Date of Award:

2015

Document Type:

Thesis

Degree Name:

Master of Science (MS)

Department:

Chemistry and Biochemistry

Department name when degree awarded

Toxicology

Advisor/Chair:

Abby D. Benninghoff

Abstract

Polycyclic aromatic hydrocarbons (PAHs) comprise an important class of environmental pollutants that are known to cause lung cancer in animals and suspected lung carcinogens in humans. PAHs are also known to cause cancer in offspring when provided to a pregnant mouse. Some evidence from cell-based studies points to PAHs as modulators of the epigenome, that is modifications to DNA structure that control the expression of genes. Inappropriate changes to the epigenome and consequently expression of cancer-critical genes are often characteristic of cancer cells. The objective of this thesis research was to determine the impact of transplacental exposure to two model PAHs on the epigenome of fetal and adult lung tissues in offspring. Specifically, we measured patterns of methylation of DNA, a type of epigenetic mark, in different types of lung tissue to assess changes in the epigenome associated with development of lung cancer. Two strategies were employed: 1) a targeted approach using ultra-deep bisulfite sequencing to precisely measure the specific pattern of methylated sites in the

promoter regulatory region for several tumor suppressor genes, including Cdkn2a, Rarb, Dapk1 and Mgmt; and 2) a broad, genome-wide approach using a microarray covering all regulatory promoter regions in the entire mouse genome. Our first approach did not yield any marked differences in methylation patterns for any of the target genes for lung tissues obtained at birth or at various ages up to 45 weeks, nor according to the type of tissue (normal, pre-neoplastic, tumor). However, the genome-wide approach did yield specific patterns of methylation in lung tumors, including distinct profiles associated with lung tumor tissue from PAH-exposed animals that were substantially different from normal lung tissue in control animals. Altogether, the research presented here identified several new target genes of interest for future studies investigating the epigenetics of PAHinitiated lung cancer. This work also provided new knowledge that exposure to PAHs can lead to distinct DNA methylation profiles in lung tumors in adult offspring.

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