Peroxisome proliferators are a broadly used class of chemicals whose presence in the environment is ubiquitous. The risk they pose to humans is unknown, however, there is a human health concern because these compounds are hepatocarcinogenic in rodents. To accurately predict any risk of these compounds to humans, it will be necessary to more fully understand the mechanisms of their action. While these mechanisms of action are currently unknown, it is believed that they act through preferential growth promotion of initiated cells. The role of the peroxisome proliferator activated receptor alpha (PPARalpha) in control of growth regulatory genes is also not known. Recent advances in high-density cDNA or toxicological insult, moreover, it will allow associations between patterns of gene expression, signaling networks and modes of action to be made. The experimental strategy of this proposal involves the use of high-density cDNA arrays to examine the effects of peroxisome proliferator treatment at different times, doses and on PPARalpha-knockout mice to obtain a global view of how peroxisome proliferators perturb cellular homeostasis.
The specific aims of this proposal are to (1) identify a characteristic group of genes associated with toxicologically relevant endpoints due to peroxisome proliferator exposure, (2) identify gene changes mediated by indirect effects of peroxisome proliferators utilizing the PPARalpha-knockout mouse and (3) use the genes identified as relevant to peroxisome proliferator exposure to construct a model that will begin to clarify the interrelationships among genes that results in a toxicological response. Results form the proposed experiments will provide a basis for which gene expression patterns in rodents and their physiological consequences are directly relevant to the response observed in humans. In addition, a strategy such as the one proposed will serve as a basis from which the mode of action of other chemicals or chemical classes can be predicted.
