Defining the in vivo mechanism of air pollutant toxicity using murine stress response biomarkers.
BackgroundAir pollution can cause a wide range of serious human diseases. For the informed instigation of interventions which prevent these outcomes there is an urgent need to develop robust in vivo biomarkers which provide insights into mechanisms of toxicity and relate pollutants to specific adverse outcomes. ObjectiveTo exemplify the application of in vivo stress response reporters in establishing mechanisms of air pollution toxicity and the application of this knowledge in epidemiological studies and potentially in disease prevention. MethodsMurine stress-reporter models (oxidative stress/inflammation, DNA damage and Ah receptor -AhR-activity) and primary mouse and primary human nasal cells were exposed to chemicals present in diesel exhaust emissions, particulate matter (PM) standards (PM2.5-SRM2975, PM10-SRM1648b) or fresh roadside PM10. Stress reporter activity was analysed by luminescence assays and histochemical approaches in a panel of murine tissues. Biochemical, genetic and pharmacological approaches were used to establish the mechanism of the stress responses observed. Pneumococcal adhesion was assessed in exposed primary human nasal epithelial cells (HPNEpC). ResultsNitro-PAHs induced Hmox1 and CYP1a1 reporters in a time- and dose-dependent, cell- and tissue-specific manner. NRF2 pathway mediated this Hmox1-reporter induction. SRM1658b, but not SRM2975, was a potent inducer of NRF2-dependent Hmox1 reporter activity in lung macrophages. Combined use of HPNEpC and in vivo reporters demonstrated that London roadside PM10 particles induced pneumococcal infection in HPNEpC mediated by oxidative stress responses. DiscussionThe combined use of in vivo reporter models with HPNEpC provides a robust approach to define the relationship between air pollutant exposure and health risks. These models can be used to hazard ranking environmental pollutants by considering the complexity of mechanisms of toxicity. These data will facilitate the relationship between toxic potential and the level of pollutant exposure in populations to be established and potentially extremely valuable tools for intervention studies.