Promotion of mouse lung tumors by bioaccumulated polychlorinated aromatic hydrocarbons.
Lung tumors initiated in infant Swiss mice by N-nitrosodimethylamine (NDMA) were promoted by a single dose of a mixture of polychlorinated biphenyls (PCBs), Aroclor 1254 (250 or 500 mg/kg) given 4 days later. The tumors were typical alveologenic adenomas, and their number increased gradually over the course of 1 year to a maximum 4-fold enhancement in average tumor number compared with those given NDMA alone. The time course pattern suggested continuous tumor stimulation by the nonmetabolized PCB congeners retained in the tissues. Content of the nine major bioretained PCB congeners in carcass, liver, and lung was determined at intervals after treatment. Several showed tissue-specific retention patterns: 2,3,3',4,4'-PCB was selectively retained in lung and liver, and 2,2',3,4,4', 5'-HCB in lung. In tests of the tumor-promoting ability of individual congeners, the 2,2',3,4,4',5'-HCB, an Ah receptor agonist, promoted lung tumors when given singly, whereas another prominent bioretained congener, the 2,2',4,4',5,5'-HCB, an Ah receptor antagonist, did not promote, and in fact abrogated the positive effect of the 2,2',3,4,4',5'-HCB. In a parallel examination of persistent biochemical effects, a single low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (5 nmole/kg) resulted in significant elevation of immunochemically detected protein and enzymatic activity of cytochrome P450 IA1 in lung for at least 12 weeks; these parameters were elevated for at least 30 weeks after a single dose of Aroclor 1254 (500 mg/kg). Taken together these results suggest that Ah-receptor-dependent induction of cytochrome P450 IA1 in mouse lung is correlated with and possibly causally involved in promotion of tumors by retained congeners.
Anderson
L M
LM
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, MD 21701.
Beebe
L E
LE
Fox
S D
SD
Issaq
H J
HJ
Kovatch
R M
RM
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics; D003043:Cocarcinogenesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009928:Organ Specificity / Q000502:physiology; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000633:toxicity*
D002273:Carcinogens; D016202:N-Methylaspartate; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls