Environmentally-induced malignancies: An in vivo model to evaluate the health impact of chemicals in mixed waste. 1998 annual progress report
'Increased risk of malignancy following exposure to genotoxic agents in the environment is a major public concern. Exposure to radiation, benzene, and organic solvents is associated with an increased risk of leukemia; however the mechanism of leukemogenesis is unknown. The authors postulate that chemical(s) that increase the rate of genomic instability and induce hematotoxicity will promote accumulation of genetically-damaged hematopoietic stem cells (hsc), and thus contribute towards development of environmentally-induced hematologic malignancy. They will use molecular and cellular approaches to establish the relationship between hematoxicity, genomic instability and production of genetically aberrant hsc and progeny in mice exposed to radiation, benzene and trichloroethylene (TCE). The goals of this project are to (1) determine whether recruitment of hsc into cycle by agents that induce hematotoxicity (i.e., pancytopenia, anemia) facilitates fixation of genetic damage in hsc exposed to environmental genotoxins in vivo. (2) Determine whether environmental genotoxins with leukemogenic potential disrupt hsc genomic integrity by inactivating cell cycle checkpoints. (3) Determine whether low dose exposures to agents that induce chronic pancytopenia/anemia and/or cyclic hemopoiesis increase fixation of genetic damage in hsc. Increased understanding of the relationship between genotoxicity, hematotoxicity and genomic instability will (a) lend insight into mechanisms underlying environmental-induction of leukemic progression, (b) facilitate development of a rationale to identify chemical combinations which synergize to increase or decrease leukemogenic potential, and (c) provide opportunities to optimize approaches for biomonitoring and risk assessment. This report summarizes work after 1.5 year of a 3 year project. Accomplishments to-date include demonstration that the cycling status of hemopoietic stem cells at the time of genotoxin exposure alters the frequency and persistence of genetically damaged hemopoietic stem cells and associated progeny (Aim 1), development of assays to measure genomic instability in hemopoietic stem cells and associated progenitors (Aim 2) and quantification of genomically aberrant hsc and progeny following radiation, benzene and TCE exposures (Aim 2). Mice with varying susceptibility to leukemogenesis have been exposed to combinations of radiation, benzene and TCE to allow assessment of the cellular and genomic perturbations associated with leukemogenesis.'
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Office of Environmental Management (EM), Office of Science and Risk Policy
- OSTI ID:
- 13596
- Report Number(s):
- EMSP-55356-98; ON: DE00013596
- Country of Publication:
- United States
- Language:
- English
Similar Records
Formaldehyde and co-exposure with benzene induce compensation of bone marrow and hematopoietic stem/progenitor cells in BALB/c mice during post-exposure period
Hematotoxicity and carcinogenicity of benzene