The objective is to identify biochemical mechanisms of teratogenicity. Focus will be on the actions of a series of N-nitroso compounds that produce embryotoxic effects. Exposures to such compounds occur daily through the ingestion of preserved meats and use of cosmetics, drugs, agricultural chemicals and cigarettes. Although 10% of all birth defects in humans have known environmental causes (viruses, drugs, environmental chemicals), approximately 70% of all human defects have an unknown etiology. Identification of additional and preventable causes of birth defects would be important to public health. It is possible that exposrue to N-nitroso (NNO) compounds may be responsible for a portion of these human birth defects. The research is designed to test the hypothesis that the embryotoxicity of a series of N-nitroso compounds can be predicted on the basis of their chemical properties (chemical structure-activity relationships).
The specific aims are: 1) To identify common chemical properties of N-nitroso compounds which correlate with patterns, frequency and severity of their embryotoxic effects. Methyl versus ethyl alkylation, 1st order versus 2nd order types of nucleophilic substitution reactions and alkylating versus carbamylating activity will be investigated. Qualitative assessments of the ability of these chemicals to induce embryotoxic effects will be made and quantitative dose-response relationships will be established for a variety of embryotoxicity parameters (embryolethality, embryo malformations, growth retardation and alterations in macromolecular content). 2) To identify biochemical alterations within the embryo which may be critical cellular changes leading to embryotoxic effects. With information from the initial phase of the project, biochemical investigations will be directed at identifying and quantitating modifications of specific macromolecules which may be critical to the process of NNO compound embryotoxicity. Intracellular sites of such modifications will be determined. Radiolabeled NNO compounds will be used to identify biochemical alterations at equivalent effective doses to identify cellular changes critical to the process of NNO compound embryotoxicity. The studies will utilize the advantages of the rodent embryo post-implantation culture system to make these analyses.
| Maltzman, T H; Mueller, B A; Schroeder, J et al. (1997) Ras oncogene mutations in childhood brain tumors. Cancer Epidemiol Biomarkers Prev 6:239-43 |
