Over the past several years, there has been growing concern that human populations are being exposed to an increasing number of potentially teratogenic agents in the form of untested drugs and chemicals, environmental pollutants, and industrial waste and byproducts. Although federal regulations require testing for teratogenicity, the rate at which new compounds enter the environment far outpaces our capacity to properly evaluate their reproducitve safety. To overcome this situation, an inexpensive screening procedure like the Ames in vitro Salmonella assay needs to be developed for detecting teratogens. However, the success of the Ames assay rests on the fact that the mechanism by which agents induce mutagenicity is known and can therefore be capitalized upon. Unfortunately, comparable knowledge regarding mechanisms of teratogenicity is not available, although the prime candidate for such a mechanism is developmental delay. The studies described in this proposal are designed to systematically evaluate the role of developmental delay as measured by four parameters: heat shock protein synthesis, inhibition of protein synthesis, morphogenetic delay and histological changes. These parameters will be evaluated in mouse embryos exposed to a series of teratogens and putative non-teratogenic agents given over a wide dose range during critical periods of development. The results should reveal if teratogens consistently differ from non-teratogens with respect to the test parameters. Those that do differ can then be tested for predicting teratogenicity. To determine which, if any, of the parameters for predicting teratogenicity can also be used to predict genetic susceptibility to teratogenesis, several inbred mouse strains with varying sensitivities to certain teratogens will be tested. If these parameters of developmental delay can be validated as predictive of teratogens in murine embryos, then it will be possible to apply the most predictive parameters to an inexpensive in vitro testing system to screen for potential teratogens.
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