Hepatic drug metabolizing enzyme activity and tumorigenesis in mice following perinatal exposure to benzo(a)pyrene.
It is known that in utero exposure to polycyclic aromatic hydrocarbon carcinogens (PAH) results in a high incidence of pulmonary and other tumors in the offspring, usually after a long latency period. The present study tested the hypothesis that perinatal exposure to benzo(a)pyrene (BP) produces alterations in microsomal mixed-function oxidase (MFO) activity that modify the response to postnatal challenge with a PAH in such a way as to render the offspring to be more susceptible to tumorigenesis, and to determine whether the gestational age at which BP exposure occurred was a determinant of the proposed alterations. Swiss mice were treated with BP on day 3, 8, 10, 12, 14, or 18 of gestation. Subgroups from each gestational-age treatment group and appropriate controls were studied for enzyme activity or were challenged with 3-methylcholanthrene (3-MC) when three months old. Female offspring of BP-treated mice had significantly elevated hepatic microsomal aminopyrine demethylase activity; cytochrome P-450 concentrations were significantly lower in male offspring. The most striking finding was the increased susceptibility to tumorigenesis of female offspring. Latency for local tumors was decreased by two weeks; tumors were more frequent and grew more rapidly. Significantly more female offspring had both local and pulmonary lesions, and the total number of pulmonary adenomas was also significantly higher. Further studies are required to determine if the developmental alterations in hepatic (MFO) activity resulting from perinatal exposure to PAH relate in a causative way to the enhanced susceptibility of female offspring to tumorigenesis.
D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D007939:Leukemia L1210 / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012098:Reproduction / Q000187:drug effects
D001580:Benzopyrenes; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases