The long term objective is to reduce the incidence of human reproductive failures through the identification of previously unknown or unsuspected reproductive toxins and through an understanding of the mechanisms by which they interfere with developmental processes. Based on previous studies in this lab and the work of others we propose to study one possible cause of reproductive failure involving the following sequence: (I) pollutants act on basement membranes in the maternal organism causing the release of the membrane specific protein laminin, (II) anti-laminin antibodies are produced and infiltrate the lumen of the uterus and (III) early embryos fail to develop because anti-laminin antibodies block the uptake and/or utilization of nutrient proteins by the endodermal cells of visceral yolk-sac. Studies are proposed using rats as well as monkeys to demonstrate that pollutants can cause the production of anti-laminin antibodies which appear in the uterine lumen and that the presence of these antibodies can be associated with reproductive failures. Additional studies with in vitro cultures of whole rat embryos are designed to identify the immunological mechanism for the embryo toxicity of anti-laminin antibody and the specific visceral yolk-sac endodermal cell function(s) blocked by the antibody. Finally, attempts will be made to overcome the embryo-toxicity of anti-laminin antibody in the intact animal by providing specifically those nutrients that were found to overcome embryo toxicity in the in vitro whole embryo culture studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004312-02
Application #
3252383
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1987-03-01
Project End
1989-02-28
Budget Start
1988-02-29
Budget End
1989-02-28
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
Earth Sciences/Resources
DUNS #
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Moephuli, S R; Klein, N W; Baldwin, M T et al. (1997) Effects of methionine on the cytoplasmic distribution of actin and tubulin during neural tube closure in rat embryos. Proc Natl Acad Sci U S A 94:543-8
Chambers, B J; Klein, N W; Nosel, P G et al. (1995) Methionine overcomes neural tube defects in rat embryos cultured on sera from laminin-immunized monkeys. J Nutr 125:1587-99
Nadler, D M; Klein, N W; Aramli, L A et al. (1995) The direct embryotoxicity of immunoglobulin G fractions from patients with systemic lupus erythematosus. Am J Reprod Immunol 34:349-55
Chambers, B J; Klein, N W; Conrad, S H et al. (1995) Reproduction and sera embryotoxicity after immunization of monkeys with the laminin peptides YIGSR, RGD, and IKVAV. Proc Natl Acad Sci U S A 92:6818-22
Ferrari, D A; Gilles, P A; Klein, N W et al. (1994) Rat embryo development on human sera is related to numbers of previous spontaneous abortions and nutritional factors. Am J Obstet Gynecol 170:228-36
Izumi, H; Garfield, R E; Makino, Y et al. (1994) Gestational changes in endothelium-dependent vasorelaxation in human umbilical artery. Am J Obstet Gynecol 170:236-45
Nosel, P G; Klein, N W (1992) Methionine decreases the embryotoxicity of sodium valproate in the rat: in vivo and in vitro observations. Teratology 46:499-507
Robbins, B; Klein, N W; Cavalcanti, H (1991) Toxicity of sera from individuals with Chagas' disease to cultured rat embryos: role of antibodies to laminin. Teratology 44:561-70
Coelho, C N; Klein, N W (1990) Methionine and neural tube closure in cultured rat embryos: morphological and biochemical analyses. Teratology 42:437-51
Weeks, B S; Gamache, P; Klein, N W et al. (1990) Acetaminophen toxicity to cultured rat embryos. Teratog Carcinog Mutagen 10:361-71

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