Mechanisms and targets involved in maternal and paternal age effects on numerical aneuploidy.

Trisomy in the human appears to be predominantly associated with maternal age. The maternal-age effect, however, shows considerable variability across affected chromosomes. Chromosome-specific variation has been reported in the shapes of the maternal-age-effect curves, including very small effects for the large chromosomes (groups A and B), linear increases (chromosome 16), and exponential increases (chromosome 21). There is also variation among chromosomes in whether the segregation errors occur predominantly at maternal meiosis I, meiosis II, and/or postfertilization mitotic divisions. There is also limited epidemiological evidence for a paternal-age effect, which was recently supported by the findings of age-related increases in sperm aneuploidy using fluorescence in situ hybridization methods. The paternal-age effect is considerably smaller than the maternal and is more likely to involve meiotic II errors of the sex chromosomes, whereas the maternal-age effect is more likely to arise from meiotic I errors producing autosomal trisomies. These and other differences suggest that constitutional aneuploidy arises by multiple mechanisms that may affect (1) the nature and timing of an initiating lesion affecting the oocyte or sperm; (2) the cellular physiology of the time of the nondisjunction event at meiosis I, II, or postfertilization; and (3) the selection against specific chromosomal aneuploidies during embryonic development. Multidisciplinary research is needed to understand the maternal and paternal-age effects on aneuploidy, to (1) identify and characterize the genes that control meiosis, recombination, and segregation; (2) identify the micro-environmental factors around the oocyte and mole germ cells that are involved in the age effects; (3) develop a laboratory animal model for the age effects; (4) characterize the role of genetics, physiology, and environmental toxicology for the paternal-age effects; and (5) identify cohorts of men and women of differing ages who have been exposed to high doses of candidate aneugens and conduct epidemiological investigations of aneuploidies transmitted to their offspring.