Age-related instability in spermatogenic cell nuclear and mitochondrial DNA obtained from Apex1 heterozygous mice

• Published in: Molecular reproduction and development Vol. 78; no. 12; pp. 906 - 919
• Main Authors: Vogel, Kristine S., Perez, Marissa, Momand, Jamila R., Acevedo-Torres, Karina, Hildreth, Kim, Garcia, Rebecca A., Torres-Ramos, Carlos A., Ayala-Torres, Sylvette, Prihoda, Thomas J., McMahan, C. Alex, Walter, Christi A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2011; Wiley-Liss
• Subjects: Age Factors; Animals; AP endonuclease; Apoptosis; base excision repair; Biological and medical sciences; Cell Nucleus - genetics; DNA - genetics; DNA - metabolism; DNA Damage; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Embryology: invertebrates and vertebrates. Teratology; Fundamental and applied biological sciences. Psychology; Heterozygote; lacI; Logistic Models; Male; Mice; Mice, Transgenic; mutagenesis; Mutagenesis - genetics; paternal age; Spermatogenesis - genetics; Spermatozoa - chemistry; Spermatozoa - physiology; transgenic mice; Vertebrata; Mammalia; Mouse; Spermatogenesis; Animal; Rodentia; Instability; Mitochondrial DNA; Cell; Age
• ISSN: 1040-452X; 1098-2795; 1098-2795
• DOI: 10.1002/mrd.21374

The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations. The lacI transgenic mouse can be used to study paternal age effects, and in this system, the prevalence of de novo mutations increases in the male germline at old ages. Mutagenesis is linked with DNA repair capacity, and base excision repair (BER), which can ameliorate spontaneous DNA damage, decreases in nuclear extracts of spermatogenic cells from old mice. Mice heterozygous for a null allele of the Apex1 gene, which encodes apurinic/apyrimidinic endonuclease I (APEN), an essential BER enzyme, display an accelerated increase in spontaneous germline mutagenesis early in life. Here, the consequences of lifelong reduction of APEN on genetic instability in the male germline were examined, for the first time, at middle and old ages. Mutant frequency increased earlier in spermatogenic cells from Apex1+/− mice (by 6 months of age). Nuclear DNA damage increased with age in the spermatogenic lineage for both wild‐type and Apex1+/− mice. By old age, mutant frequencies were similar for wild‐type and APEN‐deficient mice. Mitochondrial genome repair also depends on APEN, and novel analysis of mitochondrial DNA (mtDNA) damage revealed an increase in the Apex1+/− spermatogenic cells by middle age. Thus, Apex1 heterozygosity results in accelerated damage to mtDNA and spontaneous mutagenesis, consistent with an essential role for APEN in maintaining nuclear and mtDNA integrity in spermatogenic cells throughout life. Mol. Reprod. Dev. 78:906–919, 2011. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.