STP1027: Bridging the Gap from Short-Term Teratogenesis Assays to Human Health Hazard Assessment by Understanding Common Modes of Teratogenic Action

    Bantle, JA
    Professor and graduate research assistant, Oklahoma State University, Stillwater, OK

    Fort, DJ
    Professor and graduate research assistant, Oklahoma State University, Stillwater, OK

    Dawson, DA
    Postdoctorate fellow, University of Tennessee, Knoxville, TN

    Pages: 13    Published: Jan 1989


    Abstract

    Embryonic development depends on the timely expression of genetic information. As development proceeds, embryonic cells undergo processes such as cell division, interaction (induction), migration, differentiation, and selective death. Developmental toxicants affect one or more of these mechanisms. Whole embryo teratogenesis screening assays are best suited for hazard identification because all the developmental mechanisms are represented in the test. Cell culture and biochemical tests are better suited for determining which biochemical or cellular mechanisms are adversely affected by the toxicant. By combining data from a validated whole embryo teratogenesis test with data from cellular and biochemical tests in a battery format, a better indication of the potential human health hazard is afforded. We have tried this approach in the case of DNA synthesis inhibitors. These inhibitors are teratogenic in virtually all species tested regardless of where in the metabolic pathway they inhibit replication. DNA synthesis inhibitors, such as hydroxyurea, cytosine arabinoside, and 5-fluorouracil, were teratogenic in the Frog Embryo Teratogenesis Assay Xenopus (FETAX). These substances also inhibited DNA synthesis in a fluorometric assay using cleaving Xenopus eggs. However, they did not inhibit gene expression as measured by their inability to prevent the expression of the cloned herpes thymidine kinase gene microinjected into Xenopus Stage 6 oocytes. The combined data not only show that malformations are caused by these agents but pinpoint the developmental mechanism affected. This suggests that all species, including man, may be affected. A battery of simple tests could be developed which measures effects on the developmental mechanisms shared by all species. Risk assessment studies would still be necessary to consider dose levels and types of exposure needed to observe an effect in man.

    Keywords:

    Xenopus, teratogenesis assay, FETAX (Frog Embryo Teratogenesis Assay—, Xenopus, ), DNA synthesis, mechanisms of teratogenicity


    Paper ID: STP16766S

    Committee/Subcommittee: E47.13

    DOI: 10.1520/STP16766S


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