Arteriosclerotic plaque development is ‘promoted’ by polynuclear aromatic hydrocarbons

Abstract

In previous work we found that weekly injections of the polynuclear aromatic hydrocarbon (PAH) carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) induced spontaneous aortic plaques in cockerels to grow to a larger size and at a faster rate than plaques in control animals. To determine whether plaque-stimulating ability is related to carcinogenic potency or mutagenicity we have now tested a variety of agents, including PAH carcinogens, non-PAH carcinogens and weakly carcinogenic PAHs. Cockerels were injected weekly (from 4-20 weeks of age) with one of the following compounds: benzo[a]pyrene (B[a]P), benzo[e]pyrene (B[e]P), dibenz[a,h]anthracene (AH), dibenz[a,c]anthracene (AC), 3-methylcholanthrene (MCA), acetylaminofluorene (AAF), N-methyl-N,N'-nitro-nitrosoguanidine (MNNG) or anthracene (ANT). Plaques were present in the abdominal aortas of all animals. Plaque volumes were 8-14 times greater in AC-, B[a]P-, B[e]P-, MCA- and AH-treated cockerels than in controls. Plaques were slightly larger in the AAF-treated group than in control animals, and in the ANT- and MNNG-treated groups were indistinguishable in size from plaques in control animals. The largest plaque volumes were in AH-treated cockerels and were comparable in size to those elicited by DMBA treatment. The accelerated development of plaques is consistent with a 'promotional' role for these agents. There was a poor correlation between mutagenicity or carcinogenicity and plaque 'promotion', which may reflect a role for different metabolites in these processes.

The tar fraction of cigarette smoke does not promote arteriosclerotic plaque development.

“…There were 73 segments with plaque in the DMSO group and 74 each in the DMBA and TAR groups. As reported previously (9)(10)(11)16,19) plaque sizes were log-normally distributed, i.e., mean plaque sizes exceeded median values in all three groups (data not shown).…”

“…(The tar tested here is more rigorously dassified as cigarette smoke condensate, since it is collected in a cold trap; however, for purposes of simplicity we will refer to it as TAR). Cockerels were injected weekly (intramuscularly; im) according to our standard protocols (16,19). The tar dose was 25 mg/kg/week and the DMBA dose (Sigma, St. Louis, MO) was 10 mg/kg/week.…”

“…Sections were exposed to the Verhoffvan Gieson stain (26) to distinguish plaque from underlying artery wall and to stain collagen (red) and elastin (black). The crosssectional areas of plaques present in each plaque-containing segment were measured microscopically, as described previously (16,19), i.e., maximal depth x width of plaques. All segments with visible plaque were scored.…”

“…Polynuclear aromatic hydrocarbon (PAH) carcinogens, e.g., benzo(a)pyrene [B(a)P], and nitrosamines in the tar fraction are considered primarily responsible for the effects of CS on lung cancer and heart disease. Indeed, these and related compounds are effective at inducing or promoting these diseases experimentally, but only when administered at levels many times (often orders of magnitude) higher than the levels at which they are found in mainstream smoke or in ETS (14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…The tar fraction nitrosamine 4-(n-methyl-n-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is carcinogenic at high concentrations in rodents (14,18), had no effect on plaque development in cockerels when injected biweekly at doses of 10 mg/kg. The injection protocol we followed is effective at demonstrating the plaque-promoting effects of a variety of chemicals and environmental agents (16,19 (15,16,19,24), DMBA was a strong promoter of plaque development; however, the solubilized CS tar was totally ineffective. These findings support the conclusion that the major arteriosclerotic plaque-promoting components of CS reside in the vapor phase rather than in the tar fraction.…”