Genomic assessment of xenobiotics

Toxicogenomics can be viewed as the assessment of chemically-induced biological change through a merger of classical toxicology, high-throughput genomics and bioinformatics. In the context of toxicology, xenobiotics are chemical substances that are foreign to the biological organism they are found in. The genomic analysis of xenobiotics falls under the rubric of toxicogenomics. The growth of toxicogenomics is largely due to the complete sequencing of a growing number of genomes, coupled with the development of novel technologies that allow us to detect chemically induced changes in global gene transcription. The product of toxicogenomics is often a high-density dataset requiring computer-based methods to analyze and interpret these data. This thesis will outline work we have done to address the need for computer-based methods to analyze high density microarray data as well as well as address work we have done to further understand the mechanisms of action of a number of xenobiotics. In chapter one I will present an introduction to toxicogenomics. I will mainly focus on the utilization of microarray-based technologies to study changes in gene transcription at the level of the whole genome in response to chemical exposure. In chapter two I will discuss my work on addressing our group's need for an integrated software platform to deal with large datasets generated by whole-genome analysis of gene transcription. In chapter three, I will discuss our work in a murine model to identify candidate genes directly regulated by the aryl hydrocarbon receptor (AHR) in response to exposure to the xenobiotic, TCDD. In this work we utilize microarray-based gene expression analyses to identify a subset of high-confidence genes for subsequent use in chapter four. In chapter four, taking insight we have gained from studying mice with mutations in genes involved in the AHR signaling pathway, we have developed a more complex and informed model of AHR signaling. In chapter five, I will discuss work to elucidate signaling pathways through which polybrominated diphenyl ethers (PBDEs) act. PBDEs are environmentally ubiquitous xenobiotics used primarily as flame retardants. Finally, in chapter six I present future directions this work may take.