Carcinogens and DNA damage

Abstract

Humans are variously and continuously exposed to a wide range of different DNA-damaging agents, some of which are classed as carcinogens. DNA damage can arise from exposure to exogenous agents, but damage from endogenous processes is probably far more prevalent. That said, epidemiological studies of migrant populations from regions of low cancer risk to high cancer risk countries point to a role for environmental and/or lifestyle factors playing a pivotal part in cancer aetiology. One might reasonably surmise from this that carcinogens found in our environment or diet are culpable. Exposure to carcinogens is associated with various forms of DNA damage such as single-stand breaks, double-strand breaks, covalently bound chemical DNA adducts, oxidative-induced lesions and DNA-DNA or DNA-protein cross-links. This review predominantly concentrates on DNA damage induced by the following carcinogens: polycyclic aromatic hydrocarbons, heterocyclic aromatic amines, mycotoxins, ultraviolet light, ionising radiation, aristolochic acid, nitrosamines and particulate matter. Additionally, we allude to some of the cancer types where there is molecular epidemiological evidence that these agents are aetiological risk factors. The complex role that carcinogens play in the pathophysiology of cancer development remains obscure, but DNA damage remains pivotal to this process.

Keywords: DNA damage; bioactivation; cancer; carcinogens.

Figure 1.. Benzo[a]pyrene (B[a]P) bioactivation. Major mechanism of DNA binding by B[a]P, a pro-carcinogenic PAH.

Figure 2.. PAH-DNA immunostaining of human prostate.

(A) Representative example of PAH-DNA immunostaining in a UK prostate sample stained for carcinogenic PAH-DNA adducts: (left panel) specific PAH-DNA adduct staining is shown by nuclei stained pink and indicated by arrows; (middle panel) the corresponding absorbed serum control shows the same area with no staining and (right panel) haematoxylin staining of the same area shows localisation of nuclei. (B) Values for PAH-DNA adducts/10⁸ nucleotides, for 10 prostate samples from the U.K. and 13 samples from India, were obtained from IHC using ACIS OD/nucleus values (with absorbed serum subtracted) by calculation from a standard curve [85,86].