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.
|Sanchez, Jamila R; Reddick, Traci L; Perez, Marissa et al. (2015) Increased human AP endonuclease 1 level confers protection against the paternal age effect in mice. Mutat Res 779:124-33|
|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|
|Vogel, Kristine S; Perez, Marissa; Momand, Jamila R et al. (2011) Age-related instability in spermatogenic cell nuclear and mitochondrial DNA obtained from Apex1 heterozygous mice. Mol Reprod Dev 78:906-19|
|Xu, Guogang; Vogel, Kristine S; McMahan, C Alex et al. (2010) BAX and tumor suppressor TRP53 are important in regulating mutagenesis in spermatogenic cells in mice. Biol Reprod 83:979-87|
|Liang, Hanyu; Yoo, Si-Eun; Na, Ren et al. (2009) Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. J Biol Chem 284:30836-44|
|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|
|Xu, Guogang; Herzig, Maryanne; Rotrekl, Vladimir et al. (2008) Base excision repair, aging and health span. Mech Ageing Dev 129:366-82|
|Allen, Diwi; Herbert, Damon C; McMahan, C Alex et al. (2008) Mutagenesis is elevated in male germ cells obtained from DNA polymerase-beta heterozygous mice. Biol Reprod 79:824-31|
|Xu, Guogang; Spivak, Graciela; Mitchell, David L et al. (2005) Nucleotide excision repair activity varies among murine spermatogenic cell types. Biol Reprod 73:123-30|
Showing the most recent 10 out of 14 publications