Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation

Abstract

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (−T); (2) Trauma, No Symptoms (T − S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the −T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T − S group. There were no differences between the T − S group and − T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Keywords:

• NR3C1
• FKBP5
• placenta
• trauma
• PTSD
• pregnancy

Acknowledgments

We are grateful to the pregnant individuals who contributed to this study. We also thank the Maternal-Infant Studies Laboratory staff for their assistance with data collection.

Disclosure statement

All authors have no conflicts of interest to declare.

CRediT author statement

Laura R. Stroud: Conceptualization, Methodology, Investigation, Resources, Supervision, Project Administration, Funding Acquisition, Writing – Review and Editing.

Nancy C. Jao: Conceptualization, Methodology, Formal Analysis, Data Curation, Visualization.

L. G. Ward: Writing – Original Draft.

Sharon Y. Lee: Writing – Original Draft.

Carmen J. Marsit: Supervision, Writing – Review and Editing.

Additional information

Funding

Funding for this study and manuscript preparation was supported by the National Institutes of Health (NIH) under grants R01DA031188, R01DA044504, R01DA045492, R01DA056787, and P20GM139767 to LRS, and U24ES028507 to CJM and LRS. NCJ was supported by grants T32HL076134 and K01HL164670. LGW was supported by K23HD107296. SYL was supported by T32HD101392, P20GM139767, and American Heart Association 23CDA1039160. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. NIH had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the article for publication.

Notes on contributors

Laura R. Stroud

Laura R. Stroud, PhD, is a Professor of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, and directs the COBRE Center for Stress, Trauma, and Resilience (STAR) at The Miriam Hospital. Her research focuses on biobehavioral mechanisms underlying the intergenerational transmission of stress, trauma, and substance use.

Nancy C. Jao

Nancy C. Jao, PhD, is an Assistant Professor in the Department of Psychology at Rosalind Franklin University of Medicine and Science. Dr. Jao’s research investigates biopsychosocial and behavioral risk factors affecting health outcomes and disparities, particularly focusing on tobacco use and marginalized or vulnerable populations.

L. G. Ward

L. G. Ward, Ph.D., is a Clinical Psychologist and Assistant Professor of Psychiatry and Human Behavior at the Warren Alpert Medical School of Brown University and the Center for Preventive and Behavioral Medicine. Dr. Ward’s research focuses on strategies to promote trauma-informed obstetric care.

Sharon Y. Lee

Sharon Y. Lee, PhD, is an Assistant Professor of Psychiatry and Human Behavior at the Warren Alpert Medical School of Brown University. Dr. Lee’s research focuses on biobehavioral mechanisms linking psychological trauma and stress with increased risk for cardiovascular and other diseases.

Carmen J. Marsit

Carmen J. Marsit, PhD, is Rollins Distinguished Professor in the Ganagarosa Department of Environmental Health at the Emory Rollins School of Public Health. He is a molecular epidemiologist whose research examines the mechanisms underlying the developmental origins of health and disease focusing on impacts to the placenta.