Nongenotoxic Carcinogenicity of Chemicals: Mechanisms of Action and Early Recognition through a New Set of Structural Alerts

The article focuses on the nongenotoxic carcinogens mechanisms of action and early recognition through a new set of structural alerts. Epigenetic carcinogens are agents that act through a secondary mechanism that does not involve direct DNA damage. In reality, the demarcation is seldom absolute. Most potent genotoxic carcinogens are also endowed with epigenetic activities that may act synergistically to carry out the complete carcinogenic process. Most nongenotoxic carcinogens can indirectly cause DNA damage, facilitate mutagenesis by fixation of promutagenic DNA damage prior to repair, or increase error-prone DNA repair, while some may even be DNA reactive via a minor pathway. Carcinogenic responses, such as enhanced cell proliferation, unregulated cell growth, and aberrant cell cycle kinetics, may be determined by altered sensitivity to a wide variety of cytokines, hormones, growth factors, and other cell growth mediators that may operate via membrane receptors, signal transduction pathways, and intracellular communication processes. Mechanisms or modes of action involved in epigenetic carcinogenicity are largely heterogeneous, frequently interrelated and often tissue or organ, species/strain, and gender specific.