Infertility and other untoward reproductive and developmental outcomes, such as spontaneous abortion, fetal and neonatal death, birth defects, and genetic susceptibilities to cancer and other diseases, are associated with genetic damage occurring in germ cells and/or the early developing embryo. Test methodologies employing fluorescence in situ hybridization (FISH) to detect structural and numerical chromosome damage in sperm and early embryonic cells of rodents has been developed at Lawrence Livermore National Laboratory (LLNL) under an NIEHS-DOE Interagency agreement. We are participating in the evaluation of these test methods through the conduct of positive control experiments. The rodent sperm-FISH assays being developed provide parallel models of similar sperm-FISH assays in humans. They will be used for evaluating the aneugenic and clastogenic potential of environmental chemicals tested in NTP bioassays, as well as for addressing questions about dose response, differential stage sensitivity, the relationship of defects seen in sperm to those transmitted to the early embryo, and other important issues related to health-risks which cannot be addressed in human studies. During the past year, we conducted a repeat of our three-chromosome (X, Y and 8) mouse sperm-FISH aneuploidy experiments on the Hodgkin?s Disease chemotherapeutic regimen of Novantrone (N), Oncovin (O), and Vinblastine (V), each given via single i.v. injection at three dose-levels including a low-dose at the mg/m2 human-equivalent doses, plus Prednisone (P) given at 5 consecutive days by oral gavage. Analysis of all the NOVP data was also completed and a manuscript is in preparation. A manuscript describing results of the base-line frequencies of hyperhaploidy for chromosomes Y and 4 in 3 strains of rats (F344, SD and Wistar) was also published. Development of an X probe for the rat is near completion. As soon as the 3-chromosome (X, Y and 4) rat sperm-FISH assay methodology is in place, we plan to conduct an NOVP experiment in F-344 rats. Sperm for oxazepam treated rats has also been collected for future evaluation.
| 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 |
