Childhood cancers are among the leading causes of death in children in developing countries, and incidences of brain cancer and leukemia are increasing for unknown reasons. Identification of hazardous situations and study of underlying mechanisms are carried out for preconception, transplacental, and neonatal exposures, as part of this project. Highlights of work completed or in progress this year include study of effects related to translactational exposure, and transplacental genotoxic and carcinogenic effects of iatrogenic drugs. Breast milk is a major route of exposure to polychlorinated aromatic hydrocarbons, such as polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The genetics of responsiveness to liver tumor promotion by these chemicals, in particular the role of the Ah receptor, was studied in mice. It was found that a functional receptor was needed for promotion, but other genetic factors also contributed, since dietary PCBs promoted in B6 but not B2D2 F1 mice, while TCDD promoted in the latter but not the former strain. The chemotherapeutic drug cisplatin has been shown to be a transplacental carcinogen in rats and mice, presumed to be due to genotoxic effects through DNA adducts. The latter were at lower levels in fetal vs maternal kidney, liver, and lung, but higher in fetal brain, suggesting particular susceptibility of this fetal tissue to metal-containing carcinogens. Work is also nearing completion on the transplacental carcinogenic effects of the anti-AIDS drug, 3'- azido-3'-deoxythymidine (AZT) in mice. Although analysis is not yet complete it is clear that AZT is a genotoxic transplacental carcinogen of considerable potency, causing tumors of skin, liver, and lung.
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