Ozone increases plasma kynurenine-tryptophan ratio and impacts hippocampal serotonin receptor and neurotrophic factor expression: Role of stress hormones
- DOI
- Language of the publication
- English
- Date
- 2020-04-05
- Type
- Article
- Author(s)
- Rose, Mercedes
- Filiatreault, Alain
- Guénette, Josée
- Williams, Andrew
- Thomson, Errol M.
- Publisher
- Elsevier
Abstract
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.
Plain language summary
Health Canada conducts studies to assess potential health impacts of exposure to air pollutants. Health Canada scientists have shown that breathing in air pollutants increases the levels of stress hormones called glucocorticoids in the blood. High glucocorticoid levels have been linked with a number of brain disorders, including declines in cognition, dementia, and depression. In the present study, Health Canada scientists studied how air pollution can affect the hippocampus, a part of the brain that is important in the development of these disorders. They measured changes in the brain and blood of rats who breathed air or the common pollutant ozone, and examined whether these effects were due to glucocorticoids. They found that ozone decreased levels of factors in the brain that are important for the health of neurons, as well as decreasing levels of the serotonin precursor tryptophan in the blood. Some of these effects were linked to glucocorticoids, and some were not. This study shows that air pollutants cause changes in the blood and brain that have been linked with brain disorders, and that the stress response system of the body is involved in some of these effects. The work provides mechanistic support for studies conducted in the Canadian population examining links between exposure to air pollution and effects on the brain.
Subject
- Health,
- Health and safety