The goal of research proposed herein is extension of our understanding of the role of biotransformation in teratogenesis. In nearly 20 publications during the past 6 years we have demonstrated the importance of extraembryonic biotransformation as a determinant of the teratogenicity of specific compounds. Following this essentially qualitative phase of work, and analogous to other fields of toxicology, we wish now to determine the specific steps used to activate and inactivate teratogens and how exposures alter these steps qualitatively. We also wish to extend these studies by beginning to analyze the importance of phase II metabolic steps. Unlike study in mutagenicity and carcinogenicity, this is a new area in teratology and may hold keys to species specificity in teratogenic responses as well as enabling predictions of teratogenic potential based on molecular considerations. A second major area we wish to examine concerns metabolic capabilities of the embryo itself and their contribution to teratogen handling. Although most considerations of prenatal drug metabolism have centered around cytochrome P450-dependent steps, we also wish to examine others which may be of greater significance to the embryo, including nitroreduction. We wish to determine whether these capacities are inducible or repressible as we and others have shown for extraembryonic processes. This work is dependent on the development of HPLC profiles and determination of active metabolites generated by extraembryonic and embryonic homogenates in vitro. Metabolites would be generated under conditions found to known to be teratogenic and these would be tested in the embryo culture system and in vivo. Initial study would focus on 3 compounds or groups of compounds, (a) adriamycin (ADR), a commonly used antitumor agent which we have shown to require extraembryonic activation, (b) heterocyclic nitro compunds which we have shown to cause an unique malformation following embryonic activation and (c) rifampicin, which we have shown to cause growth retardation in the unmetabolized state (or metabolized by the embryo) but which requires extraembryonic activation for its teratogenicity. In this way, 2 major areas of metabolism, extraembryonic (maternal) and embryonic would be examined, compared and their contributions to teratogenicity examined for the first time.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD012717-07A1
Application #
3311975
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1979-04-01
Project End
1989-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Juchau, M R; Harris, C; Stark, K L et al. (1991) Cytochrome P450-dependent bioactivation of prodysmorphogens in cultured conceptuses. Reprod Toxicol 5:259-63
Shepard, T H; Fantel, A G; Kapur, R P (1991) Fetal coronary thrombosis as a cause of single ventricular heart. Teratology 43:113-7
Fantel, A G; Person, R E; Burroughs-Gleim, C et al. (1991) Asymmetric development of mitochondrial activity in rat embryos as a determinant of the defect patterns induced by exposure to hypoxia, hyperoxia, and redox cyclers in vitro. Teratology 44:355-62
Fantel, A G; Person, R E; Burroughs-Gleim, C J et al. (1990) Direct embryotoxicity of cocaine in rats: effects on mitochondrial activity, cardiac function, and growth and development in vitro. Teratology 42:35-43
Mirkes, P E; Little, S A (1990) Binding of (chloroethyl 3H) cyclophosphamide to rat embryo proteins: two-dimensional gel analysis. Teratology 41:195-204
Harris, C; Stark, K L; Luchtel, D L et al. (1989) Abnormal neurulation induced by 7-hydroxy-2-acetylaminofluorene and acetaminophen: evidence for catechol metabolites as proximate dysmorphogens. Toxicol Appl Pharmacol 101:432-46
Fantel, A G; Juchau, M R; Tracy, J W et al. (1989) Studies of mechanisms of niridazole-elicited embryotoxicity: evidence against a major role for covalent binding. Teratology 39:63-74
Shepard, T H; Fantel, A G; Fitzsimmons, J (1989) Congenital defect rates among spontaneous abortuses: twenty years of monitoring. Teratology 39:325-31
Shepard, T H; FitzSimmons, J M; Fantel, A G et al. (1989) Placental weights of normal and aneuploid early human fetuses. Pediatr Pathol 9:425-31
Fantel, A G; Juchau, M R; Burroughs, C J et al. (1989) Studies of embryotoxic mechanisms of niridazole: evidence that oxygen depletion plays a role in dysmorphogenicity. Teratology 39:243-51

Showing the most recent 10 out of 26 publications