PEROXISOME PROLIFERATORS EFFECT ON DNA METHYLATION

描述(改编自调查者摘要) 了解非遗传毒性致癌物质的作用机制，包括 由于过氧化物酶体增殖物的敏感性范围很广，所以它很重要。 属于不同的物种。控制基因表达的一种机制 DNA甲基化，即5-甲基胞嘧啶(5-MEC)的特异性变化 DNA含量。首席调查员(PI)提出， 基因甲基化上的过氧化物体增殖物将在 了解它们的机制并作为其物种的生物标记物 敏感度。有四个目的来检验这一假设。目标1将 测定大鼠肝脏中的一种敏感物种邻苯二甲酸二丁酯， 吉非罗齐、Wy-14、643和2，4-D可降低DNA、IGF2和 C-myc，同时增加间隙连接蛋白32的甲基化。通过评估基因， 被认为是低甲基化的，而基因应该是高甲基化的， 我们希望证明过氧化物酶的作用具有特异性。 DNA甲基化的增殖剂。目标2将决定是否 在大鼠肝脏中发现的甲基化变化也在小鼠肝脏中发生， 另一个敏感物种，在较不敏感的程度上 物种，叙利亚仓鼠。目标3将确定剂量-反应关系。 目标4将确定IGF2和c-myc的低甲基化是否 与它们的mRNA和蛋白表达增加有关， 连接蛋白32基因高甲基化是否与 表达减少。四种效应的物种敏感性 过氧化物酶体增殖物对DNA和基因甲基化的影响 它们的mRNA的表达将与已知的物种敏感性进行比较 它们的致癌活性，促进细胞增殖，诱导 过氧化物体和其他生物和分子活性。一种相关性 过氧化物酶体增殖物对植物生长发育的影响 DNA(基因)甲基化及其mRNA和/或蛋白的表达将 表明作为暴露于这些化学物质的生物标志物的有用性。 此外，与致癌活性的相关性将表明 该基因(S)参与了过氧化酶体的一种非遗传毒性机制 扩散者。

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.