ToxSci Advance Access published online on October 29, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn221
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CADMIUM-INDUCED DIFFERENTIAL TOXICOGENOMIC RESPONSE IN RESISTANT AND SENSITIVE MOUSE STRAINS UNDERGOING NEURULATION
1 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195 2 Center for Ecogenetics and Environmental Health and Institute for Risk Analysis and Risk Communication, Seattle, Washington 98195 3 Center on Human Development and Disability, Seattle, Washington 98195 4 Center for Child Environmental Health Risks Research, Seattle, WA 98195
To whom correspondence should be addressed at the Department of Environmental and Occupational Health Sciences, 4225 Roosevelt Way NE Suite 100, University of Washington, Seattle, WA 98105. Fax: (206) 685-4696; E-mail: faustman{at}u.washington.edu.
Received June 23, 2008; revision received October 7, 2008; accepted October 8, 2008
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Abstract |
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Common inbred mouse strains, such as the C57BL/6 (C57) and the SWV, display differences in sensitivity to environmental teratogens during gestation. For example, the C57 is more sensitive than the SWV to cadmium (Cd) exposure during neurulation, inducing a higher incidence of neural tube defects (NTDs). Here, we report, using Cd as a model teratogen, the first large scale toxicogenomic study to compare teratogen-induced gene expression alterations in C57 and SWV embryos undergoing neurulation, identifying toxicogenomic responses that associate with developmental toxicity and differential sensitivity. Using a systems-based toxicogenomic approach, comparing Cd-exposed and control C57 and SWV embryos (12 and 24h p.i. (GD8.0, ip)), we examined differentially expressed genes at multiple levels (biological process, pathway, gene) using Gene Ontology (GO) analysis, pathway mapping and cross-scatter plots. In both C57 and SWV embryos, we observed several gene expression alterations linked with cell cycle related classifications, however only in the C57 we observed upregulation of p53-dependent mediators Ccng1 and Pmaip1, previously associated with cell cycle arrest, apoptosis and NTD formation. In addition, we also identified a greater reduction in expression of nervous system development-related genes (ex. Zic1, En2, Neurog1, Elavl4, Metrn, Nr2f1, Nr2f2) in the C57 compared to the SWV (12h p.i.). In summary, our results indicate that differences in Cd-induced gene expression profiles between NTD resistant and sensitive strains within enriched biological processes (including developmental and cell cycle-related categories) associate with increased sensitivity to developmental toxicity as determined by observations of increased NTD formation, mortality (resorptions) and reduced fetal growth. Such observations may provide more detailed and useful mechanistic clues for identification of differences in life-stage specific teratogenic response.
Key Words: Cadmium; Exencephaly; Mouse; Neural tube defects; Toxicogenomics; SWV.
Presented in part at the annual meeting of the Society of Toxicology, March 25th – March 29th, 2008, Charlotte, NC