Studies using the outbred CD1 mouse strain have shown that paternal irradiation of F0 mice six to seven weeks prior to mating causes significant changes in F1 and F2 embryonic cell proliferation. These changes are revealed as a competitive cell proliferation disadvantage in chimera assays when the affected embryo is paired with a normal embryo in an aggregation chimera. This effect is transmitted to F1 and F2 embryos for 1.0 Gy of 137Cs gamma rays, does not decrease between the F0, F1 and F2 generations, and correlates with significant decreases in body weights, changes in basal levels of selected signal transduction protein kinase activities and in elevated basal levels of p53 protein in the F3 offspring. In this project, we ask whether the genetic changes underlying these heritable consequences of paternal F0 irradiation are more likely to decrease, remain unchanged, or to increase with successive generations.
Specific Aim I will be to determine whether competitive cell proliferation disadvantage in successive generations will differ when the outbred CD1 strain is replaced with the syngenic C57BL/6 strain. We will conduct a paternal F0 irradiation using C57BL/6 males to reduce differences in expressivity and will evaluate the F1, F2 and F3 offspring in chimera assays. If competitive cell proliferation disadvantage does not decrease with successive generations we will hypothesize that the genetic changes that cause this heritable effect are unstable across generations.
Specific Aim II will be to test the hypothesis that the nuclear changes that cause competitive cell proliferation disadvantage include """"""""DNA damage"""""""". We will irradiate a paternal F0 cohort that is homozygous for a p53 null mutation which may (indirectly) result in reduced DNA repair. If this hypothesis is correct, we expect the p53 null mutation to increase competitive cell proliferation disadvantage in the offspring of paternal F0 irradiation.
Specific Aim III will be to test the hypothesis that the nuclear changes that cause competitive cell proliferation disadvantage will increase in number across generations to produce successively greater changes in correlative endpoints, including protein kinase activities. This outcome would agree with the hypothesis that these heritable consequences of irradiating the paternal germline may become amplified by genomic instability across generations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006516-06
Application #
6138110
Study Section
Radiation Study Section (RAD)
Program Officer
Heindel, Jerrold
Project Start
1993-08-01
Project End
2002-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
6
Fiscal Year
2000
Total Cost
$243,164
Indirect Cost
Name
University of California Davis
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Baulch, Janet E; Li, Ming-Wen; Raabe, Otto G (2007) Effect of ATM heterozygosity on heritable DNA damage in mice following paternal F0 germline irradiation. Mutat Res 616:34-45
Baulch, Janet E; Raabe, Otto G (2005) Gamma irradiation of Type B spermatogonia leads to heritable genomic instability in four generations of mice. Mutagenesis 20:337-43
Baulch, Janet E; Raabe, Otto G; Wiley, Lynn M et al. (2002) Germline drift in chimeric male mice possessing an F2 component with a paternal F0 radiation history. Mutagenesis 17:9-13
Vance, M M; Baulch, J E; Raabe, O G et al. (2002) Cellular reprogramming in the F3 mouse with paternal F0 radiation history. Int J Radiat Biol 78:513-26
Baulch, J E; Raabe, O G; Wiley, L M (2001) Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F3 offspring. Mutagenesis 16:17-23
Lum, R M; Wiley, L M; Barakat, A I (2000) Influence of different forms of fluid shear stress on vascular endothelial TGF-beta1 mRNA expression. Int J Mol Med 5:635-41
Vance, M M; Wiley, L M (1999) Gap junction intercellular communication mediates the competitive cell proliferation disadvantage of irradiated mouse preimplantation embryos in aggregation chimeras. Radiat Res 152:544-51
Burruel, V R; Raabe, O G; Wiley, L M (1997) In vitro fertilization rate of mouse oocytes with spermatozoa from the F1 offspring of males irradiated with 1.0 Gy 137Cs gamma-rays. Mutat Res 381:59-66
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