Grant Details
Grant Number: |
5R01CA211371-04 Interpret this number |
Primary Investigator: |
Bovbjerg, Dana |
Organization: |
University Of Pittsburgh At Pittsburgh |
Project Title: |
Experimental Study of Stress and DNA Damage in Humans: Mediators and Moderators |
Fiscal Year: |
2020 |
Abstract
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.
Publications
None