This project will evaluate the potential developmental toxicity of xenobiotics using the whole embryo culture system. This system supports the normal growth and development of rodent embryos in an in vitro system and allows for the evaluation of the effects of an agent on morphological, biochemical and molecular processes. The adverse developmental effects (e.g., in utero lethality and neural tube defects) of several elemental ions, e.g. group IIIA metals (In. Ga) and arsenic have been shown in vivo. However, these effects are due to the direct effects of the metals or mediated through an effect on maternal homeostasis is unclear. Preliminary studies will address the direct effects of these agents on the conceptus, and mechanistic studies will focus on free radical generation and other biochemical effects of the agents. The mechanisms responsible for the production of cell death will be evaluated in a limb bud culture system. For these studies, the molecular and cellular effects of xenobiotics will be determined following exposure to specific agents such as retinoic acid and oxygen radical generating systems. Preliminary evidence suggests that abnormal digit formation occurs as a result of excess oxygen which is similar to the effects on many toxicants in vivo. This may suggest that the generation of oxygen radical ions may be a common mechanism of developmental toxicity.
