Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm

Abstract

This study compares the relative effects of advancing male age on multiple genomic defects in human sperm [DNA fragmentation index (DFI), chromatin integrity, gene mutations, and numerical chromosomal abnormalities], characterizes the relationships among these defects and with semen quality, and estimates the incidence of susceptible individuals for a well characterized nonclinical nonsmoking group of 97 men (22-80 years). Adjusting for confounders, we found major associations between age and the frequencies of sperm with DFI and fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia (P < 0.01) with no evidence for age thresholds. However, we found no associations between age and the frequencies of sperm with immature chromatin, aneuploidies͞diploidies, FGFR2 mutations (Apert syndrome), or sex ratio in this cohort. There were also no consistent correlations among genomic and semen-quality endpoints, except between DFI and sperm motility (r ‫؍‬ ؊0.65, P < 0.001). These findings suggest there are multiple spermatogenic targets for genomically defective sperm with substantially variable susceptibilities to age. Our findings predict that as healthy males age, they have decreased pregnancy success with trends beginning in their early reproductive years, increased risk for producing offspring with achondroplasia mutations, and risk of fathering offspring with Apert syndrome that may vary across cohorts, but with no increased risk for fathering aneuploid offspring (Down, Klinefelter, Turner, triple X, and XYY syndromes) or triploid embryos. Our findings also suggest that the burden of genomic damage in sperm cannot be inferred from semen quality, and that a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects.DNA fragmentation ͉ human sperm ͉ achondroplasia ͉ sperm FISH ͉ Apert syndrome I t has become more socially acceptable to delay fatherhood, but the heritable consequences of this trend remain poorly understood. Since 1980, U.S. birth rates have increased up to 40% for men 35-49 years and have decreased up to 20% for men under 30 (1). Although it is well known that as women age, they are at increased risk for infertility, spontaneous abortion, and genetic and chromosomal defects among offspring, the association of male aging with these outcomes has been less well characterized (2).Advancing paternal age has been implicated in a broad range of abnormal reproductive and genetic outcomes (3, 4), including diminished semen quality (5), reduced fertility (6), increased frequencies of spontaneous abortions (7, 8), Ϸ20 autosomal dominant diseases including achondroplasia (ACH) and Apert syndrome (AS; see refs. 3 and 9), and several diseases of complex etiology such as schizophrenia (10). Among transmitted chromosomal defects, sex-chromosomal aneuploidy syndromes show substantial paternal contributions with some evidence of paternal-age effects (11-13).However, the mechanisms for age dependency of paternally transmitted genomic defects are ...

The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population

“…Using a different assay for measuring DNA strand damage in sperm, the SCSA which measures the susceptibility of sperm DNA to in situ acid induced denaturation, Spano et al [7] found a strong association of DNA fragmentation index with age among men 18-55 years olds. Similar trends were found by others investigators [8,[35][36][37][38]. In contrast, Schmid et al [11] using the same methods, reported that male age only influences single strand breaks and age was not associated with sperm DNA damage under neutral conditions, which is thought to represent double strand DNA breaks.…”

“…High levels of sperm DNA damage have been reported to affect fertility potential, increase the risk of recurrent miscarriages, decrease the chances of a successful implantation, and possibly lead to negative effects on the health of offspring [4,5]. Sperm DNA integrity as assessed by terminal desoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) [6], sperm chromatin structure assay (SCSA) [7,8], and Comet assay [9], were also shown to be compromised with advancing age. However, this notion was not supported by all studies [10][11][12], and the results varied according the technique used for the detection of DNA damage.…”

The ‘extremely ancient’ chromosome that isn’t: a forensic bioinformatic investigation of Albert Perry’s X-degenerate portion of the Y chromosome

“…20 In humans, the relevance of male mutation bias is particularly manifested in older fathers, whose offspring harbor more autosomal mutations than the offspring of younger fathers. 15,34 However, it is not clear whether the huge variation in paternal age at conception assumed by Mendez et al 2 is a reasonable assumption in modern human populations, let alone in ancient ones. For instance, even among developed nations, where age at conception is delayed, generation times ranges from 20 to 30 years 35 and stands at B25 in the US.…”

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

“…Alternatively, molecular methods could be used to identify genomic mutations in exposed human populations [Foster and Sharp, 2005]. As described later in this report, molecular approaches have been developed in animal models and for somatic cells that allow for direct measurement of aneuploidy, chromosome aberrations, inversions, deletions, copy number changes, and point mutations; some of these may be immediately applicable for human germcell mutagenicity studies [Bendure and Mulvihill, 2006;Wyrobek et al, 2006].…”

“…However, they suggest that the rate and potential impact of mosaicism under biologically relevant conditions may be underestimated; somatic and germline mosaicism could make a significant contribution to sporadic and inherited genetic disease. Table I [Marchetti and Wyrobek, 2005;Wyrobek et al, 2006]. A major advantage of analyzing sperm directly vs. analyzing groups of offspring is that a much larger number of gametes per individual can be assessed for genomic defects compared with the relatively small numbers of affected offspring typically available for epidemiological studies of male-mediated effects.…”