抄録
Toxicity of volatile organic compounds (VOCs) in indoor air, such as formaldehyde (FA), Xylene (Xy) and Paradichlorobenzene (pDB), at the levels of Sick House/Building Syndrome (SHS) is difficult to assess by the ordinary inhalation animal studies; histopathological endpoints are negative for toxicity at such concentration level. Here we applied our Percellome Toxicogenomics Project that had been launched to develop a comprehensive gene network for the mechanism-based predictive toxicology using time- and dose-dependent transcriptomic responses induced by a chemical. This Project was initiated to reinforce and eventually replace the “safety factor (uncertainty factor)” widely used for the extrapolation of experimental animal data to humans. For this purpose, a normalization method designated as “Percellome” is developed (BMC Genomics 7:64, 2006) to generate mRNA expression values in “copy numbers per one cell” from microarrays and Q-PCR. Over 100 chemicals have already been tested in this Project. Here, we report that the Percellome analysis is capable of predicting functional insults that might lead to chronic toxicity.
FA, Xy and pDB at concentrations 0.08, 0.20 and 0.04 ppm, respectively, close to the “Indicative indoor exposure value of SHS (MHLW, Japan)”, were applied to the C57BL/6J mice 22hr/day x 7 days inhalation-exposure protocol (4 concentrations x 4 time points, triplicate). Lung, liver and hippocampus were analyzed. Strong suppression of gene expression related to neuronal activity in hippocampus, i.e. the immediate early genes (IEGs) including Arc, Dusp1 and Fos was shown commonly among the three chemicals. Lung and liver Percellome analysis pointed out a candidate cytokine upstream of IEGs. Our finding may be considered as a first substantial data that would explain the indefinite or unidentified complaint in SHS patients. In addition, Percellome analysis of the orally exposed lung and liver to FA, Xy and pDB will be presented for further clarification of the inter-organ relationship.
