Ljubimova Julia Y, Kleinman Michael T, Karabalin Natalya M, Inoue Satoshi, Konda Bindu, Gangalum Pallavi, Markman Janet L, Ljubimov Alexander V, Black Keith L
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
Exp Toxicol Pathol. 2013 Nov;65(7-8):1063-71. doi: 10.1016/j.etp.2013.04.002. Epub 2013 May 18.
Air pollution negatively impacts pulmonary, cardiovascular, and central nervous systems. Although its influence on brain cancer is unclear, toxic pollutants can cause blood-brain barrier disruption, enabling them to reach the brain and cause alterations leading to tumor development. By gene microarray analysis validated by quantitative RT-PCR and immunostaining we examined whether rat (n=104) inhalation exposure to air pollution particulate matter (PM) resulted in brain molecular changes similar to those associated with human brain tumors. Global brain gene expression was analyzed after exposure to PM (coarse, 2.5-10μm; fine, <2.5μm; or ultrafine, <0.15μm) and purified air for different times, short (0.5, 1, and 3 months) and chronic (10 months), for 5h per day, four days per week. Expression of select gene products was also studied in human brain (n=7) and in tumors (n=83). Arc/Arg3.1 and Rac1 genes, and their protein products were selected for further examination. Arc was elevated upon two-week to three-month exposure to coarse PM and declined after 10-month exposure. Rac1 was significantly elevated upon 10-month coarse PM exposure. On human brain tumor sections, Arc was expressed in benign meningiomas and low-grade gliomas but was much lower in high-grade tumors. Conversely, Rac1 was elevated in high-grade vs. low-grade gliomas. Arc is thus associated with early brain changes and low-grade tumors, whereas Rac1 is associated with long-term PM exposure and highly aggressive tumors. In summary, exposure to air PM leads to distinct changes in rodent brain gene expression similar to those observed in human brain tumors.
空气污染会对肺部、心血管系统和中枢神经系统产生负面影响。尽管其对脑癌的影响尚不清楚，但有毒污染物可导致血脑屏障破坏，使其能够进入大脑并引起导致肿瘤发展的改变。通过定量逆转录聚合酶链反应（RT-PCR）和免疫染色验证的基因微阵列分析，我们研究了大鼠（n = 104）吸入空气污染颗粒物（PM）是否会导致与人类脑肿瘤相关的脑分子变化。在暴露于不同粒径的PM（粗颗粒，2.5 - 10μm；细颗粒，<2.5μm；或超细颗粒，<0.15μm）和净化空气不同时间（短期，0.5、1和3个月；慢性，10个月）后，每天暴露5小时，每周4天，分析全脑基因表达。还在人类大脑（n = 7）和肿瘤（n = 83）中研究了选定基因产物的表达。选择Arc/Arg3.1和Rac1基因及其蛋白产物进行进一步检查。暴露于粗颗粒PM两周至三个月后Arc升高，10个月暴露后下降。暴露于粗颗粒PM 10个月后Rac1显著升高。在人类脑肿瘤切片上，Arc在良性脑膜瘤和低级别胶质瘤中表达，但在高级别肿瘤中表达低得多。相反，Rac1在高级别胶质瘤与低级别胶质瘤中升高。因此，Arc与早期脑变化和低级别肿瘤相关，而Rac1与长期PM暴露和高度侵袭性肿瘤相关。总之，暴露于空气中的PM会导致啮齿动物脑基因表达发生明显变化，类似于在人类脑肿瘤中观察到的变化。
