After the discovery that the two vitamin A related drugs - Accutane (registered trademark) and Tigason (registered trademark) - are human teratogens, the question has arisen if vitamin A (retinol) itself is also teratogenic if ingested as an oral supplement. Information gathered until the year 1986 from at least seven published and eleven unpublished case reports indicate the occurrence of major malformations in infants if daily intake of vitamin A during pregnancy was 25,000 IU or more. There are no epidemiological studies to provide corroborative data, but several good animal models are available.
Our aim i s to understand the biological basis (i.e., mechanism) of vitamin A-induced teratogenicity in an animal model (mouse) by studying the underlying cellular and subcellular events in susceptible and embryonic tissues. Previous studies under this project have provided evidence that a) formation of retinoic acid from retinol is the first step in this mechanism and that b) there are certain specific structural requirements in the retinoid molecule that enhance or lower its teratogenic activity.
Our specific aims are first to attempt an identification of the likeliest active natural metabolite or metabolites of retinol/retinoic acid by means of whole animal and tissue culture bioassays established previously. Radiochemical and HPLC methodologies will be used in this attempt, and synthetic retinoid compounds will be included in the analyses. Second, select variably-active retinoids from ongoing studies and use them to compare their ability to localize and interact with cellular and nuclear components in the embryonic target tissues. Cell fractionation, density gradient centrifugation, SDS/polyacrylamide gel electrophoresis, and HPLC will supplement other methods to seek the role of nuclear retinoid receptor(s) in vitamin A-induced teratogenic response. This research will bring us closer to a proposal that the physiologic and pharmacologic effects of vitamin A have a common basis.

Project Start
1985-12-01
Project End
1996-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Kochhar, D M; Jiang, H; Penner, J D et al. (1998) The use of a retinoid receptor antagonist in a new model to study vitamin A-dependent developmental events. Int J Dev Biol 42:601-8
Kochhar, D M; Jiang, H; Penner, J D et al. (1996) Differential teratogenic response of mouse embryos to receptor selective analogs of retinoic acid. Chem Biol Interact 100:1-12
Jiang, H; Soprano, D R; Li, S W et al. (1995) Modulation of limb bud chondrogenesis by retinoic acid and retinoic acid receptors. Int J Dev Biol 39:617-27
Jiang, H; Penner, J D; Beard, R L et al. (1995) Diminished teratogenicity of retinoid X receptor-selective synthetic retinoids. Biochem Pharmacol 50:669-76
Kochhar, D M; Jiang, H; Penner, J D et al. (1995) Placental transfer and developmental effects of 9-cis retinoic acid in mice. Teratology 51:257-65
Jiang, H; Gyda 3rd, M; Harnish, D C et al. (1994) Teratogenesis by retinoic acid analogs positively correlates with elevation of retinoic acid receptor-beta 2 mRNA levels in treated embryos. Teratology 50:38-43
Soprano, D R; Gyda 3rd, M; Jiang, H et al. (1994) A sustained elevation in retinoic acid receptor-beta 2 mRNA and protein occurs during retinoic acid-induced fetal dysmorphogenesis. Mech Dev 45:243-53
Soprano, D R; Harnish, D C; Soprano, K J et al. (1993) Correlations of RAR isoforms and cellular retinoid-binding proteins mRNA levels with retinoid-induced teratogenesis. J Nutr 123:367-71
Kochhar, D M; Jiang, H; Harnish, D C et al. (1993) Evidence that retinoic acid-induced apoptosis in the mouse limb bud core mesenchymal cells is gene-mediated. Prog Clin Biol Res 383B:815-25
Soprano, D R; Tairis, N; Gyda 3rd, M et al. (1993) Induction of RAR-beta 2 gene expression in embryos and RAR-beta 2 transactivation by the synthetic retinoid Ro 13-6307 correlates with its high teratogenic potency. Toxicol Appl Pharmacol 122:159-63

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