GENDER EFFECTS ON SUSCEPTIBILITY TO LIVER NEOPLASIA

产品说明： 欣顿博士和同事的研究已经建立了 青鳉（Oryzias latipes），一种小型的水族馆硬骨鱼，是一种 肝癌发生脊椎动物模型具有很高的价值， 体积小，易于维护，肿瘤发作快， 作为生物测定对象的潜力。 他们最近的研究表明， 当青鳉暴露在致癌物质二乙基亚硝胺中时 (DEN)在早期（孵化后21天），雌性更多 对肝肿瘤的发展比男性敏感。 过程 为成熟卵母细胞的形成做准备（10周 （一）以“早”为先，以“早”为先。 肝细胞（在7周或更早时观察到）。 研究人员假设 增加了对肝癌发生的性别敏感性， 是由于存在着增长效应， 可能由雌激素介导，和/或增加遗传毒性损伤，由于 致癌物质代谢或DNA加合的差异更大， 修复. 为了验证他们的假设，他们将用 具体目标如下：1A）连续定义正常的特征 青鳉的肝脏生长与性别特异性效应相关 雌激素和雌激素受体水平，以及卵黄蛋白原（VG）基因 在DEN诱导的肝癌发生过程中，解决性别 对细胞改变的特定病灶的数量和体积的影响， 他们的命运（逆转，聚合，生长，改变），预测 它们与最终肝肿瘤的关系， 1B）确定雌二醇（E2）或雌二醇（E2）的调节作用， 抗雌激素（AE）对DEN诱导的男性肝肿瘤发生率的影响 和女性青鳉，分别;和2）确定，如果性别和/或年龄 对原致癌物代谢、DNA加合物形成和DNA修复的影响 与青鳉最终的肝肿瘤有关。这个项目是一个 三个实验室高度一体化的努力，特别是 肝癌细胞病理学专长，水产 生化毒理学和风险评估。 理解性别 青鳉对肝癌发生的敏感性可能提供有价值的 关于性别对癌症形成的影响的信息 脊椎动物，并将进一步表征青鳉模型。

DESCRIPTION: The studies of Dr. Hinton and colleagues have established that the medaka (Oryzias latipes), a small aquarium teleost fish, is a highly valuable vertebrate model for hepatocarcinogenesis because of its small size, ease of maintenance, rapid tumor onset, and immense potential as a bioassay subject. Their recent studies revealed that when medaka were exposed to the initiating carcinogen diethylnitrosamine (DEN) at an early age (21 days after hatching), females were more sensitive than males to development of hepatic neoplasms. The process of maturation in preparation for formation of mature oocytes (10 weeks of age) is accompanied by an earlier doubling of the number of hepatocytes (seen at 7 weeks or earlier). The investigators hypothesize that increased gender sensitivity to hepatocarcinogenesis, exemplified by female medaka, is due to the existence of increased growth effects, likely mediated by estrogen, and/or to increased genotoxic insult, due to greater differences in carcinogen metabolism or in DNA adduction and repair. To test their hypothesis, they will perform experiments with the following specific aims: 1A) serially define features of normal hepatic growth in medaka correlating them with gender-specific effects of estrogen and estrogen receptor levels, and vitellogenin (VG) gene expression.During DEN-induced hepatocarcinogenesis, address gender effects on number and volume of specific foci of cellular alteration, and their fate (reversion, coalescence, growth, alteration) and, predict their relationship to eventual hepatic neoplasms using stochastic modeling; 1B) Determine modulatory effects of estradiol (E2) or antiestrogen (AE) on incidence of DEN-induced hepatic neoplasms in male and female medaka, respectively; and 2) establish if gender and/or age effects on procarcinogen metabolism, DNA adduct formation and DNA repair are related to eventual hepatic neoplasms in medaka. This project is a highly integrated effort among three laboratories, with particular expertise in cellular pathology of hepatocarcinogenesis, aquatic biochemical toxicology, and risk assessment. Understanding the gender sensitivity of medaka to hepatocarcinogenesis may provide valuable information about gender effects on cancer formation in other vertebrates and will further characterize the medaka model.