Polycyclic aromatic hydrocarbons (PAHs) represent a """"""""re-emerging"""""""" threat to human health. Even though exposure to PAHs via tobacco smoke is decreasing in the U.S., daily human exposures to PAHs are on the rise, likely due to the vast expansion of the coal power industry in China and the U.S. There is great concern that fetal exposure to environmental chemicals during pregnancy could be linked to adult cancers. The environmental PAHs dibenzo[a,l]pyrene (DBP) and benzo[a]pyrene (BaP) are both transplacental carcinogens in mice causing a high incidence of lung tumors in adult offspring. Alterations of the epigenome have been implicated in many cancers. Epigenetic changes in tumors mostly result in aberrant hypermethylation of gene promoter regions and inappropriate gene silencing, thus conferring a selective advantage to neoplastic cells. Hypermethylation of tumor suppressor genes has been shown in human and mouse lung cancers, including cyclin-dependent kinase inhibitor 2A (Cdkn2a), retinoic acid receptor beta (Rarb), death-associated protein kinase (Dapk1), O-6-methylguanine DNA methyltransferase (Mgmt) and H-cadherin (Cadh13). New evidence from in vitro cell culture studies suggests that BaP alters patterns of gene-specific promoter methylation. However, it is not known whether in vivo exposure to PAHs alters the epigenome to increase cancer risk. To address this significant knowledge gap, we propose to investigate the impact of gestational PAH exposure in a transplacental model of lung chemical carcinogenesis. The primary objective of this proposal is to determine the impact of gestational exposure to PAHs on the fetal and adult offspring epigenome in the mouse lung. The working hypothesis is that transplacental exposure to PAHs alters DNA methylation in the promoter region of key tumor suppressor genes leading to increased risk of lung cancer in the adult. We plan to accomplish our primary objective by pursuing the following specific aims: (1) Determine the impact of transplacental exposure to DBP and BaP on methylation of the promoter regions of the Cdkn2a, Rarb, Dapk1, Mgmt and Cadh13 genes in neonate mouse lung;assess impact of in utero exposure to PAHs on expression of DNA methyltransferase genes 1, 3a and 3b in neonate lung. (2) Assess the timing of tumor suppressor gene silencing resulting from gestational PAH exposure by measuring gene promoter methylation in adult mice (aged 15 to 45 weeks) as preneoplastic lesions develop into lung adenocarcinomas in the adults;functionally link altered DNA methylation to altered gene and protein expression. Successful completion of the proposed research will provide new knowledge about the impact of PAHs on the epigenome and establish potential epigenetic links between fetal exposure and adult disease. Should the hypothesis be supported, this would be the first demonstration that fetal exposure to PAHs causes persistent changes in the epigenome leading to increased cancer risk in the adult.

Public Health Relevance

There is great need to understand how environmental exposures during pregnancy may be linked to adult disease. New science suggests that environmental agents may modify the epigenome (that is, specific patterns of DNA structure and modifications that influence gene expression) to increase cancer risk. A significant portion of lifetime exposure to chemical carcinogens occurs during gestation and throughout breast feeding, and the fetus may be particularly susceptible to chemicals that alter the epigenome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Small Research Grants (R03)
Project #
5R03ES018919-02
Application #
8066723
Study Section
Special Emphasis Panel (ZRG1-DKUS-E (03))
Program Officer
Heindel, Jerrold
Project Start
2010-05-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$69,300
Indirect Cost
Name
Utah State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
072983455
City
Logan
State
UT
Country
United States
Zip Code
84322