Excessive intake of vitamin A compounds such as retinoic acid by pregnant animals results in a high degree of embryotoxic response--a fact recently confirmed in human patients with the use of the drug isotretinoin or 13-cis retinoic acid. Since preliminary studies indicate considerable variation between closely related synthetic analogs of vitamin A in the extent of embryotoxic response, we propose an experimental study on a mouse model to explore the mode and site of action of these therapeutic chemicals. The proposal aims to address the following inquiries: (1) Do structural modifications in any of the sites in the vitamin A molecule--such as in hydrocarbon ring, hydrocarbon side chain, or polar terminal group--alter the nature or extent of teratogenesis? (2) Are the differences in embryotoxic activity between analogs explainable on the basis of their pharmacokinetic behavior alone? If not, then (3) what intrinsic biological property is responsible for the teratogenic effects of a retinoid? Since defects in the central nervous system and skeletal tissues predominate in the fetuses exposed to retinoic acid, do these very tissues show stage-dependent variations in the levels of cellular binding proteins? (4) From among a large number of biochemical effects which ensue when embryonic cells encounter hypervitaminosis A, we propose that an initial interference in collagen biosynthesis is the most likely basis for widespread congenital dysmorphogenesis since this ubiquitous protein is needed as supportive framework during all organogenesis. This hypothesis will be tested.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD020925-01
Application #
3319411
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1985-12-01
Project End
1988-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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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; 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; 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; 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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