The role of mutagenic and carcinogenic environmental contaminants in adverse pregnancy outcome will be investigated. Define chemical exposures in vitro at discrete development periods will be used. Chemically-treated blastocyst stage embryos will be transferred to pseudopregnant surrogate mothers and subsequent post-implantation development will be studied. Previous experiments in this lab have established that preimplanatation exposure results in disruption of blastocyst function (e.g., implantation rate, resorption rate and live birth rate). Offspring developed from chemically treated blastocyst have a higher crude mortality rate (especially in the perinatal period) than offspring derived from solvent exposed blastocyst. Chemically exposed blastocysts develop into fetuses with growth retardation and gross dysmorphogenesis. Previous data suggest that blastocyst dysfunction is the result of subtle non- lethal mutations as a results of toxic exposure at the blastocyst stage of development. We will test the hypothesis with (+) syn BP 7,8-dihydrodiol 9,10-epoxides in comparison with (+) anti BP 7,8- dihydrodiol 9,10-eposides. The former are cytotoxic but not mutagenic while the latter are cytotoxic and mutagenic. We have established that endometrial lining cells have the capacity to metabolize (-)trans benzo(alpha)pyrene 7,8-dihydrodiol to BP 7,8- dihydrodiol 9,10-expoides which can than alter the development of the blastocyst into a fetus. The endometrium is a quantitatively important source of enzymes capable of bioactivation of xenobiotic compounds which can cause blastocyst dysfunction. The induction of these enzymes can be modulated by steroids. We will to establish the role of inducible bioactivation of toxic chemicals in poor pregnancy outcome and to establish the mechanism of steroid modulation of induction of such enzyme activity. Finally we will attempt to intervene in electrophilic toxic damage to the developing embryo in transgenic mice produced to overexpress the enzyme glutathione-S-transferase (Ya) which we have produced.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES003498-07A1
Application #
3250811
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-06-01
Project End
1991-06-30
Budget Start
1988-07-15
Budget End
1989-06-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
School of Medicine & Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Connelly, C S; Fahl, W E; Manoharan, T H et al. (1993) Cell-specific expression of a recombinant rat glutathione S-transferase Ya gene in transgenic mice. Pathobiology 61:7-12
Iannaccone, P M; Zhou, X; Khokha, M et al. (1992) Insertional mutation of a gene involved in growth regulation of the early mouse embryo. Dev Dyn 194:198-208
Ng, Y K; Iannaccone, P M (1992) Fractal geometry of mosaic pattern demonstrates liver regeneration is a self-similar process. Dev Biol 151:419-30
Ng, Y K; Iannaccone, P M (1992) Experimental chimeras: current concepts and controversies in normal development and pathogenesis. Curr Top Dev Biol 27:235-74
Iannaccone, P M; Van Gorder, M; Madsen, E L et al. (1991) The role of preimplantation sonographic exposure in postimplantation development and pregnancy outcome. J Ultrasound Med 10:659-64
Barch, D H; Jacoby, R F; Brasitus, T A et al. (1991) Incidence of Harvey ras oncogene point mutations and their expression in methylbenzylnitrosamine-induced esophageal tumorigenesis. Carcinogenesis 12:2373-7
Bossert, N L; Hitselberger, M H; Iannaccone, P M (1990) Protein alterations associated with N-methyl-N-nitrosourea exposure of preimplantation mouse embryos transferred to surrogate mothers. Teratology 42:147-56
Ng, Y K; Ohaki, Y; Deamant, F et al. (1990) Comparison of epidermal patch size in X-chromosome-linked mosaic and dizygotic chimeric mice. Cell Differ Dev 30:27-34
Van Winkle, L J; Iannaccone, P M; Campione, A L et al. (1990) Transport of cationic and zwitterionic amino acids in preimplantation rat conceptuses. Dev Biol 142:184-93

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