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Prenatal Stress Induces Long-Term Behavioral Sex-Dependent Changes in Rats Offspring: the Role of the HPA Axis and Epigenetics

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Abstract

Preclinical genetic studies have related stress early exposures with changes in gene regulatory mechanisms, including epigenetic alterations, such as modifications of DNA methylation, histone deacetylation, and histones acetylation. This study evaluates the effects of prenatal stress on the behavior, hypothalamus-pituitary-adrenal (HPA)-axis, and epigenetic parameters in stressed dams and their offspring. The rats were subjected to a protocol of chronic unpredictable mild stress on the fourteenth day of pregnancy until the birth of offspring. After birth, maternal care was evaluated for six days. Following weaning, the locomotor and depressive-like behaviors of the dams and their offspring (60 days old) were assessed. The HPA axis parameters were evaluated in serum from dams and offspring, and epigenetic parameters (histone acetyltransferase (HAT), histone deacetylase (HDAC), DNA methyltransferase (DNMT) activities, and the levels of histone H3 acetylated at lysine residue 9 (H3K9ac) and histone 3 acetylated at lysine residue 14 (H3K14ac)) were assessed in dams’ and offspring’ brains. Prenatal stress did not significantly influence maternal care; however, it induced manic behavior in female offspring. These behavioral alterations in the offspring were accompanied by hyperactivity of the HPA-axis, epigenetic adaptations in the activity of HDAC and DNMT, and acetylation in the histones H3K9 and H3K14. In addition, the prenatal stressed female offspring showed increased levels of ACTH compared to their male counterpart. Our findings reinforce the impact of prenatal stress on behavior, stress response, and epigenetic profile of offspring.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

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Acknowledgments

We would like to acknowledge CNPq, CAPES, FAPESC and Instituto Cérebro e Mente for the support during the development of the present study.

Funding

Translational Psychiatry Program (USA) is funded by a grant from the National Institute of Health/National Institute of Mental Health (1R21MH117636-01A1, to JQ). Center of Excellence on Mood Disorders (USA) is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation and Anne and Don Fizer Foundation Endowment for Depression Research. Translational Psychiatry Laboratory (Brazil) is funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), and Instituto Cérebro e Mente. JQ, SSV, and AIZ are CNPq Research Fellows.

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Authors and Affiliations

  1. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Taise Possamai-Della, José Henrique Cararo, Jorge M. Aguiar-Geraldo, Jefté Peper-Nascimento, Alexandra I. Zugno, João Quevedo & Samira S. Valvassori

  2. Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Gabriel R. Fries & João Quevedo

  3. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Gabriel R. Fries

  4. Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Gabriel R. Fries & João Quevedo

  5. Center for Interventional Psychiatry, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, USA

    João Quevedo

Authors
  1. Taise Possamai-Della
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  2. José Henrique Cararo
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  3. Jorge M. Aguiar-Geraldo
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  4. Jefté Peper-Nascimento
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  5. Alexandra I. Zugno
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  6. Gabriel R. Fries
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  7. João Quevedo
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  8. Samira S. Valvassori
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Contributions

Samira S. Valvassori, Alexandra I. Zugno, and João Quevedo contributed to design and development; methodological design; supervision (responsible for organizing and executing the project); analysis/interpretation and critical review. Gabriel R. Fries contribute to critical review. Taise Possamai-Della, Jorge M. Aguiar-Geraldo, Jefté Peper-Nascimento and José H. Cararo performed animal experimentation, statistical analyzes, contributed to the analysis/interpretation, literature survey, and writing.

Corresponding author

Correspondence to Samira S. Valvassori.

Ethics declarations

Ethics Approval

All experiments were approved by the local ethics committee Comissão de Ética no Uso de Animais (CEUA) from UNESC under protocol number 014/2018. In addition, we followed the Conselho Nacional de Controle de Experimentação Animal (CONCEA) recommendations for animal care.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

JQ received clinical research support from LivaNova; has speaker bureau membership with Myriad Neuroscience, Janssen Pharmaceuticals, and Abbvie; is consultant for Eurofarma; is stockholder at Instituto de Neurociencias Dr. Joao Quevedo; and receives copyrights from Artmed Editora, Artmed Panamericana, and Elsevier/Academic Press. All other authors have no conflicts of interest.

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Possamai-Della, T., Cararo, J.H., Aguiar-Geraldo, J.M. et al. Prenatal Stress Induces Long-Term Behavioral Sex-Dependent Changes in Rats Offspring: the Role of the HPA Axis and Epigenetics. Mol Neurobiol 60, 5013–5033 (2023). https://doi.org/10.1007/s12035-023-03348-1

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