In the past, most studies dealing with the nutrition of the conceptus have been performed in the early or late stages of fetal development. A number of developments permit us to perform nutritional studies during the earliest period of organogenesis. These developments include the preparation of standardized embryotoxic and teratogenic antibodies, the development of rodent embryo culture methods and the quantitation of endocytosis into a reproducible methodology. Furthermore, the unique placentation in the rodent permits one to combine the above methodologies into experiments which can define several parameters of early embryonic nutrition, as well as determine the changing roles of the yolk sac and chorioplacenta throughout gestation.
The specific aims of this program are (1) to study placental (yolk sac and chorioplacental) transport of small molecules and macromolecules (endocytosis) from early organogenesis to late gestation in normal and pathologic states utilizing in vitro (embryo culture, yolk sac culture) and in vivo techniques; 2) to study the two sources of amino acids for rat embryonic development, histiotrophic nutrition (intracellular digestion of exogenous proteins) versus the transport of exogenous free amino acids in the presence or absence of teratogenic antiserum; 3) to obtain endocytosis-reducing antibodies and/or teratogenic antibodies uncontaminated with non-specific gamma globulin by utilizing the monoclonal antibody technique; 4) to study the effect of antiserum prepared against primate yolk sac on primate development. These studies should permit the quantitation of the parameters of early embryonic nutrition and the evaluation of the role of placental dysfunction in embryopathology, as well as a reevaluation of the role of the yolk sac in early primate development. Furthermore, teratogenic antibodies provide a unique and important tool to study embryonic nutrition in the mammal during organogenesis and early fetal development. The uniqueness and importance of this research is related to several features: (1) the impact of protein and amino acid deprivation on the developing embryo can be studied both in vivo and in vitro; (2) the effect of malnutrition on the embryo can be studied without interfering with maternal nutrition; (3) these studies have clinical relevance because yolk sac dysfunction may be a contributing factor to human teratogenesis; and (4) quantifying yolk sac dysfunction which precedes teratogenesis may give us insight into the prevention of congenital malformations by either nutritional or pharmacological methods.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD018396-02
Application #
3315447
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
2
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
Carbone, J P; Brent, R L (1993) Genital and nongenital teratogenesis of prenatal progestogen therapy: the effects of 17 alpha-hydroxyprogesterone caproate on embryonic and fetal development and endochondral ossification in the C57B1/6J mouse. Am J Obstet Gynecol 169:1292-8
Grubb, J D; Koszalk, T R; Drabick, J J et al. (1991) The activities of thiol proteases in the rat visceral yolk sac increase during late gestation. Placenta 12:143-51
Jensen, M; Lloyd, J B; Vega, P et al. (1991) Multiple antigens in the rat visceral yolk sac induce teratogenic antisera. Teratology 43:601-8
Beckman, D A; Ornoy, A; Jensen, M et al. (1991) Ultrastructure and function of the rat yolk sac: damage caused by teratogenic anti-VYS serum and recovery. Teratology 44:181-92
Brent, R L; Beckman, D A (1990) Environmental teratogens. Bull N Y Acad Med 66:123-63
Carbone, J P; Baldridge, R C; Koszalka, T R et al. (1990) Characterization of cytosolic glucocorticoid receptor of fetal rat epiphyseal chondrocytes. J Steroid Biochem 35:495-505
Beckman, D A; Brent, R L (1990) Teratogenesis: alcohol, angiotensin-converting-enzyme inhibitors, and cocaine. Curr Opin Obstet Gynecol 2:236-45
Jensen, M; Lloyd, J B; Koszalka, T R et al. (1989) Preparation and developmental toxicity of monoclonal antibodies against rat visceral yolk sac antigens. Teratology 40:505-11
Koszalka, T R; Andrew, C L; Lloyd, J B et al. (1988) Carrier-mediated uptake of hexoses by the rat visceral yolk sac. Placenta 9:547-58
Beckman, D A; Brent, R L (1986) Mechanism of known environmental teratogens: drugs and chemicals. Clin Perinatol 13:649-87

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