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

A. J. Wyrobek, B. Eskenazi, S. Young, N. Arnheim, I. Tiemann-Boege, E. W. Jabs, R. L. Glaser, F. S. Pearson, D. Evenson

Research output: Contribution to journalArticle

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 non-clinical 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.

Original languageEnglish (US)
Pages (from-to)9601-9606
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number25
DOIs
StatePublished - Jun 20 2006

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Aneuploidy
DNA Damage
Chromatin
Spermatozoa
Semen Analysis
DNA Fragmentation
Mutation
Acrocephalosyndactylia
Achondroplasia
Genes
Receptor, Fibroblast Growth Factor, Type 3
Triploidy
Sperm Motility
Sex Ratio
Diploidy
Chromosome Aberrations
Embryonic Structures
Pregnancy
Incidence

Keywords

  • Achondroplasia
  • Apert syndrome
  • DNA fragmentation
  • Human sperm
  • Sperm FISH

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. / Wyrobek, A. J.; Eskenazi, B.; Young, S.; Arnheim, N.; Tiemann-Boege, I.; Jabs, E. W.; Glaser, R. L.; Pearson, F. S.; Evenson, D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 25, 20.06.2006, p. 9601-9606.

Research output: Contribution to journalArticle

Wyrobek, AJ, Eskenazi, B, Young, S, Arnheim, N, Tiemann-Boege, I, Jabs, EW, Glaser, RL, Pearson, FS & Evenson, D 2006, 'Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 25, pp. 9601-9606. https://doi.org/10.1073/pnas.0506468103
Wyrobek, A. J. ; Eskenazi, B. ; Young, S. ; Arnheim, N. ; Tiemann-Boege, I. ; Jabs, E. W. ; Glaser, R. L. ; Pearson, F. S. ; Evenson, D. / Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 25. pp. 9601-9606.
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AU - Tiemann-Boege, I.

AU - Jabs, E. W.

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