title: Induction of homologous recombination following in utero exposure to DNA-damaging agents.
abstract: Much of our understanding of homologous recombination, as well as the development of the working models for these processes, has been derived from extensive work in model organisms, such as yeast and fruit flies, and mammalian systems by studying the repair of induced double strand breaks or repair following exposure to genotoxic agents in vitro. We therefore set out to expand this in vitro work to ask whether DNA-damaging agents with varying modes of action could induce somatic change in an in vivo mouse model of homologous recombination. We exposed pregnant dams to DNA-damaging agents, conferring a variety of lesions at a specific time in embryo development. To monitor homologous recombination frequency, we used the well-established retinal pigment epithelium pink-eyed unstable assay. Homologous recombination resulting in the deletion of a duplicated 70 kb fragment in the coding region of the Oca2 gene renders this gene functional and can be visualized as a pigmented eyespot in the retinal pigment epithelium. We observed an increased frequency of pigmented eyespots in resultant litters following exposure to cisplatin, methyl methanesulfonate, ethyl methanesulfonate, 3-aminobenzamide, bleomycin, and etoposide with a contrasting decrease in the frequency of detectable reversion events following camptothecin and hydroxyurea exposure. The somatic genomic rearrangements that result from such a wide variety of differently acting damaging agents implies long-term potential effects from even short-term in utero exposures.
authors.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Drive, San Antonio, TX 78229, USA; Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Bijal
authors.initials: B
authors.lastname: Karia
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Martinez
authors.forename: Alexander J R
authors.initials: AJ
authors.lastname: Bishop
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004249:DNA Damage; D005127:Eye Color / Q000187:drug effects* / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D059765:Homologous Recombination; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D010641:Phenotype; D011247:Pregnancy; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D009153:Mutagens
keywords: DNA damaging agents; Homologous recombination; In utero exposure; In vivo; Mouse; Pink-eyed unstable
references.citation: Environ Health Perspect. 2000 Jun;108 Suppl 3:573-94
references.pmid: 10852857
references.citation: J Natl Cancer Inst. 1983 Oct;71(4):841-7
references.pmid: 6413744
references.citation: Science. 1994 Dec 2;266(5190):1573-6
references.pmid: 7985029
references.citation: Cell. 2011 Apr 29;145(3):435-46
references.pmid: 21529715
references.citation: Exp Cell Res. 1983 Feb;143(2):377-82
references.pmid: 6832224
references.citation: Carcinogenesis. 1994 Oct;15(10):2303-10
references.pmid: 7955071
references.citation: J Biol Chem. 2007 Jun 1;282(22):16441-53
references.pmid: 17428792
references.citation: Trends Biochem Sci. 1999 Jul;24(7):271-5
references.pmid: 10390616
references.citation: J Nucleic Acids. 2010 Aug 19;2010:
references.pmid: 20847942
references.citation: Teratog Carcinog Mutagen. 1989;9(4):219-37
references.pmid: 2572066
references.citation: Mol Cell Biol. 2005 Oct;25(20):8925-37
references.pmid: 16199871
references.citation: J Bacteriol. 2000 Apr;182(8):2104-12
references.pmid: 10735851
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4576-81
references.pmid: 9114032
references.citation: Mutat Res. 1999 Jun 1;427(1):1-9
references.pmid: 10354496
references.citation: J Cell Biochem. 2011 Oct;112(10):2672-82
references.pmid: 21647941
references.citation: Mol Cell Biol. 1996 Dec;16(12):6804-9
references.pmid: 8943335
references.citation: Carcinogenesis. 2002 Jan;23(1):213-6
references.pmid: 11756244
references.citation: Exp Eye Res. 1998 Nov;67(5):525-30
references.pmid: 9878214
references.citation: Mutat Res. 2003 Nov;544(2-3):279-88
references.pmid: 14644329
references.citation: Cytogenet Genome Res. 2004;104(1-4):77-86
references.pmid: 15162018
references.citation: Mutat Res. 1994 May 1;307(1):315-21
references.pmid: 7513811
references.citation: Cancer Res. 1989 Nov 15;49(22):6365-8
references.pmid: 2553254
references.citation: Lancet. 1988 Sep 17;2(8612):665-9
references.pmid: 2901525
references.citation: Mutat Res. 1989 May;226(1):1-8
references.pmid: 2716763
references.citation: Mutat Res. 1989 Mar;211(1):125-30
references.pmid: 2537925
references.citation: Mutat Res. 2004 Mar 22;547(1-2):101-7
references.pmid: 15013704
references.citation: Mutat Res. 1996 Jul 22;354(2):195-201
references.pmid: 8764948
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Feb;14(2):506-11
references.pmid: 15734979
references.citation: Cancer Chemother Rep. 1975 May-Jun;59(3):589-98
references.pmid: 54213
references.citation: Mol Cell Biol. 1999 Jul;19(7):5166-9
references.pmid: 10373565
references.citation: Mol Cell Biol. 2002 Aug;22(16):5869-78
references.pmid: 12138197
references.citation: Nucleic Acids Res. 2010 Nov;38(21):7538-45
references.pmid: 20660013
references.citation: Environ Health Perspect. 2003 Apr;111(4):389-94
references.pmid: 12676588
references.citation: Philos Trans R Soc Lond B Biol Sci. 2010 Apr 27;365(1544):1213-8
references.pmid: 20308096
references.citation: J Biol Chem. 2008 Jan 11;283(2):1197-208
references.pmid: 18025084
references.citation: BMC Cell Biol. 2003 Jul 16;4:7
references.pmid: 12866953
references.citation: Semin Oncol. 1992 Jun;19(3 Suppl 9):1-10
references.pmid: 1641648
references.citation: Anticancer Agents Med Chem. 2007 Sep;7(5):515-23
references.pmid: 17896912
references.citation: Dev Biol. 1997 Dec 1;192(1):99-107
references.pmid: 9405100
references.citation: Nat Commun. 2011 Jun 28;2:368
references.pmid: 21712816
references.citation: Trends Genet. 2002 Feb;18(2):74-82
references.pmid: 11818139
references.citation: FASEB J. 2006 Jul;20(9):1300-14
references.pmid: 16816105
references.citation: DNA Repair (Amst). 2013 Feb 1;12(2):128-39
references.pmid: 23253856
references.citation: Eur J Cancer. 1992;28A(6-7):1010-2
references.pmid: 1627365
references.citation: Biochim Biophys Acta. 1998 Oct 1;1400(1-3):139-54
references.pmid: 9748545
references.citation: Mutat Res. 1981 Nov;84(1):125-32
references.pmid: 7199115
references.citation: Methods Mol Biol. 2004;262:125-39
references.pmid: 14769959
references.citation: Cancer Res. 1989 Sep 15;49(18):5077-82
references.pmid: 2548710
references.citation: Cancer Res. 1995 Sep 15;55(18):4029-35
references.pmid: 7664276
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12071-75
references.pmid: 7991586
references.citation: Mutat Res. 2000 Dec 20;457(1-2):31-40
references.pmid: 11106796
references.citation: Cell Biol Toxicol. 1986 Dec;2(4):485-94
references.pmid: 2855799
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1):1134-7
references.pmid: 12376523
references.citation: Biochem J. 1980 Mar 1;185(3):775-7
references.pmid: 6248035
references.citation: Mol Cell Biol. 2011 Sep;31(17):3593-602
references.pmid: 21709021
references.citation: Environ Health Perspect. 2010 Sep;118(9):1326-31
references.pmid: 20406721
references.citation: Dev Biol. 1987 May;121(1):192-204
references.pmid: 3569658
references.citation: Pigment Cell Res. 2001 Apr;14(2):86-93
references.pmid: 11310796
references.citation: Mutagenesis. 1998 Nov;13(6):613-7
references.pmid: 9862193
references.citation: Carcinogenesis. 2001 Apr;22(4):641-9
references.pmid: 11285201
references.citation: Science. 1991 Oct 4;254(5028):81-6
references.pmid: 1925563
references.citation: Nature. 1980 Feb 7;283(5747):593-6
references.pmid: 6243744
references.citation: IARC Sci Publ. 1989;(96):1-15
references.pmid: 2680943
references.citation: Mutat Res. 1992 May;282(1):49-54
references.pmid: 1374158
references.citation: Mutat Res. 1996 Aug 17;355(1-2):71-89
references.pmid: 8781578
references.citation: Br J Radiol. 1997 Feb;70:130-9
references.pmid: 9135438
references.citation: Mutat Res. 1996 Jul 5;368(3-4):205-11
references.pmid: 8692226
references.citation: Environ Health Perspect. 1993 Apr;100:65-168
references.pmid: 8354183
references.citation: Mutagenesis. 2007 May;22(3):161-75
references.pmid: 17369606
references.citation: Environ Health Perspect. 2000 Jun;108 Suppl 3:595-7
references.pmid: 10852858
references.citation: J Biol Chem. 1998 Mar 6;273(10):5858-68
references.pmid: 9488723
references.citation: Nat Struct Mol Biol. 2007 Jul;14(7):677-9
references.pmid: 17603497
references.citation: Nature. 2006 Nov 23;444(7118):444-54
references.pmid: 17122850
references.citation: Environ Health Perspect. 2000 Jun;108 Suppl 3:451-5
references.pmid: 10852844
references.citation: Cancer Res. 2003 Sep 1;63(17):5335-43
references.pmid: 14500365