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Age-dependent changes in prevalence, size and proliferation of arterial lesions in cockerels. II.
Abstract:
Age-dependent changes were determined in the prevalence, frequency, size and proliferative activity of aortic lesions arising in cockerels injected weekly with the polycyclic hydrocarbon carcinogen, 7,12-dimethylbenz (a) anthracene (DMBA). Starting at 4 weeks of age, groups of 6 animals received weekly i.m. injections of DMBA (10 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO). Controls were injected with DMSO. Animals were sacrificed (DMSO). Controls were injected with DMSO. Animals were sacrificed at 4 week intervals between 8-20 weeks of age. Microscopic lesions were observed in the abdominal aortas of all animals regardless of age or treatment. At no time point were there statistically significant differences in the prevalence or frequency of lesions between DMBA-treated animals and age-matched controls. In addition, lesion areas were log-normally distributed in all groups. However, DMBA exposure elicited 2 sets of changes not seen in controls. Carcinogen treatment accelerated the time and rate of appearance of large lesions. Eight week old DMBA-treated animals displayed lesion sizes comparable to those seen in 20 week old controls. Continued exposure to DMBA resulted in sharp increases in lesion size up to 20 weeks of age. Between 12-20 weeks lesion size increased, in a nearly linear fashion, by 12X in DMBA-treated animals but only by 2X in controls. There also was a burst of lesion cell proliferation in cockerels after 12 weeks of DMBA treatment. No equivalent increase in proliferation was seen in lesion cells in controls or in medial cells of either experimental or control animals. These results demonstrate that chronic carcinogen exposure results in the accelerated development of pre-existing "spontaneous' lesions rather than the initiation of new lesions. In addition, the results indicate that lesions are not homogeneous regarding their response to proliferative stimuli. This suggests that within a lesion there may exist subpopulations of cells which are more capable of proliferating in response to DMBA, and presumably to other agents, than are the majority of lesion cells.