Parallel animal model tests to one in humans for detecting aneuploidy in sperm using fluorescent in situ hybridization (FISH) are being developed under this project. These tests will be used to evaluate the aneugenic potential of environmental chemicals tested in NTP bioassays and answer critical questions regarding the mechanisms of aneuploidy induction which cannot be addressed in humans studies. Methodology for a three chromosome (X, Y and 8) sperm-FISH assay in the mouse and a two- chromosome (Y and 4) sperm-FISH assay in the rat has been developed at Lawrence Livermore National Laboratory (LLNL) under an NIEHS-DOE Interagency agreement. We are participating in the evaluation of these methods through conduct of positive control experiments by treating male mice at NIEHS (TB 92-01) with Novantrone, Oncovin and/or Vinblastine. Hematological and testicular analyses on these mice conducted at NIEHS demonstrated dose-related toxicity with only minimal testicular effects at the low dose. Sperm of high- and mid-dose mice evaluated by FISH at LLNL, however, did not exhibit increased aneuploidy. Sperm from low-dose males are currently being scored. If our low-dose sperm-FISH evaluations are positive, a treatment regimen combining each of the three chemicals at their current lowest-dose levels and at one lower dose will be conducted to model a similar study of aneuploidy in human sperm obtained from Hodgkin's patients. In addition, an X-probe for the rat being developed by Applied Genetics Laboratory is currently being evaluated at LLNL and we are providing the rat sperm for these investigations under this project.
| Marchetti, Francesco; Bishop, Jack B; Cosentino, Lidia et al. (2004) Paternally transmitted chromosomal aberrations in mouse zygotes determine their embryonic fate. Biol Reprod 70:616-24 |
| Frias, Sara; Van Hummelen, Paul; Meistrich, Marvin L et al. (2003) NOVP chemotherapy for Hodgkin's disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21. Cancer Res 63:44-51 |
| Marchetti, F; Bishop, J B; Lowe, X et al. (2001) Etoposide induces heritable chromosomal aberrations and aneuploidy during male meiosis in the mouse. Proc Natl Acad Sci U S A 98:3952-7 |
| Schmid, T E; Lowe, X; Marchetti, F et al. (2001) Evaluation of inter-scorer and inter-laboratory reliability of the mouse epididymal sperm aneuploidy (m-ESA) assay. Mutagenesis 16:189-95 |
| Marchetti, F; Lowe, X; Bishop, J et al. (1999) Absence of selection against aneuploid mouse sperm at fertilization. Biol Reprod 61:948-54 |
