Nrf2-regulated phase II enzymes are induced by chronic ambient nanoparticle exposure in young mice with age-related impairments

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• 作者：Hongqiao Zhang^a ; Honglei Liu^a ; Kelvin J.A. Davies^a ; Constantinos Sioutas^a ; Caleb E. Finch^a ; Todd E. Morgan^a ; Henry Jay Forman^a ; ^b ; ^{hjforman@gmail.com}
• 关键词：Aging ; Detoxifying enzyme ; Nrf2 ; Antioxidant ; Particle
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 May, 2012
• 卷：52
• 期：9
• 页码：2038-2046
• 文件大小：1128 K

摘要

Many xenobiotic detoxifying (phase II) enzymes are induced by sublethal doses of environmental toxicants. However, these adaptive mechanisms have not been studied in response to vehicular-derived airborne nano-sized particulate matter (nPM). Because aging is associated with increased susceptibility to environmental toxicants, we also examined the expression of Nrf2-regulated phase II genes in middle-aged mice and their inducibility by chronic nPM. The nPM from vehicular traffic was collected in urban Los Angeles and reaerosolized for exposure of C57BL/6J male mice (3 and 18 months old) for 150 h over 10 weeks. Brain (cerebellum), liver, and lung were assayed by RT-PCR and/or Western blots for the expression of phase II enzymes, glutamate cysteine ligase (catalytic GCLC, and modifier GCLM subunits), NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), and relevant transcription factors, NF-E2-related factor 2 (Nrf2), c-Myc, Bach1. Chronic nPM exposure induced GCLC, GCLM, HO-1, NQO1 mRNA, and protein similarly in cerebellum, liver, and lung of young mice. Middle-aged mice had elevated basal levels, but showed impaired further induction by nPM. Similarly, Nrf2 increased with age and was induced by nPM in young but not old. c-Myc showed the same age and induction profile while the age increase in Bach1 was further induced by nPM. Chronic exposure to nanoparticles induced Nrf2-regulated detoxifying enzymes in brain (cerebellum), liver, and lung of young adult mice, indicating a systemic impact of nPM. In contrast, middle-aged mice did not respond above their elevated basal levels except for Bach1. The lack of induction of phase II enzymes in aging mice may be a model for the vulnerability of elderly to air pollution.