Unique gene expression patterns in liver and kidney associated with exposure to chemical toxicants

Abstract

DNA arrays containing 260 unique genes involved in phase I and II metabolism, heat shock, DNA repair, inflammation, transcription, and housekeeping were used to examine gene expression patterns in liver and kidney in response to five classes of chemicals (polyaromatic hydrocarbons: benzo(a)pyrene, 3-methylcholanthrene; DNA alkylators: dimethylnitrosamine, ethylnitrosourea; peroxisome proliferators: diethylhexylphthalate, clofibrate; heavy metals: CdCl(2), HgCl(2); and oxidative stressors: CCl(4), bromobenzene). Time course experiments in mice were carried out in both tissues for each chemical and dose-response studies were used to further evaluate several of these chemicals. Each pair of chemicals yielded a similar pattern of gene expression distinct from the other four classes of chemicals. Both peroxisome proliferators up-regulated Cyp4a10, acyl-CoA thioesterase, and insulin-like growth factor binding protein-1, whereas the DNA alkylators altered the expression of monokine induced by gamma-interferon, the metallothioneins, p21, and several acute phase proteins. For each of the five classes of chemicals tested, several genes that were induced or repressed were common in each chemical exposure, whereas other genes were unique for that specific class of compound. Both time and dose are important factors in differentiating between chemical classes. Likewise, comparison of changes in messenger RNA expression between the kidney and liver of treated animals indicates that gene arrays may be useful in determining the comparative toxicity of chemicals in various tissues but that exposure to uncharacterized chemicals will have to be monitored in several tissues.