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Research Articles, Cellular/Molecular

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 and R. Christopher Pierce
Journal of Neuroscience 6 April 2022, 42 (14) 2905-2916; DOI: https://doi.org/10.1523/JNEUROSCI.3172-20.2022
Sarah E. Swinford-Jackson
1Brain Health Institute and Department of Psychiatry, Rutgers University, RWJMS Piscataway, New Jersey 08854
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Bruno Fant
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Mathieu E. Wimmer
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
3Department of Psychology, Neuroscience Program Temple University, Philadelphia, Pennsylvania 19122
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Donovan Chan
4Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
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Melissa C. Knouse
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
3Department of Psychology, Neuroscience Program Temple University, Philadelphia, Pennsylvania 19122
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  • ORCID record for Melissa C. Knouse
Mateo Sarmiento
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Arthur S. Thomas
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Phillip J. Huffman
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Sharvari Mankame
1Brain Health Institute and Department of Psychiatry, Rutgers University, RWJMS Piscataway, New Jersey 08854
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Samantha J. Worobey
1Brain Health Institute and Department of Psychiatry, Rutgers University, RWJMS Piscataway, New Jersey 08854
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R. Christopher Pierce
1Brain Health Institute and Department of Psychiatry, Rutgers University, RWJMS Piscataway, New Jersey 08854
2Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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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.

SIGNIFICANCE STATEMENT 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 Cdkn1a gene in sire sperm. Remarkably, Cdkn1a expression was selectively decreased in offspring NAc, a brain region that regulates cocaine reinforcement.

  • addiction
  • epigenetics
  • intergenerational
  • self-administration
  • transgenerational

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The Journal of Neuroscience: 42 (14)
Journal of Neuroscience
Vol. 42, Issue 14
6 Apr 2022
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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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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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Keywords

  • addiction
  • epigenetics
  • intergenerational
  • self-administration
  • transgenerational

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