The Carcinogen-DNA Interactions Section investigates the extent, persistence and biological consequences of DNA damage, with emphasis on events relevant to parallel exposures in animal models and humans. Compounds of intensive investigation include carcinogenic drugs and environmentally-relevant pollutants. Transplacental exposure to cisplatin, which is used to treat pregnant women with ovarian cancer, is tumorigenic to rodent offspring and forms nuclear and mitochondrial (MT) DNA adducts in many tissues of fetal rats and monkeys. We have found the highest levels of cisplatin-DNA damage in liver and brain maternal and fetal MT-DNA, and have investigated fetal MT function in these tissues. In fetuses from rats given a single dose of cisplatin near the end of gestation mitochondrial cytochrome c oxidase activity was decreased 50% in heart and kidney, compared to unexposed controls, while the NADH dehydrogenase was unchanged. The nucleoside analog 3'- azido-2', 3'-dideoxythymidine (AZT) is currently used to prevent fetal HIV-1 transmission in infected pregnant women. However, compared to untreated controls, AZT given to pregnant mice (12.0 and 25.0 mg AZT/day by gavage on gestation days 12-18), induces 2-8 fold higher incidences of liver, lung, skin and female reproductive organ tumors in mouse pups grown to 1 year of age. In addition, AZT given to pregnant mice and monkeys for 37-45% of the gestation period is incorporated into nuclear and MT- DNA of multiple fetal tissues examined at term. AZT-DNA incorporation in cord blood from HIV-1-positive mothers has been observed at levels higher than those found in the fetal mice given tumorigenic AZT doses. In molecular dosimetry studies of US Army troops stationed in Kuwait, a decrease in blood cell polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels was observed when soldiers were deplored from an area of high ambient PAH concentration to one of low ambient PAH concentration. PAH-DNA adducts did not, however, correlate significantly with urinary 1-OH- pyrene glucuronide levels or high-risk metabolic polymorphisms of Cyp1A1, Gstm1 or Gstt1. In esophageal biopsies obtained in Linxian, China (in 1985) from individuals exposed to high levels of indoor smoke, immunoperoxidase staining has demonstrated the presence of nuclear PAH-DNA adducts; the development of this methodology should allow investigation of a relationship between DNA adduct formation and esophageal cancer in humans.
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