This project will examine the mechanisms of lead toxicity in terms of its effects on cellular calcium metabolism. The temporal and spatial regulation of cellular calcium is critical for a wide variety of cellular processes, for appropriate response to hormonal and electrical stimuli and for maintaining cell viability. Lead is an ubiquitous toxin available from many sources including the air, leaded-gasoline, paint, pottery, """"""""moonshine"""""""" and industrial exposure. Even at currently regulated """"""""low levels"""""""" of exposure, epidemiologic evidence continues to build associating lead with metabolic, neurologic, developmental, behavioral and cardiovascular disorders. That there is a relationship between lead and calcium has been recognized for 60 years. Many recent investigations have shown that in every tissue which has been studied, lead alters cellular calcium homeostasis and calcium-mediated cell function. The long term working hypothesis of this study is that an important subset of the variety and magnitude of disorders produced by lead intoxication are the result of lead's interference with cellular calcium homeostasis. This project will be pursued in three phases which examine the interaction between lead and calcium at three successive levels of biological organization. First, using plasma membrane vesicles, endoplasmic reticulum rich-microsomes and mitochondria isolated from rat liver, this study will characterize the direct effects of lead on celluar membrane calcium transport and the mechanisms of lead transport. Second, using liver perfusion in combination with isolated membrane fractions, this study will examine the effects of lead on hormonal regulations of calcium transport and the effects of hormones on lead transport. Finally, in vivo correlates will be determined by examining the cumulative consequences of circulating blood lead levels on the intracellular transport and storage of both lead and calcium.
