Quantitative and temporal relationships between DNA adduct formation in target and surrogate tissues: implications for biomonitoring.

Abstract

DNA-carcinogen adducts offer a potential dosimeter for environmental genotoxicants reaching the exposed individual. Because the target tissues for many chemical carcinogens are not readily accessible for monitoring adducts in humans, peripheral blood lymphocytes (PBLs) have served as surrogate sources of exposed DNA. Both benzo[a]pyrene (BaP) and benzo[b]fluoranthene (BbF) are widely distributed in the environment as components of complex mixtures, such as automobile exhaust, cigarette smoke, foods, water, and urban air. Thus, human exposure to these chemicals is widespread, and they probably contribute to overall human lung cancer risk. The interpretation of the results of such studies would be enhanced by an understanding of the pharmacokinetics of specific DNA adduct formation and persistence in both target and surrogate tissues. Polycyclic aromatic hydrocarbons (PAHs) were administered to male Sprague-Dawley rats IP at 100 mg PAH/kg body weight. Lung, liver, and PBL tissues were harvested 1, 3, 7, 14, 28, and 56 days after treatment. DNA was extracted from each tissue and 32P-postlabeling analysis of DNA adducts with nuclease P1 enhancement was conducted. In all three tissues, BaP-DNA adducts exhibit a similar pattern, reaching a maximum at 3-4 days, followed by a decrease to 56 days. For BbF, the maximum DNA adduct levels in each tissue were between 5 and 14 days after injection. By 56 days after administration, the total adducts remaining in all tissues were measurable. Correlation analyses of the amount of DNA adducts in lung or liver compared to those found in the PBL of the same animals suggest a range of correlations (R2 = 0.67-0.83).(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between DNA adduct formation by benzo[a]pyrene and expression of its activation enzyme cytochrome P450 1A1 in rat

“…Two of these adducts were tentatively identified to be dG-N 2 -BPDE (adduct spot 2) (Arlt et al, 2008; and the adduct derived from a reaction of deoxyguanosine in DNA with 9-hydroxy-BaP-4,5-epoxide (adduct spot 1) (Fig. 1) (Schoket et al, 1989;Nesnow et al, 1993;Fang et al, 2003). This BaP metabolite is bound to the exocyclic amino group of a guanine residue, and the site of attachment is most likely either the 4 or the 5 position on the BaP-4,5-epoxide (Fang et al, 2003).…”

“…Even though most of these metabolites are detoxification products, BaP-9-ol is a precursor of 9-hydroxy-BaP-4,5-epoxide which can form another adduct with deoxyguanosine ( Fig. 1) (Schoket et al, 1989;Nesnow et al, 1993;Fang et al, 2003). Thus, the levels and activities of CYP1A1 seem to be crucial for the initiation of BaPmediated carcinogenesis.…”

Polycyclic aromatic hydrocarbon exposure in oesophageal tissue and risk of oesophageal squamous cell carcinoma in north-eastern Iran

“…Regression models were adjusted for age, sex, education (any versus none), ethnicity (Turkmen versus non-Turkmen), tobacco use (ever versus never), and opium use (ever versus never). Because the lag time between PAH exposure and the highest density of PAH-DNA adducts may be relatively short,[27] regression models were also performed adjusting for age, sex, education, ethnicity, current tobacco use (yes versus no) and current opium use (yes versus no). P -values for trend were calculated using the logistic regression models by assigning values of 1–5 to quintiles 1–5, respectively.…”

A Proposed Methodology of Cancer Risk Assessment Modeling Using Biomarkers

“…Data from environmental monitoring do not reflect the level of exposure in humans, and they are often incomplete. In addition, times of measurement in the environment may not necessarily represent that of human exposure (Nesnow et al, 1993). Therefore, the use of biomarkers should be considered to be a more realistic means of biomonitoring for risk assessment than environmental monitoring (Hemminki et al, 1996;Decaprio, 1997).…”