Cadmium-Induced Differential Toxicogenomic Response in Resistant and Sensitive Mouse Strains Undergoing Neurulation

Abstract

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 24-h postinjection [p.i.] [gestational day 8.0, 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 (e.g., Zic1, En2, Neurog1, Elavl4, Metrn, Nr2f1, Nr2f2) in the C57 compared to the SWV (12-h 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.

Integration of gene chip and topological network techniques to screen a candidate biomarker gene (CBG) for predication of the source water carcinogenesis risks on mouse Mus musculus

“…Even if the pollutant concentrations were lower and might not lead to acute toxicity, but their sub-acute, chronic, and genetic toxicities also may be harmful on animals exposed to YZR-SDW-NJ for a lifetime. It is because that the low-dose exposures with the organic pollutants could alter the cell cycle, MAPK signaling pathway, TGF-b signaling pathway, aberrant of cell cycles at least and lead to tumor progression and malignant transformation (Massague 2008;MacDonald et al 2009;Andrew et al 2007;Perez et al 2008;Robinson et al 2009;Cebrat et al 2004;Jacobson et al 2010;Johanson et al 2007;Bespalova et al 2010;Makarov et al 2009). Selecting of seed genes from the differently expressed genes (DEGs)…”

Genomic expression profiles in liver of mice exposed to purified terephthalic acid manufacturing wastewater

“…The DEGs associated with MAPK signaling pathway included crk, prkca, gadd45b, ppp3cc, gadd45g, cacna1f and egfr. It has been indicated that low-dose exposure to arsenic [30] and cadmium [31] can significantly alter the regulation of mouse MAPK signaling pathway. Usually, activation of this pathway can promote cell division, and aberrance of MAPK has been implicated in several human diseases including inflammation and cancers [32].…”

“…Cell cycle is a typical biological pathway and can be easily altered by carcinogenic contaminants such as disinfection by-products [28], arsenic [30], cadmium [31] and benzo(a)pyrene [38]. TA was also found to induce bladder epithelial cell proliferation in rats [39].…”

Effects of Metallic Elements on Reproduction and Development

“…There is increasing evidence that maternal Cd exposure causes relatively specific forelimb ectrodactyly (the deficiency or absence of one or more central digits) in mouse strains when administered during early limb development (Robinson et al, 2009(Robinson et al, , 2011. Cdinduced fetal malformations might be associated with impairment of placental development and a reduction in placental transport capacity.…”