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NOVP Chemotherapy for Hodgkin’s Disease Transiently Induces Sperm Aneuploidies Associated with the Major Clinical Aneuploidy Syndromes Involving Chromosomes X, Y, 18, and 21¹

Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California 94550 [S. F., P. V. H., X. R. L., A. J. W.]; Laboratorio de Citogenetica, Instituto Nacional de Pediatria Secretaria de Salud and Facultad de Ciencias, Universidad Nacional Autónoma de Mexico, Mexico Distrito Federal [S. F.]; Departments of Experimental Radiation Oncology [M. L. M.] and Lymphoma and Myeloma [F. B. H.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030; and the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [M. D. S., J. B. B.]

The objective of this research was to determine whether Novantrone, Oncovin, Velban, and Prednisone (NOVP) combination chemotherapy for Hodgkin’s disease increases the frequencies of the specific types of aneuploid sperm that might elevate the risk of fathering a child with one of the major clinical aneuploidy syndromes, i.e., Down (disomy 21 sperm), Edward (disomy 18 sperm), Turner (nullisomy sex sperm), XYY (disomy Y sperm), triple X (disomy X sperm), or Klinefelter (XY sperm). A four-chromosome multicolor sperm fluorescence in-situ hybridization assay that simultaneously evaluates chromosomes 18, 21, X, and Y was applied to semen provided by four healthy men and to repeated samples of eight Hodgkin’s disease patients before treatment, 35–50 days after treatment to examine the effects of treatment on male meiotic cells, and 1–2 years after treatment to measure the persistence of damage. There were chromosome-specific variations in baseline frequencies and significant inductions of all of the detectable types of sperm aneuploidies: XY sperm (14-fold increase), disomy 18 (7-fold), nullisomy sex (3-fold), disomy 21 (3-fold), and disomy X and Y (2-fold each). Disomy 21 was about twice as frequent as disomy 18, and neither showed a preferential segregation with a sex chromosome. Extrapolating across the genome, 18% of sperm carried a numerical abnormality after NOVP treatment of meiotic cells. Induced effects did not persist to 1–2 years after treatment, suggesting that persistent spermatogonial stem cells were not sensitive to NOVP. These findings establish the hypothesis that conception shortly after certain chemotherapies can transiently increase the risks of fathering aneuploid pregnancies that terminate during development or result in the birth of children with major human aneuploidy syndromes.

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