Correlation between biomarkers of polycyclic aromatic hydrocarbon exposure and electrophilic tissue burden in a rat model

Abstract

This study was aimed at investigating the correlation between biomarkers of exposure to polycyclic aromatic hydrocarbons and, more specifically, at examining the role of urinary 1-hydroxypyrene (1-OHP) as a reliable measure of internal dose linked to the electrophilic tissue burden (ETB), assessed as covalent binding of the ultimate carcinogen benzo( a)pyrene diolepoxide (BaPDE) with cellular proteins in target organs. The protocol included experimental verification of a previously proposed algorithm for adjustment of reference values for urinary 1-OHP with exposure to different mixtures of polycyclic aromatic hydrocarbons in a rat model. Hence, the relationships between ETB in liver, lung, and heart as well as the BaPDE-haemoglobin adducts level on the one hand, and urinary/faecal 1-OHP or urinary/faecal 3-hydroxybenzo( a)pyrene (3-OHBaP) on the other hand have been examined. Male Sprague-Dawley rats received intraperitoneally, once daily for 10 consecutive days, binary mixtures of benzo( a)pyrene (BaP) and pyrene (P) in three different exposure scenarios corresponding to BaP/P ratios of 0.2, 1 and 5, with three doses of BaP (2, 6 and 20 mg/kg) for each scenario. The ETB levels were measured as the ultimate analyte benzo( a)pyrene tetrol (BaPTeT) obtained after mild acid hydrolysis of BaPDE adducts with proteins. It was experimentally confirmed that: (1) urinary 1-OHP is a reliable biomarker linked to the ETB in tissues that are targets for carcinogenicity, such as lung, for the BaP/P ratios of 0.2 and 1 (linear regression p=0.0099 and 0.0293, respectively); (2) urinary 3-OHBaP is correlated with the BaPDE-haemoglobin adducts for all three exposure scenarios ( p=0.0011 for BaP/P=0.2, p<0.0001 for BaP/P=1 and p=0.0099 for BaP/P=5). The experimental relationship between ETB and urinary 1-OHP was used to interpolate biological limit values for the urinary metabolite assuming three arbitrary critical levels of ETB. These were compared with the values calculated from the algorithm using the BaP/P ratio 1 mixture as a reference. The ratios of calculated to observed values varied from 1.0 to 1.6 for the BaP/P 0.2 mixture, and from 1.9 to 3.0 for the BaP/P 5 mixture. The results obtained in the present study indicate that the algorithm mentioned above applies well for two of the three exposure scenarios corresponding to realistic occupational BaP/P ratios of 0.2 and 1. This suggests that, using ETB as an endpoint, the proposed algorithm will reasonably predict the critical value of urinary 1-OHP for mixtures having different BaP/P ratios. Stronger linear relationships between ETB in all chosen tissues and 1-OHP or 3-OHBaP excretion were obtained with urinary metabolites than with their faecal analogues. Thus urinary 1-OHP and 3-OHBaP are more reliable biomarkers in biological monitoring strategies.

Binary Mixtures of Polycyclic Aromatic Hydrocarbons Display Nonadditive Mixture Interactions in an In Vitro Liver Cell Model

“…A common pitfall for estimating PAH toxicity is the erratic variations of environmental mixtures and the many possible biotransformation pathways for PAHs in organisms. Toxicity could result from receptor competition, impaired cellular uptake, protein binding, impaired cellular functions, disrupted intercellular communications, mutations, among others . Binary mixture data are a necessary first step in elucidating interactions in complex mixtures.…”

“…Toxicity could result from receptor competition, impaired cellular uptake, protein binding, impaired cellular functions, disrupted intercellular communications, mutations, among others. (14,16,40) Binary mixture data are a necessary first step in elucidating interactions in complex mixtures. More complex mixtures, such as ternary or quaternary, can further improve current knowledge on complex interactions.…”

The Relationship between Maternal and Fetal CYP1A1 Genotype in Smokers and Nonsmokers to Benzo(a)pyrene Hemoglobin Adducts

“…Many PAH are carcinogenic and mutagenic. Benzo[a]pyrene undergoes metabolism by CYP1A1 to epoxides which are further metabolized by epoxide hydrolases to dihydrodiols which can be further activated to the highly carcinogenic benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide ( Figure 1) (17,(53)(54)(55)(56)(57)(58)(59)(60). Of the four possible diol epoxides, (+)-(7R,8S,9S,10S) diol epoxide-2 was found to be the most potent carcinogen.…”

A correlation study applied to biomarkers of internal and effective dose for acrylonitrile and 4-aminobiphenyl in smokers

“…A moderate correlation was reported between free NNAL and N 7 -MEG in a group of urothelial carcinoma patients split between smokers and non-smokers (Lee et al, 2008). BPDE-haemoglobin adducts but not the albumin adduct were highly correlated with the urinary polyaromatic hydrocarbon 1-hydroxypyrene (Tzekova et al, 2004). Interestingly another study conducted with smokers and non-smokers reported no correlation between the BPDE–haemoglobin adduct and cotinine whilst a moderate correlation was reported between the BPDE–albumin adduct and cotinine (Pastorelli et al, 2000; Wang et al, 2007).…”