DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS
Open Access
- Author:
- Ramadoss, Preeti
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 01, 2005
- Committee Members:
- Gary H Perdew, Committee Chair/Co-Chair
Jeffrey Maurice Peters, Committee Member
Richard John Frisque, Committee Member
Avery August, Committee Member
David John Vandenbergh, Committee Member - Keywords:
- Aryl Hydrocarbon Receptor
TCDD
XAP2
Relative Ligand Affinity - Abstract:
- The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the transcription of several genes in reponse to binding ligand. AhR ligands include a structurally diverse group of chemicals, and some of these are major environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to these chemicals results in a variety of toxic responses, and the AhR is thought to mediate most, if not all of these adverse reactions. There are a number of intra- and inter-species differences in terms of the relative sensitivity to the toxic effects of AhR ligands, and there is also considerable variation in the AhR’s amino acid sequence between species. It is likely that the differences in the AhR are partly responsible for the differences in sensitivity to TCDD between species. Mouse models are most commonly used in toxicological studies to evaluate the risk upon exposure to AhR ligands and the data is extrapolated to estimate risk to humans. If there are substantial differences between the mouse AhR (mAhR) and human AhR (hAhR) that lead to variation in response to ligand exposure, there may be a need to develop a more suitable model to estimate toxicological risk to humans. This work characterized some of the biochemical differences between mAhR and hAhR and found that there were a number of differences between mAhR and hAhR. This variation could contribute to differences in response to ligand at the molecular level. hAhR exhibits nucleo-cytoplasmic shuttling properties that are different from mAhR, and hAhR is not influenced in the same way as mAhR by the chaperone protein XAP2. hAhR also has a 10-fold lower apparent ligand affinity than mAhR. Some of these differences appear to be due to the sequence variation in the poorly conserved transactivation domain of the receptor. This study also attempted to identify novel AhR target genes through the use of chromatin immunoprecipitation coupled with microarrays, and this method can eventually be adapted to perform in vivo chromatin immunoprecpitations from tissue. In summary, these studies will help provide a better understanding of the molecular mechanisms through which the AhR mediates a toxic response upon exposure to ligands.