The utility of gene expression profiling in hazard identification

The utility of gene expression profiling in hazard identification has been examined for a limited number of chemicals, including dibutyl phthalate and acetaminophen (Euling et al., 2011, Kienhuis et al., 2011 and Makris et al., 2010). Toxicogenomic profiles of alachlor exposure in rat olfactory mucosa (Genter et al., 2002) and dimethylarsenic (DMA) exposure in human cultured bladder cells and rat bladder epithelium (Sen et al., 2005 and US EPA, 2005) have also provided IWR-1 useful information for two final

assessments of acetochlor and arsenicals (US EPA, 2004 and US EPA, 2006). Our data demonstrate that gene expression profiles can also be viewed as effective predictors of the biological effects of CBNP exposure. For example, inflammatory responses manifested at the gene expression level and detected using DNA microarrays and classified in this work using KEGG pathway analyses and previously in the same mice using ingenuity pathway

analysis (Bourdon et al., 2012a) are entirely consistent with the observed pulmonary influx of inflammatory markers (e.g., MS-275 research buy neutrophils, eosinophils and lymphocytes). The number of genes perturbed and the magnitude of expression changes in these pathways correlates with dose and time. In addition, observed transcriptomic changes associated with perturbations of cell cycle networks, alterations of non-homologous end-joining, and p53 signalling support the sustained genotoxicity observed in the mice, although dose and time correlations were not as apparent (e.g., levels of DNA strand breaks remained relatively constant at the two highest exposure doses (Bourdon et al., 2012b) whereas induction of DNA repair genes decreased Metformin chemical structure with dose and time). The transcriptomic changes associated with alterations in glutathione metabolism and free radical scavenging correlate with induction

of DNA formamidopyrimidine DNA glycoslase (FPG) sensitive sites (an indicator of oxidative DNA damage) early after the exposure. The persistence of this response is an indication of an adaptive response to oxidative stress in the lungs of the mice. Interestingly, CBNP-induced alterations in gene expression profiles also revealed a pulmonary acute phase response and unexpected changes in lipid homeostasis, which were subsequently supported by measured decreases in plasma high density lipoprotein (HDL) (Bourdon et al., 2012a). The strong association between CBNP-induced gene expression profiles and apical endpoints collectively support the use of toxicogenomics for hazard identification of NMs, and perhaps more importantly, for highlighting unexpected adverse outcomes. Moreover, ongoing work within the Organization for Economic Co-operation and Development (OECD) is actively developing adverse outcome pathways (AOP) approaches that are expected to provide tangible methods by which systems biology endpoints can be used in human health risk assessment.

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