DNA BIOMARKERS IN ECOLOGICAL IMPACT ASSESSMENTS

大量的自由基诱导的改变发生在 暴露于环境化学物质的鱼的肝DNA。 这些涉及 开环反应形成甲酰胺基嘧啶（FIMI）衍生物， 羟基化反应形成8-OH-加合物。 前一种变化， 通过GC-MS技术证明，来自OH诱导的自由基X8 OH（其中 X是腺嘌呤或鸟嘌呤）通过还原途径，后者 结构通过氧化途径由相同的自由基产生。 月初 在暴露的各个阶段，OH攻击主要是针对女性的， 结构. 这可能是有利的，因为这些结构终止于 DNA复制和缓慢的细胞分裂。 在多大程度上， 还原或氧化途径的遵循取决于细胞 氧化还原状态 氧化改变，如8-OH-Gua，可能涉及 在启动和广泛的沉积铁聚集在肝脏 暴露的鱼类可能反映了坏死事件， 肿瘤发生 增加暴露最终导致大量的 增加8-OH-加合物的比例。 22统计基数 我们已经开发了与乳腺癌发生有关的模型， 实验室（特异性和灵敏度大于 90%）。 大量的自由基诱导的碱基改变表明， 地方和全球的变化是一个巨大的可能的后果， 对DNA的激进攻击 这些变化是通过确定 通过傅里叶变换红外光谱改变官能团振动 光谱法（FT-IR）。 实质性和潜在的诊断性变化是 与乳腺癌发生有关。 因此，在这方面， 综合GC-MS和FT-IR模型处于最后开发阶段。 在初步研究中获得了可比的GC-MS/FT-IR数据， 暴露在污染物中的鱼 因此，我们建议开发类似的 暴露的鱼的模型。 英国比目鱼将从受污染的 和非污染区进行GC-MS/FT-IR分析。 集成的GC-MS/FT-IR模型将形成建立 遗传毒性损伤和癌症风险。 这些数据将 与来自体外实验的数据相比， 自由基生成条件。 细胞铁沉积的影响， 铁蛋白状态、DNA熔点值和相关参数将被 考虑到，特别是为了了解 致癌作用 总体目标是开发DNA生物标志物， 癌症风险评估的相关多组分预测模型. 超级基金网站。

Substantial radical-induced alterations occur in the nucleotide bases of hepatic DNA of fish exposed to environmental chemicals. These involve ring-opening reactions forming formamidopyrimidine (Fapy) derivatives and hydroxylation reactions forming 8-OH-adducts. The former alterations, evinced by GC-MS techniques, arise from the OH-induced radical X8OH (where X is either adenine or guanine) via reductive pathways and the latter structures arise from the same radical via oxidative pathways. In early stages of exposure, the OH assault is channeled primarily toward Fapy structures. This is likely favorable in that these structures terminate DNA replication and slow cell division. The degree to which either athe reductive or oxidative pathways are followed is dependent upon the cellular redox status. Oxidative alterations, such as 8-OH-Gua, are likely involved in initiation and extensive deposits of iron aggregates in the liver of exposed fish probably reflect necrogenic events that are pivotal in tumorigenesis. Increased exposure ultimately leads to a substantial increase in the proportion of 8-OH-adducts. Twenty-two statistical base models relating to breast carcinogenesis have been developed in our laboratory (a number having a specificity and sensitivity greater than 90%). The substantial radical-induced base alterations suggested that local and global changes were a likely consequence of the substantial radical attack on the DNA. Such changes were evinced by determining alterations in function group vibrations through Fourir Transform Infrared Spectroscopy (FT-IR). Substantial and potentially diagnostic changes were observed in relation to breast carcinogenesis. As a consequence, integrated GC-MS and FT-IR models are in final stages of development. Comparable GC-MS/FT-IR data have been obtained in preliminary studies with fish exposed to contaminants. Accordingly, we propose to develop similar models for exposed fish. English sole will be obtained from contaminated and non-contaminated areas and GC-MS/FT-IR analyses will be performed. Integrated GC-MS/FT-IR models will then form of a basis for establishing genotoxic injury and cancer risk at Superfund sites. These data will be compared with data from in vitro experiments with pure substrates under radical-generating conditions. The influence of cellular iron deposits, ferritin status, DNA melting point values and related parameters will be factored in, notably with a view to understanding promotional aspects of carcinogenesis. The overall goal is the development of DNA biomarkers and related multi-component predictive models for cancer risk assessment at Superfund sites.