Advanced paternal age is less well publicized than advanced maternal age, but paternal age can also have a significant impact on reproductive health. Approximately 5% of liveborn human offspring have a genetic disorder and of these, approximately 20% are due to germline de novo mutations. Several autosomal dominant disorders are associated with advanced paternal age. These data indirectly indicate an increased mutant frequency in the male germline with age. The mechanisms mediating the increased mutant frequency are not understood. Our long-term goal is to identify and delineate the mechanisms by which DNA integrity is lost with advanced paternal age. Toward this end, we identified a mouse model, the lacl transgenic mouse line, that exhibits increased spontaneous mutant frequencies in the lacl transgene recovered from spermatogenic cells of older mice. We propose to use the lacl transgenic mouse model in our efforts to define the molecular mechanisms involved in advanced paternal age. The hypothesis to be tested is that the ability to maintain male germline DNA integrity declines with increased age.
The specific aims are: 1) to assess base excision repair activity in nuclear extracts prepared from spermatogenic cells obtained from mice at various ages, 2) to assess the role of apoptosis in male germline DNA integrity at various ages, and 3) to determine the impact of induced DNA damage in male germ cells of mice at various ages. The studies are focused on understanding the contribution of pathways that are believed to contribute substantially to maintaining genetic integrity, namely the DNA base excision repair pathway and apoptosis. This study will advance our understanding of the fundamental mechanisms involved in male germline integrity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021163-04
Application #
6931583
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Bellino, Francis
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$348,280
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Xu, Guogang; McMahan, C Alex; Walter, Christi A (2014) Early-life exposure to benzo[a]pyrene increases mutant frequency in spermatogenic cells in adulthood. PLoS One 9:e87439
Xu, Guogang; McMahan, C Alex; Hildreth, Kim et al. (2012) Ionizing radiation-induced mutant frequencies increase transiently in male germ cells of older mice. Mutat Res 744:135-9
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Xu, Guogang; Intano, Gabriel W; McCarrey, John R et al. (2008) Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis. Mutat Res 654:150-7
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Street, K A; Xu, G; Hall, K L et al. (2005) Rat synapsin 1 promoter mediated transgene expression in testicular cell types. DNA Cell Biol 24:133-40

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