Jay Kimball Kidney
Project title: Modulation of Nitrosourea Toxicity in Rodent Embryonic Cells by O6-benzylguanine, a Depletor of O6-methylguanine-DNA Methyltransferase
Completed in: 1993
Low levels of a variety of N-nitroso (NNO) compounds are present throughout the modern human environment with exposure occuring from food, water, air, tobacco usage and industrial and consumer products. These compounds are also formed endogenously in reactions mediated by bacteria and macrophages. Concern regarding human exposure to NNO compounds is reinforced by their tumorigenicity in 40 animal species, the fact that they are multi-organ carcinogens in animals, and their production of similar cellular and molecular damage in animal and human tissue. NNO compounds are also teratogenic, mutagenic, cytotoxic, and transplacentally carcinogenic in developing animals.
Our studies were performed using the micromass culture system that has previously been utilized in our laboratory to evaluate the effects of NNO compound exposures on developing rodent embryonal cells. In these cultures, midbrain (CNS) and limb bud (LB) cells from 12.5 day post-coitum pregnant rats are cultured separately for 5 days and evaluated for viability and differentiation. NNO compounds have been shown to be effective inhibitors of differentiation in both CNS and LB cultures.
The aim of this study was to explore the impact of MGMT inhibitors on the in vitro developmental toxicity of NNO compounds.