title: Benzo[a]pyrene enhances lipid peroxidation induced DNA damage in aorta of apolipoprotein E knockout mice.
abstract: The genotoxic compound benzo[a]pyrene (B[a]P) enhances atherosclerotic plaque progression, possibly by inducing oxidative stress and subsequent lipid peroxidation (LPO). Since LPO plays a key role in atherosclerosis, stable LPO derived DNA modifications such as 1,N6-ethenodeoxy-adenosine (epsilondA) and 3,N4-ethenodeoxy-cytidine (epsilondC) may be useful biomarkers for in vivo oxidative stress. In this study, benzo[a]pyrene-diol-epoxide (BPDE)-DNA, epsilondA and epsilondC were determined by 32P-postlabelling in apolipoprotein E knockout (ApoE-KO) mice treated with 5mg/kg B[a]P by gavage. After 4 days, BPDE-DNA adduct levels were higher in aorta (10.8 +/- 1.4 adducts/10(8) nucleotides) than in lung (3.3 +/- 0.7, P < 0.05), which is a known target organ for B[a]P. Levels of epsilondA were higher in aorta of B[a]P-exposed animals than in unexposed controls (8.1 +/- 4.4 vs 3.4 +/- 2.1 adducts per 10(8) parent nucleotides, P < 0.05). On the other hand, epsilondC levels were not affected by B[a]P exposure. Serum low density lipoprotein (LDL) levels were lower in B[a]P-exposed mice than in controls (9.3 +/- 3.7 and 13.3 +/- 4.0mmol/l, respectively), whereas high density lipoprotein (HDL) levels were higher (1.4 +/- 1.6 and 0.4 +/- 0.3mmol/l, respectively). Consequently, a three-fold difference in the LDL/HDL ratio was observed (P = 0.001). epsilondA levels were positively related with plasma HDL concentrations (R = 0.68, P = 0.02), suggesting that the HDL mediated protection of the vessel wall against reactive lipid peroxides was reduced in B[a]P-exposed apoE-KO mice. Our observations show that direct as well as lipid peroxidation induced DNA damage is formed by B[a]P in aorta of apoE-KO mice, which may be involved in atherosclerotic plaque progression. This study further indicates that etheno-DNA adducts are useful biomarkers for in vivo oxidative stress in atherosclerosis.
authors.affiliation: German Cancer Research Center (DKFZ), Div. Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Roger
authors.initials: R
authors.lastname: Godschalk
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Curfs
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
authors.forename: Frederik-Jan
authors.initials: FJ
authors.lastname: Van Schooten
authors.forename: Jagadeesan
authors.initials: J
authors.lastname: Nair
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D002273:Carcinogens; D018736:DNA Adducts; D008055:Lipids; D008074:Lipoproteins; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA