RETINOIDS--CONCEPTAL BIOTRANSFORMATION/DYSMORPHOGENESIS

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The long-range goal of the proposed research is to provide a better understanding of the mechanisms whereby retinoids produce dysmorphogenesis in developing embryos. Concern for dysmorphogenic, teratogenic and other embryotoxic effects of retinoids is very high because of widespread usage of these agents in therapy, as nutritional supplements and, potentially, as cancer chemopreventives. At least one retinoid (13-cis-retinoic acid) is recognized as a potent human teratogen and others are highly suspect. Recently, evidence has accumulated to suggest that biotransformation of retinoids may play a critical role in the morphogenic as well as dysmorphogenic effects of these important chemicals. In addition, recently published data have shown that tissues of the conceptus per se actively participate in a variety of biotransforming reactions that play pivotal roles in the dysmorphogenicity of several model chemicals. The specific purpose of the proposed study is to initiate investigations into the expression within specific conceptal tissues of functional proteins capable of catalyzing conversion of 13-cis-retinoic acid, all-trans-retinoic acid and retinol (as model substrates/dysmorphogens) to respective metabolic products. Tissues will be investigated during the critical stage of organogenesis and will include the embryo proper, visceral yolk sac, ectoplacental cone, parietal yolk sac (including Reichert's membrane) and decidua. In experiments with cultured whole conceptuses, generation of specific metabolites will be compared and, where applicable, correlated with the incidence of specific dysmorphogenic effects. The parent retinoids will be placed in the culture medium and also will be placed in direct contact with embryonic tissues via microinjections into the amniotic cavity and/or exocoelomic space. Biotransformation reactions to be investigated include isomerizations, dehydrogenations, glucuronidations and monooxygenations. Newly developed and highly sensitive hplc techniques will permit analyses of small quantities of metabolites, rendering the proposed studies feasible. Relevance of obtained information will be probed by comparisons with data obtained from experiments in vivo. Results should provide health professionals and regulatory agencies a more rational basis for providing advice and counsel to pregnant women with respect to their exposure to various retinoidal substances.