The long range objective of this research is to identify biochemical mechanisms of developmental toxicity. Since one out of thirty-three live births results in a child with a birth defect and 70% of these human birth defects have an unknown etiology, the identification of additional and preventable causes of adverse pregnancy outcomes is of utmost importance to public health. In particular this project will focus on one class of ubiquitous environmental and occupational pollutants, N-nitroso compounds (NNO), that have been identified as carcinogens, mutagens, and teratogens in vivo. Although these agents have been identified as toxicants with a variety of target organ systems and endpoints, little mechanistic evaluations have been done on their ability to cause developmental toxicity. This grant will extend my initial observations on important chemical properties of NNO compounds that relate to their developmental toxicity potential and will additionally examine cellular alterations that may be critical to the process of developmental toxicity.
The specific aims of this proposal are: 1) To further investigate the role of carbamylation versus alkylation in the in vitro developmental toxicity of NNO compounds. Hypothesis: Carbamylation and not alkylation of cellular macro- molecules is the critical cellular change leading to NNO compound induced developmental toxicity. 2) To examine the effects of developmental toxicants on the normal expression of cellular oncogenes (proto-oncogenes). Hypothesis: NNO compounds cause alterations in the normal expression of cellular oncogenes (proto-oncogenes) and these tissue- and time-specific alterations can be correlated with the in vitro developmental toxicity of these agents. 3) To determine if the developmental toxicity of NNO compounds is modulated by compounds known to effect other NNO toxic endpoints. Hypothesis: Studies using known modulators of NNO compound toxicity (ellagic acid, N-acetylcysteine, L-buthionine-S,R- sulfoximine) will provide insight regarding the reactive intermediates responsible for NNO induced developmental toxicity. To accomplish these aims both the rodent post-implantation embryo culture system and the midbrain and limb micromass in vitro systems will be applied. These in vitro embryo culture systems offer numerous advantages to address these specific aims.
|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|