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Cocaine-Induced Changes in Sperm Cdkn1a Methylation Are Associated with Cocaine Resistance in Male Offspring
Swinford-Jackson, Sarah E. Fant, Bruno Wimmer, Mathieu E. Chan, Donovan Sarmiento, Mateo Thomas, Arthur S. Huffman, Phillip J. Mankame, Sharvari Worobey, Samantha J.
Swinford-Jackson, Sarah E.
Fant, Bruno
Wimmer, Mathieu E.
Chan, Donovan
Sarmiento, Mateo
Thomas, Arthur S.
Huffman, Phillip J.
Mankame, Sharvari
Worobey, Samantha J.
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Journal article
Date
2022-04-06
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Psychology and Neuroscience
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http://dx.doi.org/10.1523/jneurosci.3172-20.2022
Abstract
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 (Cdkn1a). Cdkn1a mRNA also was selectively increased in the NAc of cocaine-sired male (but not female) offspring. Cocaine self-administration also enhanced Cdkn1a expression in the accumbens of cocaine-sired rats. These results suggest that changes in Cdkn1a 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 Cdkn1a 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 Cdkn1a 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.
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Cocaine-Induced Changes in Sperm Cdkn1a Methylation Are Associated with Cocaine Resistance in Male Offspring Sarah E. Swinford-Jackson, Bruno Fant, Mathieu E. Wimmer, Donovan Chan, Melissa C. Knouse, Mateo Sarmiento, Arthur S. Thomas, Phillip J. Huffman, Sharvari Mankame, Samantha J. Worobey, R. Christopher Pierce Journal of Neuroscience 6 April 2022, 42 (14) 2905-2916; DOI: 10.1523/JNEUROSCI.3172-20.2022
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Society for Neuroscience
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The Journal of Neuroscience, Vol. 42
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