PEROXISOME PROLIFERATORS EFFECT ON DNA METHYLATION

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DESCRIPTION (Adapted from the Investigator's Abstract) Understanding the mechanism of nongenotoxic liver carcinogens including peroxisome proliferators is important due to the wide range of sensitivity of different species. One mechanism for controlling the expression of genes is DNA methylation, i.e., specific changes in 5-methylcytosine (5-MEC) content of DNA. The principal investigator (PI) proposes that the effect of peroxisome proliferators on methylation of genes would be useful in understanding their mechanism and as biomarkers for their species sensitivity. There are four aims to test this hypothesis. Aim 1 will determine in rat liver, a sensitive species, whether dibutyl phthalate, gemfibrozil, Wy-14,643, and 2,4-D decrease methylation of DNA, IGF2 and c-myc while increasing methylation of connexin 32. By evaluating genes that are expected to be hypomethylated and a gene that should be hypermethylated, we hope to demonstrate specificity for the effect of peroxisome proliferators on DNA methylation. Aim 2 will determine whether the alterations in methylation found in rat liver also occurs in mouse liver, another sensitive species, and to a lesser degree in a less sensitive species, Syrian hamsters. Aim 3 will determine dose-response relationships. Aim 4 will determine whether hypomethylation of IGF2 and c-myc are associated with an increased expression of their mRNA and protein and whether hypermethylation of the connexin 32 gene is associated with decreased expression. The species sensitivity of the effect of the four peroxisome proliferators on the methylation of DNA and genes and on the expression of their mRNA will be compared to known species sensitivity of their carcinogenic activity, enhancement of cell proliferation, induction of peroxisomes, and other biological and molecular activity. A correlation between the species sensitivity of the effect of peroxisome proliferators on DNA (gene) methylation and the expression of their mRNA and/or protein would indicate usefulness as biomarkers of exposure to these chemicals. Furthermore, a correlation with carcinogenic activity would indicate the involvement of the gene(s) in a nongenotoxic mechanism for peroxisome proliferators.