MUTAGENESIS AND CARCINOGENESIS STUDIES IN P53 (+/-) OR LACI:P53 (+/-) MICE

P53 ( /-) 或 LACI:P53 ( /-) 小鼠的突变和致癌研究

• 批准号: 5202144
• 负责人: J E FRENCH
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5202144
• 关键词: acrylamides; benzene; carcinogen testing; chemical carcinogen; chemical carcinogenesis; epoxides; gene mutation; genetic strain; genetically modified animals; genotype; laboratory mouse; loss of heterozygosity; mutagen testing; mutagens; neoplasm /cancer genetics; preneoplastic state; reserpine; tumor suppressor genes

Mice with only a single wild type p53 allele provide a distinct target for mutagens and are analogous to humans at risk due to heritable forms of cancer, e.g., the Li-Fraumeni syndrome. The reduction in p53 gene by this "germline first hit" increases the probability that a second mutagenic event will cause either loss of p53 tumor suppressor function or gain of transforming activity by requiring (at minimum) only a single mutation. Using the same route and dose-regiment as 104-week chronic NTP bioassays of benzene, p-cresidine (aromatic amine), p-anisidine, 4-vinyl-1-cyclohexene diepoxide (VCD), N-methyl-o-acrylamide (NMOA), and reserpine, we exposed p53 (+/-) or lacIq:p53 (+/-) F1 C57Bl/6 mice in order to determine the sensitivity of p53 deficient mice to mutagenic carcinogens. Benzene, p-cresidine, and VCD (trans-species mutagenic carcinogens) were positive. Chemical- and tissue-specific tumors were observed after 24 weeks of exposure. Confirmation of tissue-specificity and mutagenicity was determined using the rescued lacIq gene and determining the in vivo mutant frequency. Extensive evaluation of control and benzene, p-cresidine, or VCD induced tumors have or are in the process of being examined for p53 mutations or LOH. (2) Acute and sub-chronic exposures (oral) of the aromatic amine, p-cresidine, or benzene, will be used to induce pre-neoplastic lesions and tumors in target tissues for sampling over time to determine early genetic lesions using DNA and RNA analyses (p53 mutations and/or LOH). In addition, lacI mutant frequency will be used to determine chemically induced genetic stress in the target tissues.

只有一个野生型p53等位基因的小鼠提供了一个明显的靶点 对于诱变剂，类似于人类由于可遗传形式而处于危险之中 癌症，例如李-弗劳梅尼综合征。抑癌基因P53的缺失 这种“生殖系第一次命中”增加了第二次命中 突变事件会导致P53抑癌功能的丧失 或通过(最低限度)只需要一个 突变。使用与104周慢性NTP相同的路线和剂量方案 苯、对氯仿(芳香胺)、对苯甲胺、 4-乙烯-1-环己烯二环氧化物(VCD)、N-甲基-邻丙烯酰胺(NMOA)和 利血平，将P53(+/-)或lacIq：P53(+/-)F1 C57BL/6小鼠暴露于 为了测定P53基因缺陷小鼠对诱变的敏感性 致癌物质。苯、对氯沙林和VCD(跨物种诱变剂 致癌物)呈阳性。 24周后观察化学和组织特异性肿瘤。 曝光。组织特异性和致突变性的确认 用回收的lacIq基因进行测定和体内测定 突变频率。对控制和苯进行了广泛的评估， P-Csidine或VCD诱导的肿瘤已经或正在 检查P53突变或杂合性缺失。(2)急性和亚慢性接触 (口服)芳香胺、对氯沙林或苯，将用于 在靶组织中诱导癌前病变和肿瘤进行采样 随着时间的推移，使用DNA和RNA分析确定早期遗传损伤 (p53突变和/或杂合性缺失)。此外，Laci突变频率将为 用于确定目标体内化学诱导的遗传应激 纸巾。