Defining the in vivo mechanism of air pollutant toxicity using murine stress response biomarkers

Francisco Inesta-Vaquera, Lisa Miyashita, Jonathan Grigg, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
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Abstract

Air 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. We exemplify for a first time the application of in vivo stress response reporters in establishing mechanisms of air pollution toxicity and the application of this knowledge in epidemiological studies. We first demonstrated the utility of reporter mice to understand toxicity mechanisms of air pollutants using diesel exhaust particles compounds. We observed that nitro-PAHs induced Hmox1 and CYP1a1 reporters in a time- and dose-dependent, cell- and tissue-specific manner. Using in vivo genetic and pharmacological approaches we confirmed that the NRF2 pathway mediated this Hmox1-reporter induction stress reporter activity. We then correlated the activation of stress-reporter models (oxidative stress/inflammation, DNA damage and Ah receptor -AhR- activity) with responses in primary human nasal cells exposed to chemicals present in particulate matter (PM; PM2.5-SRM2975, PM10-SRM1648b) or fresh roadside PM10. To exemplify their use in clinical studies, Pneumococcal adhesion was assessed in exposed primary human nasal epithelial cells (HPNEpC). The combined use of HPNEpC and in vivo reporters demonstrated that London roadside PM10 particles induced pneumococcal infection in HPNEpC mediated by oxidative stress responses. The combined use of in vivo reporter models with human data thus provides a robust approach to define the relationship between air pollutant exposure and health risks. Moreover, these models can be used in epidemiological studies 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 for disease prevention.
Original languageEnglish
Article number164211
Number of pages19
JournalScience of the Total Environment
Volume888
Early online date15 May 2023
DOIs
Publication statusPublished - 25 Aug 2023

Keywords

  • Air pollution
  • Biomarker
  • Epidemiological studies
  • Mechanism of toxicity

ASJC Scopus subject areas

  • Pollution
  • Waste Management and Disposal
  • Environmental Engineering
  • Environmental Chemistry

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