Mechanisms leading to the formation of micronuclei containing sex chromosomes differ with age.

The frequency of spontaneously occurring micronuclei (MN) increases with age, with many of these MN containing sex chromatin. However, it is not known if this MN frequency increase is attributable to a higher number of the same cellular events that occur in younger people, or if a different sex chromosomal instability mechanism(s) arises with age. To gain insight regarding this question, the total number of signals present in MN and their corresponding binucleates, was scored in older (ages 40-80+ y.o.; n=40) compared to younger (7-39 y.o.; n=19) individuals using probes specific for the X and Y chromosomes. In 19.9% of the cells scored at least one sex chromatin positive micronucleus was present. A significant decrease in cells having a "corrective" loss pattern (i.e. trisomy rescue, leading to euploid binucleates following sex chromatin exclusion into the MN) was observed with increasing age for the Y chromosome in males (p=0.022) and the X chromosome in females (p=0.004). In addition, a significant increase (p<0.001) in cells having multiple signals beyond those expected from a single cellular error was observed in the older compared to younger study participants, with these imbalances resulting from cells having either a single micronucleus with multiple signals, or cells having multiple MN. Collectively, these findings suggest that age-related increases in MN frequencies reflect both gains in the occurrence of similar cellular errors, as well as changes in the types of chromosomal findings that occur. Importantly, these results also illustrate that while MN frequencies reflect acquired abnormalities, they may also reflect cellular responses to "correct" an error, particularly when evaluated in young individuals. Therefore, when analyzing MN frequencies, one may also wish to evaluate the imbalances present in both the binucleates and MN to facilitate the recognition of varying cellular responses to environmental or genotoxic exposures.