Air pollution is associated with adverse impacts on the brain, including cognitive decline and increased incidence of dementia, depression and anxiety; however, underlying mechanisms remain unclear. We have shown that both ozone and particulate matter activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing plasma glucocorticoids and altering mRNA profiles in multiple tissues including the brain. HPA axis dysregulation has been associated with central nervous system impacts, including key effects in the hippocampus; accordingly, we hypothesized that pollutant-dependent increases in glucocorticoid levels impact biological pathways relevant to brain health. Fischer-344 rats were treated with metyrapone (0 or 50 mg/kg), a glucocorticoid synthesis inhibitor, and exposed to ozone (0 or 0.8 ppm) for 4 h (n = 5/group) to investigate the role of glucocorticoids in ozone-dependent effects on tryptophan metabolism and expression of serotonin receptors and neurotrophic factors. Ozone increased plasma levels of the tryptophan metabolite kynurenine (~2-fold) and decreased tryptophan levels (~1.2 fold). Hippocampal expression of serotonin receptors exhibited differential regulation following exposure, and expression of key neurotrophic factors (brain-derived neurotrophic factor, vascular endothelial growth factor A, insulin-like growth factor-1, tyrosine kinase receptor B, b-cell lymphoma 2) was decreased. Some, but not all effects were abrogated by metyrapone treatment, suggesting both glucocorticoid-dependent and -independent regulation. Exposure to exogenous corticosterone (10 mg/kg) followed by clean air reproduced the ozone effects that were blocked with metyrapone, confirming the specificity of effects to glucocorticoids. These results indicate that ozone can modify pathways relevant to brain health and establish a role for the HPA axis in mediating these effects.

中文翻译：

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臭氧可增加血浆犬尿氨酸-色氨酸的比率，并影响海马血清素受体和神经营养因子的表达：应激激素的作用。

空气污染与对大脑的不利影响相关，包括认知能力下降和痴呆，抑郁和焦虑的发生率增加；但是，基本机制仍不清楚。我们已经表明，臭氧和颗粒物都激活下丘脑-垂体-肾上腺（HPA）轴，增加血浆糖皮质激素并改变包括大脑在内的多种组织的mRNA谱。HPA轴失调与中枢神经系统影响有关，包括对海马体的关键影响。因此，我们假设糖皮质激素水平的污染物依赖性增加会影响与脑部健康相关的生物途径。Fischer-344大鼠接受甲氨蝶呤（0或50 mg / kg），糖皮质激素合成抑制剂治疗，并暴露于臭氧（0或0）。8 ppm）持续4小时（n = 5 /组），以研究糖皮质激素在臭氧依赖的色氨酸代谢以及血清素受体和神经营养因子表达中的作用。臭氧增加了色氨酸代谢物犬尿氨酸的血浆水平（约2倍），降低了色氨酸水平（约1.2倍）。暴露后海马血清素受体的表达表现出不同的调节作用，关键神经营养因子（脑源性神经营养因子，血管内皮生长因子A，胰岛素样生长因子-1，酪氨酸激酶受体B，b细胞淋巴瘤2）的表达为减少了。甲吗啡酮治疗可以消除部分但不是全部作用，提示糖皮质激素依赖性和非依赖性调节。暴露于外源性皮质类固醇（10 mg / kg），然后暴露于空气中，重现了甲吡酮所阻断的臭氧作用，证实了其对糖皮质激素的特异性。这些结果表明，臭氧可以改变与大脑健康有关的途径，并在介导这些作用方面为HPA轴发挥作用。