The genotoxicity testing battery is highly sensitive for detection of chemical carcinogens. However, it features a low specificity and provides only limited mechanistic information required for risk assessment of positive findings. This is especially important in case of positive findings in the in vitro chromosome damage assays, because chromosome damage may be also induced secondarily to cell death. An increasing body of evidence indicates that toxicogenomic analysis of cellular stress responses provides an insight into mechanisms of action of genotoxicants. To evaluate the utility of such a toxicogenomic analysis we evaluated gene expression profiles of TK6 cells treated with four model genotoxic agents using a targeted high density real-time PCR approach in a multilaboratory project coordinated by the Health and Environmental Sciences Institute Committee on the Application of Genomics in Mechanism-based Risk Assessment. We show that this gene profiling technology produced reproducible data across laboratories allowing us to conclude that expression analysis of a relevant gene set is capable of distinguishing compounds that cause DNA adducts or double strand breaks from those that interfere with mitotic spindle function or that cause chromosome damage as a consequence of cytotoxicity. Furthermore, our data suggest that the gene expression profiles at early time points are most likely to provide information relevant to mechanisms of genotoxic damage and that larger gene expression arrays will likely provide richer information for differentiating molecular mechanisms of action of genotoxicants. Although more compounds need to be tested to identify a robust molecular signature, this study confirms the potential of toxicogenomic analysis for investigation of genotoxic mechanisms.
Female reproductive properties, early embryonic development, and serum estradiol and progesterone levels of the senescence-accelerated mouse (SAM)-prone (SAM-P) strain were compared with those of a SAM-resistant (SAM-R) strain. The reproductive life span of SAM-P (from 11.4 to 25.0 weeks old) was shorter than that of SAM-R (11.1 to 41.6 weeks old), and the total number of SAM-P pups was 41.7% less than from SAM-R. The reproductive senescence of SAM-P is more accelerated than that of SAM-R. At 15 weeks old, the maximum litter size of SAM-P was noted and was 33.7% smaller than that of SAM-R. Although no differences in the numbers of ovulated and fertilized ova were observed between two strains, the number of implants in SAM-P was 21.6% less than in SAM-R. Cell cleavage was delayed in embryos of SAM-P (8% morula, at day 2 of pregnancy) compared to SAM-R (48%). At day 3 of pregnancy, 9% and 33% of the embryos were blastocysts in SAM-P and SAM-R, respectively. At day 1 of pregnancy, serum estradiol level in SAM-P was 18.2% higher than in SAM-R, whereas the serum progesterone level in SAM-P was 46.2% lower than in SAM-R. The unbalance of estradiol and progesterone levels in SAM-P was considered to be the cause of the delay in early embryonic development, and then the decrease of implantation and a smaller litter size.
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