Chronic exposure to the carcinogenic compound benzo[a]pyrene induces larger and phenotypically different atherosclerotic plaques in ApoE-knockout mice.
Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon with atherogenic and carcinogenic properties. The role of B[a]P in carcinogenesis is well established, and thought to exert via enzymatic activation into reactive metabolites that are capable of binding to the DNA leading to uncontrolled proliferation. However, the mechanism underlying the atherogenic properties of B[a]P is still unclear. Therefore, the effects of chronic B[a]P exposure on atherosclerotic plaque development in apolipoprotein E knockout (apoE-KO) mice were studied. ApoE-KO mice were orally treated with 5 mg/kg/bw B[a]P once per week for 12 or 24 consecutive weeks. Levels of reactive B[a]P metabolites in the arterial tree (from the aortic arch until the iliac artery bifurcations) were high as shown by the level of B[a]P DNA-binding products measured in DNA isolated from the entire aorta (38.9 +/- 4.8 adducts/10(8) nucleotides). Analysis of atherosclerotic lesions in the aortic arch showed no influence of B[a]P on location or number of lesions. Moreover, no increased levels of p53 nuclear protein accumulation or cell proliferation, as detected by immunohistochemistry, were seen in the plaques of the B[a]P-exposed animals. However, the effects of B[a]P on advanced lesions were obvious: advanced plaques were larger and more prone to lipid core development and plaque layering at both 12 and 24 weeks (P < 0.05). In the B[a]P-exposed animals advanced plaques contained more T-lymphocytes and macrophages than in the control animals at both end points (P < 0.05). These data suggest that B[a]P does not initiate atherosclerosis in apoE-KO mice, but accelerates the progression of atherosclerotic plaques via a local inflammatory response.
Curfs
Daniëlle M J
DM
Department of Health Risk Analysis and Toxicology, University of Maastricht, Maastricht, The Netherlands.
Lutgens
Esther
E
Gijbels
Marion J J
MJ
Kockx
Mark M
MM
Daemen
Mat J A P
MJ
van Schooten
Frederik J
FJ
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000139:chemically induced* / Q000473:pathology*; D001564:Benzo(a)pyrene / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
D001057:Apolipoproteins E; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene