The likelihood of a chromosomally abnormal conception increases strikingly with age, and is a contributory factor in the age-related decrease in fertility in women. The basis of the age effect remains unknown, but recent molecular studies indicate that meiosis I (MI, the time at which homologous chromosomes segregate) is a critical time point in the genesis of most age-related trisomies. In this proposal we outline direct studies of human oocytes using cytological, cytogenetic, and molecular methodology to examine genetic recombination, spindle formation, and chromosome disjunction at MI. Recent advances in oocyte retrieval and In vitro maturation of oocytes now make such studies not only highly feasible, but also imperative if we are to understand the origins of the age-related increase in aneuploidy. Equally important, advances in molecular cytogenetics permit the identification of specific chromosomes at metaphase in these oocytes, so results can be obtained that are relevant to the chromosomes that most frequently malsegregate. The combined data from the proposed studies will provide information on the mechanism(s) responsible for the maternal age effect. Ultimately this knowledge may be useful in designing programs for clinical intervention. For example, if age-related changes in the periovulatory environment are found to increase the frequency of meiotic non-disjunction, then hormone therapy or In vitro maturation of oocytes may provide women over the age of 35 with art increased likelihood of achieving a normal pregnancy. This type of therapeutic intervention could ultimately shift the focus of reproductive health care for women over the age of 35 from prenatal diagnosis to detect abnormal pregnancies to preconception therapy to increase the likelihood of a normal pregnancy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD031866-04
Application #
2403392
Study Section
Special Emphasis Panel (SRC (04))
Project Start
1994-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hunt, Patricia A; Jackson, Jodi M; Horan, Sonia et al. (2008) The mouse A/HeJ Y chromosome: another good Y gone bad. Chromosome Res 16:623-36
Hall, Heather; Hunt, Patricia; Hassold, Terry (2006) Meiosis and sex chromosome aneuploidy: how meiotic errors cause aneuploidy; how aneuploidy causes meiotic errors. Curr Opin Genet Dev 16:323-9
Koehler, Kara E; Voigt, Robert C; Thomas, Sally et al. (2003) When disaster strikes: rethinking caging materials. Lab Anim (NY) 32:24-7
Hodges, C A; Ilagan, A; Jennings, D et al. (2002) Experimental evidence that changes in oocyte growth influence meiotic chromosome segregation. Hum Reprod 17:1171-80
Hodges, Craig A; Hunt, Patricia A (2002) Simultaneous analysis of chromosomes and chromosome-associated proteins in mammalian oocytes and embryos. Chromosoma 111:165-9
Hunt, Patricia A; Hassold, Terry J (2002) Sex matters in meiosis. Science 296:2181-3
Bean, Christopher J; Hassold, Terry J; Judis, LuAnn et al. (2002) Fertilization in vitro increases non-disjunction during early cleavage divisions in a mouse model system. Hum Reprod 17:2362-7
Bean, C J; Hunt, P A; Millie, E A et al. (2001) Analysis of a malsegregating mouse Y chromosome: evidence that the earliest cleavage divisions of the mammalian embryo are non-disjunction-prone. Hum Mol Genet 10:963-72
Hodges, C A; LeMaire-Adkins, R; Hunt, P A (2001) Coordinating the segregation of sister chromatids during the first meiotic division: evidence for sexual dimorphism. J Cell Sci 114:2417-26
Hassold, T; Sherman, S; Hunt, P (2000) Counting cross-overs: characterizing meiotic recombination in mammals. Hum Mol Genet 9:2409-19

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