Graduation Year

2024

Document Type

Thesis

Degree

M.S.P.H.

Degree Name

MS in Public Health (M.S.P.H.)

Degree Granting Department

Public Health

Major Professor

Monica Uddin, Ph.D.

Committee Member

Derek Wildman, Ph.D.

Committee Member

Chengqi Wang, Ph.D.

Keywords

adverse childhood experiences, cortisol reactivity, DNA methylation, sex differences, Stress response

Abstract

Childhood trauma has been shown to significantly impact physical and mental health outcomes, leading to conditions such as heart disease, diabetes, depression, and difficulties in decision-making and maintaining relationships. Exposure to such trauma has the potential to dysregulate an individual’s stress response system, resulting in abnormal cortisol levels. Many studies suggest a lasting impact of early-life stress on DNA methylation patterns and, separately, cortisol stress reactivity. In addition, there are known sex differences in exposure to childhood trauma and cortisol reactivity; yet studies to date have not investigated whether there is an association to DNA methylation. This study utilized a pre-existing dataset consisting of DNA methylation and cortisol values for 43 men and 42 women who experienced varying levels of childhood trauma to test whether there are sex differences in the association between DNA methylation and cortisol stress reactivity. A stratified analysis was conducted to detect differentially methylated regions (DMRs), separately for each sex, using the mCSEA package in R. 1093 Significant DMRs were identified in males, and 596 in females. The CpGs beta values for the DMRs of interest were extracted for each sex and the average was taken, along with the average cortisol levels for each participant. A correlation analysis was run between sex-stratified DMRs and cortisol for a total of 21 DMRs of interest, seven unique in females, seven unique in males, and seven that were shared amongst sexes. The correlation analysis for seven DMRs shared between males and females indicated that three out of the seven DMRs were significantly, negatively correlated (p < 0.05): SLC39A7 and BRD2 for males, and HOXA5 for females; none of these DMRs were significantly correlated for both sexes. Additionally, among the seven shared DMRs, four displayed opposite directions of effect, with three showing negative correlations between methylation and cortisol in men vs. positive correlations in women. Among the four DMRs that displayed opposite directions of effect, two were significantly correlated for males and none were significantly correlated for females. The correlation analysis looking at seven unique, sex-specific DMRs displayed no significant correlations with cortisol in this study. A better understanding of these mechanisms has the potential to provide better insight into how stress-related disorders manifest differently, or similarly, in men and women and improve long-term health outcomes and sex-specific treatment options.

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