title: Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors.
abstract: In humans, errors in meiotic chromosome segregation that produce aneuploid gametes increase dramatically as women age, a phenomenon termed the "maternal age effect." During meiosis, cohesion between sister chromatids keeps recombinant homologs physically attached and premature loss of cohesion can lead to missegregation of homologs during meiosis I. A growing body of evidence suggests that meiotic cohesion deteriorates as oocytes age and contributes to the maternal age effect. One hallmark of aging cells is an increase in oxidative damage caused by reactive oxygen species (ROS). Therefore, increased oxidative damage in older oocytes may be one of the factors that leads to premature loss of cohesion and segregation errors. To test this hypothesis, we used an RNAi strategy to induce oxidative stress in Drosophila oocytes and measured the fidelity of chromosome segregation during meiosis. Knockdown of either the cytoplasmic or mitochondrial ROS scavenger superoxide dismutase (SOD) caused a significant increase in segregation errors, and heterozygosity for an smc1 deletion enhanced this phenotype. FISH analysis indicated that SOD knockdown moderately increased the percentage of oocytes with arm cohesion defects. Consistent with premature loss of arm cohesion and destabilization of chiasmata, the frequency at which recombinant homologs missegregate during meiosis I is significantly greater in SOD knockdown oocytes than in controls. Together these results provide an in vivo demonstration that oxidative stress during meiotic prophase induces chromosome segregation errors and support the model that accelerated loss of cohesion in aging human oocytes is caused, at least in part, by oxidative damage.
authors: Department of Biological Sciences, Dartmouth College, Hanover, NH 03755.
authors: Adrienne T
authors: AT
authors: Perkins
authors: Department of Biological Sciences, Dartmouth College, Hanover, NH 03755.
authors: Thomas M
authors: TM
authors: Das
authors: Department of Biological Sciences, Dartmouth College, Hanover, NH 03755.
authors: Lauren C
authors: LC
authors: Panzera
authors: Department of Biological Sciences, Dartmouth College, Hanover, NH 03755 sharon.e.bickel@dartmouth.edu.
authors: Sharon E
authors: SE
authors: Bickel
mesh_terms: D000782:Aneuploidy; D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D016922:Cellular Senescence / Q000502:physiology; D002842:Chromatids / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology*; D003434:Crossing Over, Genetic; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008297:Male; D008423:Maternal Age; D008540:Meiosis / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D009630:Nondisjunction, Genetic; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000009:adverse effects; D011995:Recombination, Genetic / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000098550:Structural Maintenance of Chromosome Protein 1; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: maternal age effect; meiosis; oxidative damage; reactive oxygen species; superoxide dismutase