The objectives of this proposal are to develop an in vitro human-rodent placental model to establish normal function, and to determine the pharmacokinetics and toxicity of environmental agents, e.g., heavy metals, without risk to either mother or fetus. Specifically, the aims are (1) to establish a physiologically and morphologically functional perfusion system for evaluating human placentae from normal mothers and those exposed to environmental toxins, e.g., smoking mothers; (2) to develop a human-rodent placental model for directly examining the pharmacokinetics and toxicity of environmental agents using cadmium as a prototype; (3) to correlate cadmium exposure with trophoblastic structure and function in the human placenta and determine (a) the mechanisms by which cadmium induces its change and (b) the role of zinc and selenium in modifying the effects of Cd; (4) to study the types of trophoblastic proteins to which cadmium binds and the induction characteristics for placental metallothionein, when there is no other potential source for metallothionein. Three general technics will be utilized for these studies: A) in vitro human placental lobule perfusion (hormone synthesis and release; amino acid transport-bidirectional transfer; membrane integrity-inulin transfer; maternal/fetal pO?2?, pCO?2?, pH, glucose, blood pressure and flow rate; blood flow distribution (microspheres), mitochondrial Ca?++? levels, pharmacokinetics of Cd and morphology); B) in vitro slice technic (incubation with specific agents to determine uptake and binding/metabolism under identical conditions for rodent and human; C) in vivo Wistar rat toxicity studies (general toxicity analysis, hormonal status (estrogens, progesterones), organ blood flow (microspheres), pharmacokinetics, mitochondrial calcium levels, and morphology. This research is targeted at the adaptability of the trophoblast to environmental exposure whether in man or in animal as reflected in these morphological, biochemical, and physiological responses. However, equally important is the continuing development of physiological, biochemical, morphological and endocrinological standards now for 7 hrs. but progressing toward an 18-24 hr. perfusion. With such a human-rodent placental model, the potential for determining normal function, pharmacokinetics and compromise to the human placenta may be investigated without risk to either mother or baby.
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