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Lipid peroxidation index of particulate matter: Novel metric for quantifying intrinsic oxidative potential and predicting toxic responses.

ABSTRACT: Using particulate matter (PM) mass as exposure metric does not reveal the intrinsic PM chemical characteristics or toxic potential, which is crucial for monitoring the sources of emission causing adverse health effects and developing risk mitigating strategies. Oxidative stress and ensuing lipid peroxidation (LPO) in the lung are crucial underlying mechanisms of action by which PM drives cardiorespiratory disease. In the current study, we have postulated and demonstrated that the intrinsic potential of PM to elicit LPO, defined as "LPO index" as a novel approach for characterizing oxidative potential of PM (PM^OP) and predicting biological toxicity. First, we exposed unsaturated phosphatidylcholine (PC), an abundant phospholipid in the cell membrane, pulmonary surfactant, and lipoproteins to PM and analyzed the total burden of LPO byproducts generated as a measure of LPO index using a LPO reporter dye, BODIPY-C11. PM exposure resulted in a concentration-dependent increase in LPO. Second, we developed a novel method to expose the captured serum apoB100 lipoprotein particles to PM or its constituents and assessed the levels of specific oxidized-phospholipid on apoB100 particles by immunoassay using E06 monoclonal antibody (mab) that recognizes only PC containing oxidized-phospholipids (Ox-PCs). The immunoassay was highly sensitive to evaluate the PM LPO index and was modifiable by metal quenchers and exogenous antioxidant and radical quenchers. Third, to prove the pathophysiological relevance of Ox-PCs, we found that PM exposure generates Ox-PCs in mice lungs, pulmonary surfactant and lung cells. Fourth, we observed that treatment of macrophages with BAL fluid from PM exposed mice or PM-exposed pulmonary surfactant stimulated IL-6 production, which was abrogated by neutralization of Ox-PCs by mab E06 suggesting that Ox-PCs in lungs are proinflammatory. Overall, our study suggests that Ox-PCs as a probe of PM LPO index is a biologically relevant pathogenic biomarker and has a high value for evaluating PM^OP.

SUBMITTER: Dey SK

PROVIDER: S-EPMC8633009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Numerous toxicological studies have highlighted the association between urban particulate matter (PM) and increased respiratory infections and lung diseases. The adverse impact on the lungs is directly linked to the complex composition of particulate matter, initiating reactive oxygen species (ROS) production and consequent lipid peroxidation. Excessive ROS, particularly within mitochondria, can destroy subcellular organelles through various pathways. In this study, we confirmed the induction of ferroptosis, an iron-dependent cell death, upon exposure to an urban PM using RT-qPCR and signaling pathway analysis. We used KRISS CRM 109-02-004, the certified reference material for the analysis of particulate matter, produced by the Korea Research Institute of Standards and Science (KRISS). To validate that ferroptosis causes lung endothelial toxicity, we assessed intracellular mitochondrial potential, ROS overproduction, lipid peroxidation, and specific ferroptosis biomarkers. Following exposure to the urban PM, a significant increase in ROS generation and a decrease in mitochondrial potential were observed. Furthermore, it induced hallmarks of ferroptosis, including the accumulation of lipid peroxidation, the loss of antioxidant defenses, and cellular iron accumulation. In addition, the occurrence of oxidative stress as a key feature of ferroptosis was confirmed by increased expression levels of specific oxidative stress markers such as NQO1, CYP1B1, FTH1, SOD2, and NRF. Finally, a significant increase in key ferroptosis markers was observed, including xCT/SLC7A11, NQO1, TRIM16, HMOX-1, FTL, FTH1, CYP1B1, CHAC1, and GPX4. This provides evidence that elevated ROS levels induce oxidative stress, which ultimately triggers ferroptosis. In conclusion, our results show that the urban PM, KRISS CRM, induces cellular and mitochondrial ROS production, leading to oxidative stress and subsequent ferroptosis. These results suggest that it may induce ferroptosis through ROS generation and may offer potential strategies for the treatment of lung diseases.

Project description:BackgroundParticulate matter ≤10 μm in aerodynamic diameter (PM10) and diet quality are risk factors for systemic inflammation, which is associated with preterm birth (PTB). PM10 and a pro-inflammatory diet (assessed by the Dietary Inflammatory Index [DII®]) have been individually evaluated as causes of PTB and differences by offspring sex have been reported for the DII. However, additional studies are needed to evaluate joint effects of these associations to inform intervention efforts.ObjectivesTo evaluate the independent and joint effects of PM10 and energy-adjusted DII (E-DII) on PTB risks.MethodsPM10 estimates were generated from daily citywide averages for 1216 pregnant women from three subcohorts of the Early Life Exposures in Mexico to Environmental Toxicants study using data from the Mexico City Outdoor Air Monitoring Network. Among a subset of participants (N = 620), E-DII scores were calculated using a validated food frequency questionnaire. Cox Proportional Hazards models were run for select periods during pregnancy and entire pregnancy averages for E-DII and PM10. We assessed for potential non-linear associations using natural splines.ResultsIn adjusted models, PM10 exposure was associated with increased risks of PTB for a range of values (58-72 μg/m3) during the second trimester, while negative associations were seen during the second (≥74 μg/m3) and third trimesters (55-65 μg/m3). Analyses conducted using distributed lag models for periods closer to delivery (max lag = 90) did not show negative associations between PM10 exposure and preterm birth, and indeed positive significant associations were observed (estimates and figures). E-DII was not associated with PTB and there was no evidence of effect modification by infant sex. There was no evidence of interaction between PM10 and E-DII and the risk of preterm birth.DiscussionAssociations between PM10 and PTB in Mexico City varied over time and across levels of PM10. Our findings of negative associations in the second and third trimesters, which are contrary to the hypothesized relationship between PM10 and PTB, may be due to a number of factors, including live birth bias and the exposure period evaluated. Differences in results for the periods evaluated suggest that PM10 from shorter exposure windows may play a more proximal role in initiating preterm labor.

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Lipid peroxidation index of particulate matter: Novel metric for quantifying intrinsic oxidative potential and predicting toxic responses.

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