title: Spontaneous mutagenesis is enhanced in Apex heterozygous mice.
abstract: Germ line DNA directs the development of the next generation and, as such, is profoundly different from somatic cell DNA. Spermatogenic cells obtained from young adult lacI transgenic mice display a lower spontaneous mutant frequency and greater in vitro base excision repair activity than somatic cells and tissues obtained from the same mice. However, spermatogenic cells from old lacI mice display a 10-fold higher mutant frequency. This increased spontaneous mutant frequency occurs coincidentally with decreased in vitro base excision repair activity for germ cell and testicular extracts that in turn corresponds to a decreased abundance of AP endonuclease. To directly test whether a genetic diminution of AP endonuclease results in increased spontaneous mutant frequencies in spermatogenic cell types, AP endonuclease heterozygous (Apex(+/-)) knockout mice were crossed with lacI transgenic mice. Spontaneous mutant frequencies were significantly elevated (approximately twofold) for liver and spleen obtained from 3-month-old Apex(+/-) lacI(+) mice compared to frequencies from Apex(+/+) lacI(+) littermates and were additionally elevated for somatic tissues from 9-month-old mice. Spermatogenic cells from 9-month-old Apex(+/-) lacI(+) mice were significantly elevated twofold compared to levels for 9-month-old Apex(+/+) lacI(+) control mice. These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells.
authors.affiliation: Department of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, 78229-3900, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Huamani
authors.forename: C Alex
authors.initials: CA
authors.lastname: McMahan
authors.forename: Damon C
authors.initials: DC
authors.lastname: Herbert
authors.forename: Robert
authors.initials: R
authors.lastname: Reddick
authors.forename: John R
authors.initials: JR
authors.lastname: McCarrey
authors.forename: Mark I
authors.initials: MI
authors.lastname: MacInnes
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
authors.forename: Christi A
authors.initials: CA
authors.lastname: Walter
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D017930:Genes, Reporter; D006579:Heterozygote; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016296:Mutagenesis; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000201:enzymology; D013154:Spleen / Q000201:enzymology; D013737:Testis / Q000033:anatomy & histology
chemical_list: D004247:DNA; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase