene expression; Information transfer; Kinases; Male; Males; MicroRNAs - metabolism; miRNA; mRNA; Nucleus Accumbens; Offspring; Perturbation; Progeny; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Sperm; Spermatozoa - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3172-20.2022

Paternal environmental perturbations can influence the physiology and behavior of offspring. For example, our previous work showed reduced cocaine reinforcement in male, but not female, progeny of rat sires that self-administered cocaine. The information transfer from sire to progeny may occur through epigenetic marks in sperm, encompassing alterations in small noncoding RNAs, including microRNAs (miRNAs) and/or DNA methylation. Here, no reliable changes in miRNAs in the sperm of cocaine- relative to saline-experienced sires were identified. In contrast, 272 differentially methylated regions were observed in sperm between these groups. Two hypomethylated promoter regions in the sperm of cocaine-experienced rats were upstream of cyclin-dependent kinase inhibitor 1a ( ). mRNA also was selectively increased in the NAc of cocaine-sired male (but not female) offspring. Cocaine self-administration also enhanced expression in the accumbens of cocaine-sired rats. These results suggest that changes in may play a role in the reduced cocaine reinforcing efficacy observed in cocaine-sired male rats. Introducing a 90 d delay between sire self-administration and breeding reversed both cocaine resistance and the increase in accumbens mRNA in male offspring, indicating that cocaine-induced epigenetic modifications are eliminated with sperm turnover. Collectively, our results indicate that cocaine self-administration produces hypomethylation of in sperm and a selective increase in the expression of this gene in the NAc of male offspring, which is associated with blunted cocaine reinforcement. The relatively new field of transgenerational epigenetics explores the effects of environmental perturbations on offspring behavior and physiology. Our prior work in rats indicated that male, but not female, progeny of sires that self-administered cocaine displayed reduced cocaine reinforcement. The information transfer from sire to progeny may occur through heritable epigenetic marks in sperm, including DNA methylation. The present findings revealed two hypomethylated promoter regions upstream of the gene in sire sperm. Remarkably, expression was selectively decreased in offspring NAc, a brain region that regulates cocaine reinforcement.