Abstract
It is generally accepted that exposure to particulate matter (PM) increases the risk of cardiovascular-related morbidity and mortality, though the exact mechanism behind this has yet to be elucidated. Oxidative stress plays a potentially important role in the mechanism of toxicity, with Nrf2 serving as a major antioxidant gene. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential cardiotoxicity induced by real-ambient PM exposure and the potential role of Nrf2 and related signaling in this endpoint. After 6- or 11-weeks exposure to PM, ICP-mass spectrometry was used to assess the metal depositions in the heart tissue following PM exposure. Functional and morphological changes in the hearts were investigated with echocardiography and histopathology, and oxidative stress levels were assessed with a serum malondialdehyde content assay. In the further mechanistic study, an RNA-seq technique was utilized to assess the gene transcription status in the hearts of C57/B6 mice exposed to PM with or without Nrf2 knockout. The expression levels of genes of interest were then further investigated with quantitative real-time PCR and western blotting. The results indicated that PM exposure resulted in significant elevation of sodium, potassium, selenium, and ferrum levels in mouse heart tissue. Meanwhile, significantly altered heart function and morphology were observed. Interestingly, Nrf2 knockout led to abolishment of PM-induced effects in several functional parameters but not the morphological changes. Meanwhile, elevated malondialdehyde content was observed in Nrf2 knockout animals. RNA-seq results revealed thousands of genes altered by PM exposure and/or Nrf2 knockout, and this affected several pathways, such as MAPK, phagosome, calcium signaling, and JAK-STAT. In subsequent molecular studies, enhanced nuclear translocation of Nrf2 was also observed following PM exposure, while the MAPK signaling pathway along with related JAK-STAT and TGF-β1 pathway genes, such as p38MAPK, AKT, TAK1, JAK1, STAT3, GRB2, TGFb1, and SMAD2, were confirmed to be affected by PM exposure and/or Nrf2 knockout. The data suggested that PM may induce cardiotoxicity in C57/B6 mice in which Nrf2 plays both protective and detrimental roles involving cardiac-related pathways, such as MAPK, JAK-STAT, and TGF-β1.
Highlights
Exposure to particulate matter (PM) is an environmental risk factor for human health
The results (Figure 5) indicated that the phosphorylated SMAD2 levels were significantly increased by nuclear factor (erythroid-derived 2)-like 2 (Nrf2) knockout, but they were effectively decreased by PM exposure; PM exposure remarkably elevated the phosphorylation levels of p38MAPK, while Nrf2 knockout enhanced the phosphorylation even further
While no significant changes were detected in phosphorylated JAK1 levels, elevated Grb2 and phosphorylated STAT3 expression levels were observed following PM exposure, which were effectively decreased in Nrf2 knockout animals comparing to wildtype counterparts
Summary
Exposure to particulate matter (PM) is an environmental risk factor for human health. The relatively small size of PMs, especially the PMs with a diameter smaller than 2.5 um (PM2.5) allows them to be inhaled into deeper respiratory tracts, even into the circulatory system, and to induce detrimental health effects within the cardiopulmonary system (Brook et al, 2004; Almendra et al, 2017). While developed countries, such as the United States and Japan, displayed acceptable levels of ambient PM, some areas of the world displayed relatively high levels, far beyond the healthy levels set by the World Health Organization (Puett et al, 2011; Zhou et al, 2015; Gorai et al, 2018; Khan et al, 2018), posing a significant threat to human health. Further investigation is urgently needed to facilitate a better understanding of PM-induced cardiotoxicity and risk assessment
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