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.
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