title: Gene expression changes in rat brain after short and long exposures to particulate matter in Los Angeles basin air: Comparison with human brain tumors.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States. Electronic address: ljubimovaj@cshs.org.
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kleinman
authors.forename: Natalya M
authors.initials: NM
authors.lastname: Karabalin
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.forename: Pallavi
authors.initials: P
authors.lastname: Gangalum
authors.forename: Janet L
authors.initials: JL
authors.lastname: Markman
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ljubimov
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
mesh_terms: D000397:Air Pollution / Q000009:adverse effects*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D015141:Los Angeles; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D052638:Particulate Matter / Q000009:adverse effects*; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D052638:Particulate Matter; C107953:RAC1 protein, human; C092069:activity regulated cytoskeletal-associated protein; D020830:rac1 GTP-Binding Protein
keywords: Air pollution particles; Arc/Arg3.1; Brain tumor; Chronic exposure; Gene microarray; Rac1