Diesel exposure has been associated with significant exacerbations in heart disease but the underlying mechanisms by which these exacerbations are mediated and the possible effects of in utero and early life exposure are poorly understood. We have found that mice exposed to diesel exhaust in utero and/or early in life develop increased left ventricular hypertrophy and a predisposition to heart failure as adults. Specificall, we have found that male mice exposed to diesel exhaust in utero and/or early in life develop left ventricular hypertrophy compared to those exposed to filtered air, while female mice exposed in utero and postnatally develop decreased ejection fraction. When the male mice undergo aortic banding, they progress more rapidly to heart failure than the filtered air controls. We hypothesize that in utero exposure to diesel exhaust creates epigenetic modifications in the hearts of exposed animals that predispose to myocardial hypertrophy and/or heart failure as adults, in possibly a gender specific fashion. Accordingly, we propose to examine genome wide epigenetic modifications in neonatal and adult mouse hearts after in utero exposure to diesel exhaust. We will also examine how these modifications vary by gender and alter global RNA expression patterns immediately after exposure and after transverse aortic constriction, a potent inducer of cardiac hypertrophy. We predict that diesel exhaust will induce epigenetic changes that alter expression of genes that confer susceptibility to hypertrophy and heart failure.

Public Health Relevance

Exposure to air pollution has been linked to cardiovascular disease but the mechanisms by which it causes heart failure are unknown. Understanding how air pollution causes heart failure and how it increases susceptibility to individuals exposed prenatally or early in life will have important implications for preventing air pollution related cardiovascular illness in human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES023581-01A1
Application #
8771328
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Heindel, Jerrold
Project Start
2014-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$261,000
Indirect Cost
$111,000
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195