Wogan G N
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
Environ Health Perspect. 1992 Nov;98:167-78. doi: 10.1289/ehp.9298167.
Molecular epidemiology is increasingly being applied in studies of cancer risks derived from exposure to environmental carcinogens of both endogenous and exogenous origins. Analytical methods have been developed that are capable of detecting and quantifying levels of covalent adducts of several important classes of carcinogens with cellular DNA and blood proteins. Methods of sufficient sensitivity and specificity to detect ambient levels of exposure are in current use. These are being used in studies related to tobacco use (polycyclic aromatic hydrocarbons, aromatic amines, tobacco-specific nitrosamines); dietary exposures (aflatoxins, N-nitrosamines, heterocyclic amines); medicinal exposures (cisplatin, alkylating agents, 8-methoxypsoralen, ultraviolet photoproducts); occupational exposures (aromatic amines, polycyclic aromatic hydrocarbons, oxides of ethylene and styrene, and vinyl chloride); and oxidative damage (8-hydroxyguanine, thymine glycol). Methodologic improvements together with their expanded use in feasibility studies continue to produce results that support the validity of this approach for detecting and quantifying exposure to carcinogens. Genetic markers are also being used to detect early biological responses in efforts to link carcinogen exposure to initiating events in the carcinogenesis process. These include, in addition to traditional cytogenetic markers (e.g., chromosomal aberrations, sister chromatid exchange, micronuclei), other alterations in chromosomal structure such as restriction fragment length polymorphisms, loss of heterozygosity, and translocation markers. Specific genetic changes have recently been identified as critical molecular events in the initiation and development of many cancers. Important among these are activation of oncogenes, especially those of the ras family, and inactivation of tumor-suppressor genes (e.g., p53 and Rb) by point mutations and/or chromosomal deletions and other structural changes. Although some of these changes are known to occur in chemically induced tumors of experimental animals, the possible role of chemical carcinogens in the induction of genetic abnormalities in human cancers has yet to be determined. Continuing investigations employing the methods of molecular epidemiology promise to provide further evidence concerning these relationships. Future investigations employing newly developed molecular biological methods, in particular those based on polymerase chain reaction amplification of DNA, to identify alterations in DNA and chromosomal structure, combined with methods for characterizing exposure to carcinogens and early effects, have great potential for further elucidating the role of genotoxic agents in the etiology of human cancers and also for the development of strategies for their prevention.
分子流行病学越来越多地应用于研究内源性和外源性环境致癌物暴露所致的癌症风险。已开发出一些分析方法，能够检测和定量几种重要类型致癌物与细胞DNA和血液蛋白质的共价加合物水平。目前使用的方法具有足够的灵敏度和特异性，可检测环境暴露水平。这些方法正用于与烟草使用（多环芳烃、芳香胺、烟草特有的亚硝胺）、饮食暴露（黄曲霉毒素、N-亚硝胺、杂环胺）、药物暴露（顺铂、烷化剂、8-甲氧基补骨脂素、紫外线光产物）、职业暴露（芳香胺、多环芳烃、乙烯和苯乙烯氧化物以及氯乙烯）以及氧化损伤（8-羟基鸟嘌呤、胸腺嘧啶乙二醇）相关的研究。方法学的改进及其在可行性研究中的广泛应用不断产生结果，支持这种检测和定量致癌物暴露方法的有效性。遗传标记也被用于检测早期生物学反应，以努力将致癌物暴露与致癌过程中的起始事件联系起来。除了传统的细胞遗传学标记（如染色体畸变、姐妹染色单体交换、微核）外，这些还包括染色体结构的其他改变，如限制性片段长度多态性、杂合性缺失和易位标记。最近已确定特定基因变化是许多癌症起始和发展中的关键分子事件。其中重要的是癌基因的激活，尤其是ras家族的癌基因，以及肿瘤抑制基因（如p53和Rb）通过点突变和/或染色体缺失及其他结构变化而失活。尽管已知其中一些变化发生在实验动物的化学诱导肿瘤中，但化学致癌物在人类癌症遗传异常诱导中的可能作用尚未确定。采用分子流行病学方法的持续研究有望提供有关这些关系的进一步证据。未来采用新开发的分子生物学方法，特别是基于DNA聚合酶链反应扩增的方法来识别DNA和染色体结构改变，并结合表征致癌物暴露和早期效应的方法，在进一步阐明遗传毒性剂在人类癌症病因中的作用以及制定预防策略方面具有巨大潜力。
