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Research Article

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Colin D. Glen and Yuri E. Dubrova
  1. Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom

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PNAS first published January 30, 2012; https://doi.org/10.1073/pnas.1119396109
Colin D. Glen
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Yuri E. Dubrova
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  • For correspondence: Yed2@leicester.ac.uk
  1. Edited* by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved January 10, 2012 (received for review November 29, 2011)

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Abstract

The genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in the offspring of male mice treated with three commonly used chemotherapeutic agents: cyclophosphamide, mitomycin C, and procarbazine. The doses of paternal exposure were approximately equivalent to those used clinically. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat locus Ms6-hm was established in DNA samples extracted from sperm and bone marrow of the offspring of treated males. After paternal exposure to any one of these three drugs, expanded simple tandem repeat mutation frequencies were significantly elevated in the germ line (sperm) and bone marrow of their offspring. This observed transgenerational instability was attributed to elevated mutation rates at the alleles derived from both the exposed fathers and from the nonexposed mothers, thus implying a genome-wide destabilization. Our results suggest that paternal exposure to a wide variety of mutagens can result in transgenerational instability manifesting in their offspring. Our data also raise important issues concerning delayed transgenerational effects in the children of survivors of anticancer therapy.

  • epigenetic
  • genetic risk

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: Yed2{at}leicester.ac.uk.
  • Author contributions: C.D.G. and Y.E.D. designed research; C.D.G. performed research; Y.E.D. analyzed data; and C.D.G. and Y.E.D. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1119396109/-/DCSupplemental.

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Exposure to anticancer drugs can result in transgenerational genomic instability in mice
Colin D. Glen, Yuri E. Dubrova
Proceedings of the National Academy of Sciences Jan 2012, 201119396; DOI: 10.1073/pnas.1119396109

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Exposure to anticancer drugs can result in transgenerational genomic instability in mice
Colin D. Glen, Yuri E. Dubrova
Proceedings of the National Academy of Sciences Jan 2012, 201119396; DOI: 10.1073/pnas.1119396109
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