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Abstract
The frequency of egg aneuploidy and trisomic pregnancies increases with maternal age. To what extent individual approaches can delay the "maternal age effect" is unclear because multiple causes contribute to chromosomal abnormalities in mammalian eggs. We propose that ovulation frequency determines the physiological aging of oocytes, a key aspect of which is the ability to accurately segregate chromosomes and produce euploid eggs. To test this hypothesis, ovulations were reduced using successive pregnancies, hormonal contraception, and a pre-pubertal knockout mouse model, and the effects on chromosome segregation and egg ploidy were examined. We show that each intervention reduces chromosomal abnormalities in eggs of aged mice, suggesting that ovulation reduction delays oocyte aging. The protective effect can be partly explained by retention of chromosomal Rec8-cohesin that maintains sister chromatid cohesion in meiosis. In addition, single-nucleus Hi-C (snHi-C) revealed deterioration in the 3D chromatin structure including an increase in extruded loop sizes in long-lived oocytes. Artificial cleavage of Rec8 is sufficient to increase extruded loop sizes, suggesting that cohesin complexes maintaining cohesion restrict loop extrusion. These findings suggest that ovulation suppression protects against Rec8 loss, thereby maintaining both sister chromatid cohesion and 3D chromatin structure and promoting production of euploid eggs. We conclude that the maternal age effect can be delayed in mice. An implication of this work is that long-term ovulation-suppressing conditions can potentially reduce the risk of aneuploid pregnancies at advanced maternal age.
Highlights
The maternal age effect is the socio-pathological phenomenon that the frequency of trisomic pregnancies increases dramatically with maternal age
We propose that ovulation frequency determines the physiological aging of oocytes, a key aspect of which is the ability to accurately segregate chromosomes and produce euploid eggs
We show that each intervention reduces chromosomal abnormalities in eggs of aged mice, suggesting that ovulation reduction delays oocyte aging
Summary
The maternal age effect is the socio-pathological phenomenon that the frequency of trisomic pregnancies increases dramatically with maternal age. The incidence of trisomic pregnancies is 3% for women in their 20s and rises to >30% for women in their 40s.1. Most trisomies arise from chromosome missegregation in the meiosis I division of female germ cells (oocytes).[2,3,4,5] The resulting aneuploid eggs produce aneuploid fetuses upon fertilization. Aneuploidy is the leading cause of mental retardation and miscarriages.[6] Most aneuploid pregnancies with the exception of trisomy 21, trisomy 18 (Edward syndrome), trisomy 13 (Pa€tau syndrome), and monosomy X0 (Turner syndrome) are incompatible with life.[7] Despite understanding the etiology of trisomic pregnancies, the causes of increased chromosome missegregation in aging oocytes have remained enigmatic
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