Both exogenous (e.g., ionizing radiation) and endogenous (e.g., metabolic processes) factors are known to cause considerable DNA damage on a daily basis. Robust DNA repair mechanisms normally repair damage within minutes, but repair is not perfect. With each repair comes the risk of an error that could result in introduction of a DNA mutation contributing to increased risk of carcinogenesis. The overarching hypothesis of our program of research is that repeated exposures to daily psychological stresses may contribute to increased risk of cancer by repeatedly causing DNA damage. Support for a link between psychological stress and DNA damage comes from: 1) correlational studies in humans; 2) experimental stress studies in animals; and, 3) tissue culture studies demonstrating increased DNA damage after brief exposure to stress hormones, and prevention by specific neuroendocrine receptor blocking (e.g., with the beta-adrenergic antagonist, propranolol). Critically lacking are experimental studies to establish that increases in DNA damage in humans can be caused by psychological stress and reduced by propranolol. The goal of the research described here is to address those gaps in our knowledge. A diverse sample of participants (50% women, 50% African American) will be exposed to a controlled laboratory social stress challenge (Trier Social Stress Test, TSST), which is the most highly validated, broadly effective, and widely used stressor in human biobehavioral research. Total DNA damage (primary study outcome) in peripheral blood mononuclear cells (PBMCs) collected before and after exposure to the TSST will be assessed by single cell gel electrophoresis under alkaline conditions (the highly validated Comet assay) using a newly developed CometChip system. The involvement of beta- adrenergic pathways will be tested using an innovative ?Combined Propranolol/TSST Paradigm?, with one study group randomly assigned (double blind) to receive a single dose of a safe and effective beta-adrenergic receptor antagonist 60 minutes prior to the TSST (Propranolol Group, n=80), while another will receive matching placebo (Placebo Group, n=120).
Aim 1 : To experimentally test the hypothesis that exposure to an acute psychological stress causes increased DNA damage in humans (Aim 1.1), while concurrently testing the hypothesis that these effects can be reduced by pharmacological blockade of beta-adrenergic receptors (Aim 1.2).
Aim 2 : To investigate increases in blood levels of catecholamines as mediators of the effects of acute stress on DNA damage (primary hypothesis), as well as explore other potential mediators (e.g., cortisol).
Aim 3 : To examine key demographic (race, sex, age) and baseline biological variables (anti-oxidant activity, DNA repair capacity) as susceptibility/resiliency factors (moderators) of stress-induced DNA damage. The planned research will establish psychological stress as a cause of DNA damage in humans, providing critical support for new areas of research to explore: 1) effects of stress-induced DNA damage on cancer risk; 2) specific molecular mechanisms responsible; 3) more selective novel interventions to prevent such effects.

Public Health Relevance

The planned research with a diverse sample of participants (50% women, 50% African American, aged 20-59 years) will provide a first critical test of the hypothesis that acute psychological stress can cause DNA damage in humans. If experimental exposure to a standardized social stress causes significant increases in DNA damage, it would provide strong support for future research to: 1) determine the mechanisms responsible; 2) examine possible relationships to risk of cancer; and, 3) develop innovative interventions to prevent the effects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211371-03
Application #
9614916
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Green, Paige A
Project Start
2017-01-16
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213