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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005177-17
Application #
6100773
Study Section
Special Emphasis Panel (CCTP)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
1998
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Pratt, M Margaret; Sirajuddin, Paul; Poirier, Miriam C et al. (2007) Polycyclic aromatic hydrocarbon-DNA adducts in cervix of women infected with carcinogenic human papillomavirus types: an immunohistochemistry study. Mutat Res 624:114-23
Divi, Rao L; Leonard, Sarah L; Walker, Brettania L et al. (2007) Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age. Toxicol Sci 99:203-13
Gunter, Marc J; Divi, Rao L; Kulldorff, Martin et al. (2007) Leukocyte polycyclic aromatic hydrocarbon-DNA adduct formation and colorectal adenoma. Carcinogenesis 28:1426-9
van Gijssel, Hilde E; Leil, Tarek A; Weinberg, Wendy C et al. (2007) Cisplatin-DNA damage in p21WAF1/Cip1 deficient mouse keratinocytes exposed to cisplatin. Mutagenesis 22:49-54
Divi, Rao L; Haverkos, Kathryn J; Humsi, Juliette A et al. (2007) Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen 48:179-89
Divi, Rao L; Leonard, Sarah L; Kuo, Maryanne M et al. (2007) Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Environ Mol Mutagen 48:201-9
Mahadevan, Brinda; Arora, Vikram; Schild, Laura J et al. (2006) Reduction in tamoxifen-induced CYP3A2 expression and DNA adducts using antisense technology. Mol Carcinog 45:118-25
Keshava, Channa; Divi, Rao L; Whipkey, Diana L et al. (2005) Induction of CYP1A1 and CYP1B1 and formation of carcinogen-DNA adducts in normal human mammary epithelial cells treated with benzo[a]pyrene. Cancer Lett 221:213-24
Divi, Rao L; Leonard, Sarah L; Kuo, Maryanne M et al. (2005) Cardiac mitochondrial compromise in 1-yr-old Erythrocebus patas monkeys perinatally-exposed to nucleoside reverse transcriptase inhibitors. Cardiovasc Toxicol 5:333-46
Olivero, Ofelia A; Tejera, Agueda M; Fernandez, Juan J et al. (2005) Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells. Mutagenesis 20:139-46

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