Topics under study include the extent of DNA (genomic, mitochondrial, telomeric) adduct formation and persistence, and the biological consequences of DNA damage in cultured cells, animal models and human tissues. The compounds of intensive investigation include cisplatin, 3'-azido-2',3'-dideoxy-thymidine (AZT), polycyclic aromatic hydrocarbons (PAHs), and aromatic amines. Cisplatin, a chemotherapeutic agent used to treat pregnant women discovered to have ovarian cancer, is tumorigenic to the offspring of mice and rats when administered as a single dose during gestation. We have shown that cisplatin crosses the placenta and induces widespread genomic DNA adduct formation in many tissues of fetal rats and monkeys. In addition, higher mitochondrial-DNA damage, as compared to genomic-DNA damage was observed in fetal liver and brain. The anti-HIV drug AZT induces vaginal tumors in chronically exposed mice and rats, and we have demonstrated dose-related vaginal AZT-DNA incorporation and cell proliferation in mouse. The drug is currently in widespread use to prevent fetal HIV transmission in infected pregnant women. We have used AZT exposure in pregnant mice and monkeys to model human pregnancy, and have demonstrated that AZT crosses the placenta and becomes incorporated into genomic and mitochondrial DNA of many fetal tissues. In addition, current studies (at 1 year after birth) indicate that AZT is a transplacental carcinogen for liver, lung and skin of mice. Studies with human tumor cells have demonstrated that AZT targets telomeres, and chronic culturing in the presence of this drug leads to an irreversible and significant shortening of telomere size. Molecular dosimetry studies of US Army soldiers stationed in Kuwait, individuals in China exposed to smoky coal fumes, and workers from the aluminum foundry and vulcanizing industries are in progress. In the US Army troops, a decrease in blood cell PAH-DNA adduct levels accompanied a change in work venue from areas with higher, to areas with lower, ambient PAH levels. Studies are in progress to compare PAH-DNA adduct levels with PAH urinary metabolites and metabolic polymorphisms in these soldiers.
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