Miller Desinia B, Karoly Edward D, Jones Jan C, Ward William O, Vallanat Beena D, Andrews Debora L, Schladweiler Mette C, Snow Samantha J, Bass Virginia L, Richards Judy E, Ghio Andrew J, Cascio Wayne E, Ledbetter Allen D, Kodavanti Urmila P
Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
Metabolon Incorporation, Durham, NC, USA.
Toxicol Appl Pharmacol. 2015 Jul 15;286(2):65-79. doi: 10.1016/j.taap.2015.03.025. Epub 2015 Mar 31.
Air pollution has been linked to increased incidence of diabetes. Recently, we showed that ozone (O3) induces glucose intolerance, and increases serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause systemic changes in metabolic homeostasis and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.0ppm, 6h/day for two days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0ppm O3, 6h/day for either one or two consecutive days, and systemic metabolic responses were determined immediately after or 18h post-exposure. O3 increased serum glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h-post second exposure. O3 increased circulating metabolites of glycolysis, long-chain free fatty acids, branched-chain amino acids and cholesterol, while 1,5-anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, proteolysis and lipolysis. Liver gene expression increased for markers of glycolysis, TCA cycle and gluconeogenesis, and decreased for markers of steroid and fat biosynthesis. Genes involved in apoptosis and mitochondrial function were also impacted by O3. In conclusion, short-term O3 exposure induces global metabolic derangement involving glucose, lipid, and amino acid metabolism, typical of a stress-response. It remains to be examined if these alterations contribute to insulin resistance upon chronic exposure.
空气污染已被证明与糖尿病发病率的增加有关。最近，我们发现臭氧（O3）会导致葡萄糖不耐受，并使雄性挪威棕色大鼠的血清瘦素和肾上腺素增加。在本研究中，我们假设暴露于O3会引起代谢稳态的全身性变化，并且血清代谢组学和肝脏转录组学分析将提供相关机制的见解。在第一个实验中，雄性Wistar Kyoto（WKY）大鼠每天暴露于过滤空气（FA）或浓度为0.25、0.50或1.0ppm的O3中，持续6小时，共两天，以确定其对葡萄糖耐量和肺损伤的浓度相关影响。在第二个实验中，大鼠每天暴露于FA或1.0ppm O3中，持续6小时，连续暴露一天或两天，在暴露后立即或18小时后测定全身代谢反应。在第一天，O3会使血清葡萄糖和瘦素增加。葡萄糖不耐受在两天的暴露过程中持续存在，但在第二次暴露后18小时恢复。O3会增加糖酵解、长链游离脂肪酸、支链氨基酸和胆固醇的循环代谢产物，而1,5-脱水葡萄糖醇、胆汁酸和三羧酸循环的代谢产物则减少，这表明血糖控制、蛋白水解和脂肪分解受损。参与糖酵解、三羧酸循环和糖异生的肝脏基因表达增加，而参与类固醇和脂肪生物合成的基因表达减少。参与细胞凋亡和线粒体功能的基因也受到O3的影响。总之，短期暴露于O3会导致包括葡萄糖、脂质和氨基酸代谢在内的整体代谢紊乱，这是典型的应激反应。长期暴露后这些改变是否会导致胰岛素抵抗仍有待研究。
