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 mammalian germ cells. Test methodologies employing fluorescence in situ hybridization (FISH) to detect structural and numerical chromosome damage in sperm and early embryonic cells of rodents have 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, by providing sperm from NTP bioassays, and by performing analyses of all data. 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, work has continued on development of an X probe for the rat with evaluation of additional YAC probes. 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. BAC and YAC probes for mouse chromosomes 2 and 16 supplied by AGL were evaluated; the chromosome 16 BAC probes did not provide a suitable signal for the epididymal sperm assay (ESA) but the chromosome 16 YAC probes for both 2 and 16 look promising and are undergoing additional evaluation. Sperm samples from an NTP rat study on oxazapam have been collected and frozen for future evaluation. Sperm samples from mice treated with benzene in another NTP bioassay have also been collected and frozen for future evaluation. - fluorescence in situ hybridization, FISH, chromosome damage, birth defects, infertility, NOVP, mice, rats
| 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 |
