The mouse embryo chimera assay is a very sensitive test for detecting in vivo exposure of the mammalian germ cell to ionizing radiation. This exposure produces a competitive embryonic cell proliferation disadvantage that becomes expressed by the embryo from the exposed parent when challenged by cell-cell contact with a control embryo in an aggregation chimera. The detection limits of this assay for low-LET ionizing radiation (gamma or x rays) are between 0.005 Gy and 0.01 Gy for parental male irradiation and between 0.05 Gy and 0.15 Gy for parental female irradiation. During the current funding period we were successful in achieving our major objective, which was to determine whether the radiosensitive target for the assay was nuclear or extranuclear. The evidence we obtained strongly favors the hypothesis for a nuclear radiosensitive target in this competitive renewal application, we now wish to test hypotheses regarding the possible consequences of damage to this nuclear target and the predictive value of the chimera assay for transmitted embryonic effects using nuclear endpoints.
Specific Aim 1 will test the hypothesis that this nuclear target consists of genes that affect cell proliferation rate through their impact on the efficiency of growth factor/receptor autocrine """"""""loops"""""""". This hypothesis is based upon the known expression of several functional autocrine loops by the early embryo and on the accumulating evidence that growth factors, their receptors, associated signal transduction components and transcription factors are radiosensitive in a wide variety of cell lines and tissues.
Specific Aims 2 and 3 are concerned with the predictive value of the chimera assay for embryonic effects resulting from parental exposures to ionizing radiation. As is the case for Specific Aim 1, the hypotheses tested here are predicated upon a nuclear radiosensitive target for the chimera assay.
Specific Aim 2 will test the hypothesis that higher doses to the female germ line (0.3 Gy - 0.5 Gy of 137 Cs gamma radiation) will result in a temporal correlation between positive results of the chimera assay and the stages of oogenesis that transmit increases in developmental anomalies as reported in the literature (e.g., the specific locus test).
Specific Aim 3 will test the hypothesis that there will be temporal correlations between positive results from the chimera assay and increases in frequencies of chromosomal aberrations detected in their germ cells by fluorescence in situ hybridization in males.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES005409-04
Application #
2154082
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1991-03-01
Project End
1997-02-28
Budget Start
1994-03-01
Budget End
1995-02-28
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Davis
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Wiley, L M; Baulch, J E; Raabe, O G et al. (1997) Impaired cell proliferation in mice that persists across at least two generations after paternal irradiation. Radiat Res 148:145-51
Straume, T; Raabe, O G; Walsh, K J et al. (1997) Transmitted proliferation disadvantage from mouse oocytes labeled in vivo with [3H]thymidine: radiosensitive target considerations. Mutat Res 374:11-9
Straume, T; Raabe, O G; Walsh, K J et al. (1996) Mouse immature oocytes irradiated in vivo at 14-days of age and evaluated for transmitted effects using the aggregation embryo chimera assay. Mutat Res 356:269-73
Wiley, L M; Van Beek, M E; Raabe, O G (1994) Embryonic effects transmitted by male mice irradiated with 512 MeV/u 56Fe nuclei. Radiat Res 138:373-85
Wiley, L M; Raabe, O G; Khan, R et al. (1994) Radiosensitive target in the early mouse embryo exposed to very low doses of ionizing radiation. Mutat Res 309:83-92
Brice, E C; Wu, J X; Muraro, R et al. (1993) Modulation of mouse preimplantation development by epidermal growth factor receptor antibodies, antisense RNA, and deoxyoligonucleotides. Dev Genet 14:174-84
Oudiz, D J; Walsh, K; Wiley, L M (1993) Ethylene glycol monomethyl ether (EGME) exposure of male mice produces a decrease in cell proliferation of preimplantation embryos. Reprod Toxicol 7:101-9
Straume, T; Raabe, O G; Walsh, K J et al. (1993) Inherited effects from irradiated mouse immature oocytes detected in aggregation embryo chimeras. Mutat Res 287:243-51
Blankenship, A L; Suffia, M C; Matsumura, F et al. (1993) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) accelerates differentiation of murine preimplantation embryos in vitro. Reprod Toxicol 7:255-61
Wiley, L M; Wu, J X; Harari, I et al. (1992) Epidermal growth factor receptor mRNA and protein increase after the four-cell preimplantation stage in murine development. Dev Biol 149:247-60