| The toxic action of many chemicals is controlled at the transcriptional level. The use of transcriptional profiling, or monitoring of global transcriptional changes, is an emerging field with great scientific potential. This thesis work applies transcriptional profiling to the field of toxicology. The hypothesis is that poisons may be understood through the transcriptional changes they elicit. The first chapter sets the background and clearly states our hypothesis relating to how transcriptional profiling can be used to understand the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or "dioxin"). In the second chapter, we review the current state of the art of transcriptional profiling and the important technological advancements that have led to its widespread use in toxicology. Also reviewed are the important statistical and organizational advancements that have greatly increased the power and applicability of transcriptional profiling to various biomedical fields. The third chapter describes the establishment of a large transcriptional profile database of toxic chemicals and conditions. Using this database, we provide evidence that chemicals of similar mechanism of action produce similar transcriptional profiles. Through interrogation of this database, we have begun to develop "signatures" of toxic responses that can lead investigators directly to pathways of interest for chemicals. The fourth chapter includes a comprehensive transcriptional analysis that is an effort to understand the mechanism of action of a single toxicant, TCDD. The use of transcriptional profiling, in conjunction with classical toxicological techniques, allowed us to test for the idea that separate pathways to pathological events can be delineated using transcriptional profiling. |
