Human DNA adduct measurements: state of the art.

Abstract

Human DNA adduct formation (covalent modification of DNA with chemical carcinogens) is a promising biomarker for elucidating the molecular epidemiology of cancer. Classes of compounds for which human DNA adducts have been observed include polycyclic aromatic hydrocarbons (PAHs), nitrosamines, mycotoxins, aromatic amines, heterocyclic amines, ultraviolet light, and alkylating cancer chemotherapeutic agents. Most human DNA adduct exposure monitoring has been performed with either 32P-postlabeling or immunoassays, neither of which is able to chemically characterize specific DNA adducts. Recently developed combinations of methods with chemical and physical end points have allowed identification of specific adducts in human tissues. Studies are presented that demonstrate that high ambient levels of benzo[a]pyrene are associated with high levels of DNA adducts in human blood cell DNA and that the same DNA adduct levels drop when the ambient PAH levels decrease significantly. DNA adduct dosimetry, which has been achieved with some dietary carcinogens and cancer chemotherapeutic agents, is described, as well as studies correlating DNA adducts with other biomarkers. It is likely that some toxic, noncarcinogenic compounds may have genotoxic effects, including oxidative damage, and that adverse health outcomes other than cancer may be correlated with DNA adduct formation. The studies presented here may serve as useful prototypes for exploration of other toxicological end points.

Polycyclic aromatic hydrocarbon-DNA adduct formation in prostate carcinogenesis

“…While it is not clear which type of adducts, stable or unstable, have a greater role in carcinogenesis, both kinds likely have some carcinogenic potential [50,51]. Adduct formation is thought to be a necessary but not sufficient step in PAHinduced carcinogenesis, but it is likely to be directly relevant to the ability of PAH to cause mutations and cancer [52]. If an adduct forms and is not repaired, a mutation in the DNA code can occur during cell division, propagating the damage in successive generations of the cell [53].…”

Biomarkers for assessing reproductive development and health: Part 1--Pubertal development.

“…Some of those described to date include the presence of a parent compound or metabolite (Hecht 2002); proliferation and differentiation indices (Iatropoulos and Williams 1996); apoptotic end points (Samaha et al 1997); formation of DNA adducts or damage (Poirier and Weston 1996); chromosomal abnormalities (Lucas 1997); micronuclei formation (Schoket et al 1999); expression of specific genes (Riggins 2001); changes in gene expression profile (single or multiple genes) (Thomas et al 2001); and measurement of enzyme activity (Chen et al 1999), to name but a few. In some cases different biomarkers can be used to measure the same indicator.…”

Molecular Epidemiology of Breast Cancer: Development and Validation of Acetylation Methods for Carcinogen-DNA Adduct Detection

“…In this study, 14 C was measured relative to 13 C and then normalized to the ratio of 14 C/ 12 C using the Australian National University sugar standard [23] as reference. For AMS analysis, HPLC samples were converted to graphite by a two step process involving combustion of the samples to C0 2 followed by reduction to filamentous graphite, as described previously [24].…”

“…Detection methods based on immunoassay or 32 P-postlabeling may be sensitive enough [12], but lack the desired specificity unless combined with micropreparative steps (e.g. immunoaffinity chromatography) [13][14][15]. These additional analytical steps tend to reduce sensitivity and increase labor and/or cost beyond acceptable limits [16,17].…”