title: Electrophilic tissue burden in male Sprague-Dawley rats following repeated exposure to binary mixtures of polycyclic aromatic hydrocarbons.
abstract: The aim of this study was to investigate the electrophilic tissue burden (ETB) formation, assessed as covalent binding of the ultimate carcinogen benzo( a)pyrene diolepoxide (BaPDE) with cellular proteins, in liver, lung and heart, as well as with haemoglobin (Hb) following repeated exposure to binary mixtures of benzo( a)pyrene (BaP) and pyrene (P). Male Sprague-Dawley rats were injected intraperitoneally, once daily for 10 consecutive days, with binary mixtures of BaP and P in three different exposure scenarios corresponding to BaP/P ratios of 0.2, 1 and 5 and with three dose levels of BaP (2, 6 and 20 mg/kg) for each scenario. ETB levels were measured as the ultimate analyte benzo( a)pyrene tetrol (BaPTeT) obtained after mild acid hydrolysis of BaPDE-adducts with proteins. A high-performance liquid chromatography fluorescence technique was used to quantify the analyte. Similar ETB levels (within a factor of 4) were observed in all tissues studied at any given binary dose. However, the ETB generally tended to be somewhat higher in metabolically active tissues (i.e. liver and lung) than in metabolically non-active tissues (i.e. heart and Hb). Lack of influence of pyrene on ETB levels in all tissues was confirmed over the binary dose range examined. Linear BaP-dose-dependent ETB formation in all tissues (at P</=0.05) was observed. Linear regressions were found for all between-tissue relationships of ETB over the exposure doses, with best linear correlations obtained for ETB in heart versus Hb ( R(2)=0.709; P<0.0001) and ETB in lung versus Hb ( R(2)=0.507; P<0.0001). The results thus suggest that BaPDE-Hb adducts could serve as a surrogate of the ETB, namely in tissues that are potential targets for carcinogenicity such as lung. The results obtained in this study indicate the role of the ETB as a promising molecular biomarker of the potential cellular damage resulting from intracellular covalent binding in animal studies.
authors.affiliation: Département de santé environnementale et santé au travail, Université de Montréal, Station Centre-ville, PO Box 6128, QC H3C 3J7, Montréal, Canada.
authors.forename: Adela
authors.initials: A
authors.lastname: Tzekova
authors.forename: Suzanne
authors.initials: S
authors.lastname: Leroux
authors.forename: Claude
authors.initials: C
authors.lastname: Viau
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000493:pharmacokinetics* / Q000633:toxicity*; D011721:Pyrenes / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004338:Drug Combinations; D011084:Polycyclic Aromatic Hydrocarbons; D011721:Pyrenes; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide