Of the many congenital deformities seen in animals those involving the limbs are among the most common, especially ectromelia, phocomelia and micromelia. Often these conditions result from an unwitting exposure of the organism to substances of unknown teratogenic potential at a sensitive phase of embryogenesis. It would be useful to know why a substance is selectively harmful to only one or a few biological structures and only within a narrow window of time. The organophosphorus (OP) and alkylcarbamate (AC) insecticides can produce a cadre of deformities which in avia includes micromelia. These cholinergic agents reduce the NAD content of the whole organism, not just of the afflicted tissues, and the resulting NAD deficit has been blamed for the deformities. But under some circumstances micromelia occurs even when the NAD level is normal. The insecticides also decrease the availability of free tryptophan (TRP) in the embryo, perhaps by inhibiting yolk sac proteases. TRP is a precursor in the synthesis of proteins and NAD. Supplementary TRP or nicotinamide (Nam) can counteract the deformations. Insulin and 6-aminonicotinamide (6AN) cause deformities of the beak and limbs like those produced by the insecticides and they too are antagonized by TRP or Nam. These similarities suggest that the metabolic problems caused by the insecticides, insulin and 6AN are alike. There are 5 principal objectives of this study. The first 3 deal with the ways in which the OP insecticides, 6AN and insulin affect the availability of NAD and the free amino acids, particularly TRP, in the embryo and whether certain antiteratoges counteract the amino acid and NAD changes. The fourth objective is aimed at discovering whether the failures of limb development caused by the teratogens are due to attenuation of the production of structural macromolecules in the limbs. The search for such targets will involve the use of immunohistological and electrophoretic methods and monoclonal antibodies that have been generated against core constituents of the leg of the 6 day embryo. The 5th objective addresses questions similar to those of the 4th except that limb bud tissues in micromass culture, rather than in the intact limb of the embryo, will be the biological subject. This integrated study should provide us with a better understanding of the specific causes of micromelia in avian embryos that result from the actions of three teratogens.
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