Date of Award

5-1-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Epidemiology

First Advisor

Helen C Meier

Committee Members

Paul L Auer, Rebecca H Konkel, Dale P Sandler, Amanda M Simanek

Keywords

Biological embedding, Breast cancer, Cellular aging, DNA methylation, Early life trauma, Epigenetic modification

Abstract

The experience of trauma and psychosocial stress over the life course can have lasting impacts on health. Childhood and adolescence may serve as a particularly sensitive period during which trauma may become biologically embedded and affect adult health. Evaluating the pathways through which early life trauma can affect biological mechanisms of disease development provides insight into the early origins and etiology of adverse health outcomes in adulthood and provides potential targets to help mitigate their effects.

Using data from the Sister Study, a large prospective cohort study of women residing in the U.S. or Puerto Rico aged 35 to 74 with a sister previously diagnosed with breast cancer, we examined the relationship between early life trauma and three indicators of adult health—1) incident breast cancer risk, 2) DNA methylation of the glucocorticoid receptor gene (NR3C1), and 3) leukocyte telomere length. Much of the previous literature has depended upon summative trauma scores, traditional trauma domains (e.g., sexual trauma, physical trauma, household dysfunction), or single traumatic events to represent early life adversity. However, early life traumatic experiences rarely occur in isolation and the experience of trauma in early life is a risk factor for future revictimization. This dissertation utilizes a latent class approach to evaluate the effect of specific profiles of early profiles on the three measures of adult health and biological embedding of trauma, as well as uses a sensitive period life course model to examine whether early life trauma impacts 1) NR3C1 methylation and 2) leukocyte telomere length in adulthood independent of later life trauma or if adult trauma mediates these associations.

The findings from this dissertation suggest that the relationship between early life trauma and these three indicators of adult health are complex. There were no associations between traditional measures of early life trauma (e.g., summative scores or trauma domains) and incident breast cancer risk; however, compared to women who were classified in the latent class of early life trauma consisting of low early life trauma (i.e., the average probability of reporting any type of early life trauma was less than 2% across all possible traumatic events), the rate of incident breast cancer overall, as well as pre- and post- menopausal breast cancer, appeared higher among women belonging to the latent class of early life trauma consisting of both sexual trauma and family drug, alcohol, and/or mental health issues. This latent class of early life trauma was also associated with hypomethylation of cytosine-phosphate-guanine (CpG) sites located in the gene body of NR3C1. This association was also observed in a sensitive period life course model whereby the direct effect of early life trauma on decreased methylation was independent of trauma in adulthood. Finally, leukocyte telomere length was statistically significantly shorter in women classified in the latent class consisting of high early life trauma experience (i.e., the average probability of reporting each early life traumatic event was approximately 32%) compared to women classified in the latent class of low early life trauma experience independent of any indirect effect through trauma in adulthood.

The findings from this dissertation emphasize that the effect of early life trauma on incident breast cancer risk, NR3C1 methylation, and leukocyte telomere length in adulthood may be more nuanced than what is captured via a cumulative trauma score, assessment of a single traumatic event, or traditional trauma domains can capture. Traumatic experiences differ in duration and intensity and various traumatic experiences tend to cluster and cooccur, likely contributing to unique patterns of biological embedding, behavioral responses, and socioenvironmental trajectories that may further differentiate how early life trauma affects adult health. Measures that capture the unique combinations of concomitant early life trauma profiles are needed to fully elucidate the effects of different experiences of early life trauma on adult health. Doing so can assist in designing programs and early life interventions to address those trauma profiles that are most detrimental to future health. Furthermore, the experience of trauma can occur across the life course. Utilizing life course models can help to better understand the relationship between the experience of early life trauma and adult manifestations of the biological embedding of stress and trauma. The findings from this dissertation contribute to a more robust understanding of the relationship between early life trauma and incident breast cancer risk, adult circulating NR3C1 methylation, and leukocyte telomere length in adulthood and support the need to identify opportunistic windows for interventions over the life course in order to minimize these negative health outcomes and their impacts. Future research will need to continue to utilize complex measures of early life trauma and a life course framework before a unified picture of the association between the nuanced roles of early life trauma in shaping these health outcomes can be fully elucidated.

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