Advancing Age Has Differential Effects on DNA Damage, Chromatin Integrity, Gene Mutations, and Aneuploidies in Sperm

Abstract

ABSTRACT

Although delaying fatherhood has become somewhat more popular, the heritable sequelae of this practice are not well understood. Advancing paternal age has, however, been implicated in numerous abnormal reproductive and genetic outcomes, including poorer semen quality, reduced fertility, and more frequent spontaneous abortions, as well as some 20 autosomal-dominant diseases such as Apert syndrome and achondroplasia. The investigators examined the effects of advancing male age on multiple genomic defects in sperm (reflected in the DNA fragmentation index [DFI]), chromatin integrity, gene mutations, and numeric chromosomal abnormalities. Participants were 97 men ranging in age from 22 to 80 years who were in good to excellent health and did not smoke. They were predominantly a white and highly educated population. Semen specimens were obtained after an average of 5 days without sexual activity.

Age correlated positively with all 5 DFI end points analyzed. Thirty men, nearly one third of those studied, had percent DFI values at or above those previously associated with an increased risk of male infertility. After adjusting for age and abstinence, the frequency of sperm with high DNA stainability did not correlate with DFI end points. Age did correlate with fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia. No associations were noted between age and the frequency of sperm with immature chromatin, aneuploidies or diploidies, or FGFR2 mutations (as in Apert syndrome). There also were no consistent correlations among genomic and semen quality end points except for an association between DFI and sperm motility. Male age did not correlate with the sperm sex ratio.

Men who choose to delay fatherhood may be less likely to experience a successful pregnancy. Unlike older women, however, older men do not seem to be at increased risk of trisomic or triploid pregnancies. Semen quality does not reflect the presence of genomic damage to sperm. A small number of older men do appear to be at increased risk of transmitting multiple genetic and chromosomal defects.