HERITABILITY OF EMBRYONIC RADIOSENSITIVE TARGETS

使用远系繁殖的CD 1小鼠品系的研究表明， 在交配前6 - 7周对F0小鼠进行辐照 F1和F2胚胎细胞增殖的显著变化。 这些 这些变化被揭示为竞争性细胞增殖劣势 在嵌合体试验中，当患病胚胎与正常胚胎配对时， 聚集嵌合体中的胚胎。这种影响被传递到F1， 137 Cs γ射线照射1.0戈伊的F2代胚胎， F0，F1和F2代，并与显着降低， 体重、选定信号转导基础水平的变化 蛋白激酶活性和p53蛋白基础水平升高 在F3后代中。 在这个项目中，我们要问的是 父系F0的这些遗传后果的潜在变化 辐射更可能减少，保持不变，或 随着一代又一代的增长。 具体目标我将确定是否竞争细胞 在连续世代中的增殖不利条件将有所不同， 用同基因C57 BL/6菌株替换远交的CD 1菌株。 我们将使用C57 BL/6雄性进行父代F0照射，以减少 表现力的差异，并将评估F1，F2和F3 嵌合体试验中的后代。 如果竞争性细胞增殖 我们的缺点不会随着后代的发展而减少， 假设导致这种遗传效应的基因变化 是不稳定的。 具体目标二将是检验核变化的假设， 导致竞争性细胞增殖不利因素包括“DNA 损害”。 我们将照射一个纯合子的父本F0队列， p53无效突变，可能（间接）导致DNA修复减少。 如果这一假设是正确的，我们预计p53无效突变 增加竞争性细胞增殖对后代不利 父亲的F0辐射。 第三个具体目标是检验核变化的假设， 导致竞争性细胞增殖不利因素将增加， 在几代人之间不断产生更大的变化， 相关终点，包括蛋白激酶活性。 这 结果将同意的假设，这些遗传 照射父系生殖系的后果可能会被放大 基因组的不稳定性。

Studies using the outbred CD1 mouse strain have shown that paternal irradiation of F0 mice six to seven weeks prior to mating causes significant changes in F1 and F2 embryonic cell proliferation. These changes are revealed as a competitive cell proliferation disadvantage in chimera assays when the affected embryo is paired with a normal embryo in an aggregation chimera. This effect is transmitted to F1 and F2 embryos for 1.0 Gy of 137Cs gamma rays, does not decrease between the F0, F1 and F2 generations, and correlates with significant decreases in body weights, changes in basal levels of selected signal transduction protein kinase activities and in elevated basal levels of p53 protein in the F3 offspring. In this project, we ask whether the genetic changes underlying these heritable consequences of paternal F0 irradiation are more likely to decrease, remain unchanged, or to increase with successive generations. Specific Aim I will be to determine whether competitive cell proliferation disadvantage in successive generations will differ when the outbred CD1 strain is replaced with the syngenic C57BL/6 strain. We will conduct a paternal F0 irradiation using C57BL/6 males to reduce differences in expressivity and will evaluate the F1, F2 and F3 offspring in chimera assays. If competitive cell proliferation disadvantage does not decrease with successive generations we will hypothesize that the genetic changes that cause this heritable effect are unstable across generations. Specific Aim II will be to test the hypothesis that the nuclear changes that cause competitive cell proliferation disadvantage include "DNA damage". We will irradiate a paternal F0 cohort that is homozygous for a p53 null mutation which may (indirectly) result in reduced DNA repair. If this hypothesis is correct, we expect the p53 null mutation to increase competitive cell proliferation disadvantage in the offspring of paternal F0 irradiation. Specific Aim III will be to test the hypothesis that the nuclear changes that cause competitive cell proliferation disadvantage will increase in number across generations to produce successively greater changes in correlative endpoints, including protein kinase activities. This outcome would agree with the hypothesis that these heritable consequences of irradiating the paternal germline may become amplified by genomic instability across generations.