Lead toxicity is a major public health problem in the United States. The results of the second National Health and Nutrition Examination Survey demonstrated a highly significant inverse correlation of blood lead level with growth, suggesting a biologic effect of the metal ion on developmental aspects of the epiphyseal growth plate. It is unclear, however, whether the effect of lead is mediated through a systemic pathway or a specific effect on the growth plate chondrocytes. This proposal seeks to explore the relationship between direct lead effects on cartilage metabolism and the detrimental results of lead on skeletal growth. The research goals are to examine and fully characterize lead's effects on chondrocyte phenotype in vitro. These studies will utilize an avian model of growth plate differentiation which has been well characterized in our laboratory. Specifically the experiments will define the effects of lead on proliferation, alkaline phosphatase expression, matrix proteins and proteoglycan synthesis in cell culture. Subsequent studies will focus on identification of the specific mechanisms of lead effects on growth plate chondrocytes. These studies will explore the role of lead on the autocrine and paracrine regulation of chondrocyte differentiation by determining the ability of the cells to respond to, or synthesize, these regulator molecules in the presence of the ion. In the final phase of these studies we will examine the in vivo effects of lead on growth plate structure and function in a whole animal model as well as in a new cell pellet culture model that retains features of the intact tissue. A detailed cellular and molecular characterization of the effects of lead on chondrocyte phenotype that is focused on mechanisms of the toxicity will significantly enhance our understanding of the adverse effects of this agent on the developing skeleton.