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

doi:10.1073/pnas.0506468103

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

*Biosciences Directorate, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94550;
^§School of Public Health, University of California, Berkeley, CA 94720-7380;
^¶Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089;
^‖Institute of Genetic Medicine, Center for Craniofacial Development and Disorders, Departments of Pediatrics, Medicine, and Surgery, Johns Hopkins University, Baltimore, MD 21205;
**Department of Biology, Massachusetts College of Liberal Arts, North Adams, MA 01247; and
^††Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007

Edited by James E. Cleaver, University of California, San Francisco, CA, and approved April 21, 2006
↵ ^†A.J.W. and B.E. contributed equally to this work. (received for review August 12, 2005)

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, aneuploidies/diploidies, 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.

Footnotes

^‡To whom correspondence should be sent at the present address:
Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 74R157, Berkeley, CA 94720.
E-mail: ajwyrobek{at}gmail.com
Author contributions: A.J.W. and B.E. designed research; A.J.W., B.E., S.Y., N.A., I.T.-B., E.W.J., R.L.G., F.S.P., and D.E. performed research; A.J.W., B.E., N.A., I.T.-B., E.W.J., and R.L.G. contributed new reagents/analytic tools; A.J.W., B.E., S.Y., N.A., I.T.-B., E.W.J., R.L.G., F.S.P., and D.E. analyzed data; and A.J.W., B.E., and S.Y. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

ACH,

achondroplasia;

AS,

Apert syndrome;

DFI,

DNA fragmentation index;

HDS,

high DNA stainability;

AGES,

age and genetic effects in sperm;

C.I.,

confidence interval;

%DFI,

percent DFI.
Freely available online through the PNAS open access option.