Chemical-induced DNA damage and human cancer risk

Abstract

For more than 200 years human cancer induction has been known to be associated with a large variety of chemical exposures. Most exposures to chemical carcinogens occur as a result of occupation, pollution in the ambient environment, lifestyle choices, or pharmaceutical use. Scientific investigations have revealed that the majority of cancer causing chemicals, or chemical carcinogens, act through "genotoxic" or DNA damaging mechanisms, which involve covalent binding of the chemical to DNA (DNA adduct formation). Cancer-inducing exposures are typically frequent and/or chronic over years, and the accumulation of DNA damage or DNA adduct formation is considered to be a necessary requirement for tumor induction. Studies in animal models have indicated that the ability to reduce DNA damage will also result in reduction of tumor risk, leading to the hypothesis that individuals having the highest levels of DNA adducts may have an increased cancer risk, compared to individuals with the lowest levels of DNA adducts. Here we have reviewed twelve investigations showing 2- to 9-fold increased Relative Risks (RR) or Odds Ratios (OR) for cancer in (the 25% of) individuals having the highest DNA adduct levels, compared to (the 25% of) matched individuals with the lowest DNA adducts. These studies also provided preliminary evidence that multiple types of DNA adducts combined, or DNA adducts combined with other risk factors (such as infection or inflammation), may be associated with more than 10-fold higher cancer risks (RR = 34-60), compared to those found with a single carcinogen. Taken together the data suggest that a reduction in human DNA adduct level is likely to produce a reduction in human cancer risk.

Figure 1.

Molecular structures of stable carcinogen-DNA adducts formed by covalent binding with deoxyguanosine (shown in boxes) in DNA. (A) N-(deoxyguanosin-8-yl)-2-(amino)fluorene (dG-C8-AF, R=H, or dG-C8-AAF, R=acetyl), formed when N-hydroxyl-aminofluorene reacts with the C8 position of deoxyguanine. (B) (7R)-N²-(10-(7β,8α,9α-trihydroxy-7,8,9,10-tetrahydro-benzo(a)pyrene)-yl)-deoxyguanosine (BPdG) is the major carcinogenic adduct formed between benzo(a)pyrene and the exocyclic amino group of deoxyguanosine; (C) 8,9-dihydro-8-(2,6-diamino-6-formamido-4-oxo-3,4-dihydropyrimid-5-yl-amino) (AFB₁-N7-guanine) is the major ring-opened adduct of aflatoxin B₁ formed with the C8 position of the deoxyguanine imidazole ring.