Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Neurotoxicol Teratol. 2012 Sep-Oct;34(5):530-3. doi: 10.1016/j.ntt.2012.08.004. Epub 2012 Aug 28.
A primary public health concern regarding environmental chemicals is the potential for persistent effects from long-term exposure, and approaches to estimate these effects from short-term exposures are needed. Toluene, a ubiquitous air pollutant, exerts well-documented acute and persistent CNS-mediated effects from a variety of exposure scenarios, and so provides a useful case for determining whether its persistent effects can be predicted from its acute effects on the CNS. We recently reported that acute inhalation of toluene produced transcriptional effects in rat brain 18 h following a single, acute 6-h exposure to toluene. The goal of the present study was to determine whether these acute effects are also evident after long-term (sub-chronic) exposure to toluene, and thereby provide a mechanistic basis for predicting its persistent effects from short-term exposures. Male Long-Evans rats were exposed to toluene via inhalation (0, 10, 100, 1000 ppm, n=5/dose), 6h/day for 64 days, excluding weekends. The day following the final exposure, total mRNA was extracted from the cerebral cortex and striatum, and gene expression evaluated using Affymetrix arrays. Principal component analysis using all samples showed a clear discrimination of tissues, with striatum having more within-group variance than cortex. Differentially-expressed genes (DEGs) whose expression was altered by toluene were identified in each tissue by ANOVA followed by mapping to pathways. Analysis of striatum revealed 22, 57, and 94 significant DEGs for the 10 ppm, 100 ppm, and 1000 ppm doses, respectively, far fewer than the 3352 DEGS previously observed after acute exposure. In addition, the direction of change in the 57 DEGs common to both exposures differed between acute and sub-chronic exposure scenarios. Thus, relative to acute toluene exposure, sub-chronic exposure yielded both quantitative and qualitative differences in transcriptional response. Based on the current data, long-term gene expression changes after toluene inhalation cannot be readily predicted by acute responses.
公众主要关注环境化学物质的潜在持久性影响，需要寻求从短期暴露中评估这些影响的方法。甲苯是一种普遍存在的空气污染物，从各种暴露情况中都能产生有充分文献记录的急性和持久性中枢神经系统介导的影响，因此为确定其持久性影响是否可以从其对中枢神经系统的急性影响来预测提供了一个有用的案例。我们最近报道，单次急性 6 小时甲苯吸入后 18 小时，甲苯会在大鼠脑中产生转录效应。本研究的目的是确定这些急性效应是否也在长期（亚慢性）甲苯暴露后明显，从而为从短期暴露预测其持久性影响提供机制基础。雄性长耳大白鼠通过吸入（0、10、100、1000 ppm，每组 5 只）暴露于甲苯，每天 6 小时，共 64 天，不包括周末。末次暴露后一天，从大脑皮层和纹状体中提取总 mRNA，并使用 Affymetrix 芯片评估基因表达。使用所有样本进行的主成分分析显示，组织之间有明显的区分，纹状体的组内方差大于皮层。通过方差分析（ANOVA）后映射到途径，在每个组织中确定了甲苯改变表达的差异表达基因（DEGs）。对纹状体的分析显示，10 ppm、100 ppm 和 1000 ppm 剂量分别有 22、57 和 94 个显著的 DEGs，远少于以前急性暴露后观察到的 3352 个 DEGs。此外，两种暴露情况下共同的 57 个 DEGs 的变化方向也不同。因此，与急性甲苯暴露相比，亚慢性暴露在转录反应中产生了定量和定性的差异。根据当前数据，甲苯吸入后的长期基因表达变化不能通过急性反应来预测。
