The Environment as a Variable to Calibrate Mouse Models of Human Disease

描述(申请人提供)：大多数致癌物与DNA形成共价产物或加合物。加合物被认为是驱动将正常细胞转化为癌细胞的基因变化，然后癌细胞长大为肿瘤。因此，影响加合物形成或去除的因素很可能是人类致癌易感性的重要决定因素。此外，破坏DNA的试剂可以修饰与癌症没有直接关系的靶点；直接或间接地，DNA破坏剂可能在引发或促进一系列其他疾病方面发挥重要作用。下面描述的工作是为了了解DNA加合如何与其他可由现代分析工具测定的生化因素相结合，以确定与年龄和性别相关的环境因素的敏感性差异。这项工作的主要重点是黄曲霉毒素B1(AFB1)，这是一种重要的人类致癌物质，与大多数肝细胞癌病例有关，特别是当毒素与肝炎病毒协同作用时。我们的工作将解决知识中的四个差距。首先，我们将提供B6C3F1小鼠在从胎儿到婴儿期和成年期的特定时间点的高分辨率生物网络图，并确定这些网络对AFB1的反应。其次，我们产生的基因网络数据将被用于敏感地检测DNA加合物，使用一种工具，甚至可以检测到接触过DNA加合物的母亲的胎儿中的加合物。加速器质谱仪(AMS)将被用来研究DNA加合物在生命的敏感和抵抗阶段的形成和命运。第三，我们将给小鼠注射一种化学干预剂，萝卜硫素，我们预计它将改变代谢网络，保护出生前、婴儿和成年动物免受这种环境侮辱。最后，我们将结合使用AFB1的实验，对NTP数据集中的四种化合物的遗传毒性效应进行更有限的调查。这些附加剂包括4-氨基联苯(ABP)、2-氨基-1-甲基-6-苯基咪唑并[4，5-b]吡啶(PhIP)、丙烯酰胺和17-雌二醇(E_2)。这项研究的一个重要目标是开发一系列新的生物标记物，这些标记物可以应用于小鼠模型，然后应用于其他模型，用于预测环境制剂对人类的影响。

DESCRIPTION (provided by applicant): Most carcinogens form covalent products, or adducts, with DNA. Adducts are believed to drive the genetic changes that convert normal cells into cancer cells, which then outgrow into a tumor. Factors that influence the formation or removal of adducts, therefore, are likely to be important determinants of human susceptibility to carcinogenesis. Moreover, agents that damage DNA can modify targets not directly relevant to cancer; directly or indirectly, DNA damaging agents may play important roles in initiating or promoting a host of other diseases. The work described below is an effort to understand how DNA adduction integrates with other biochemical factors, determinable by modern analytical tools, to define the differences in sensitivity to environmental agents that are associated with age and gender. The main focus of the work deals with aflatoxin B1 (AFB1), an important human liver carcinogen that is associated with most cases of hepatocellular carcinoma, especially when toxin works in concert with hepatitis viruses. Our work will address four gaps in knowledge. First, we shall provide a high resolution map of the biological networks of both genders of the B6C3F1 mouse at specific time points from fetus through infancy and adulthood and determine how those networks respond to AFB1. Second, the gene network data we produce will be anchored to sensitive detection of DNA adducts, using a tool that will even detect adducts in the fetus of an exposed mother. Accelerator Mass Spectrometry (AMS) will be used to examine the formation and fate of DNA adducts at sensitive and resistant stages of life. Third, we shall administer to mice a chemo-interventive agent, sulphoraphane, that we expect will alter metabolic networks in a manner that will protect pre- born, infant and adult animals from this environmental insult. Finally, our experiments with AFB1 will be coupled with a more limited investigation of the genotoxic effects of four compounds from the NTP data set. These additional agents include4-aminobiphenyl (ABP), 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), acrylamide and 17¿-estradiol (E2). An important goal of this research is the development of a host of new biomarkers that can be applied to the mouse model, and later other models that are used to predict the impact of environmental agents on humans.