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Effects of Real-Ambient PM_2.5 Exposure on Lung Damage Modulated by Nrf2^-/.

ABSTRACT: Previous studies have shown that long-term exposure to fine particulate matter (PM_2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM_2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM_2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2^-/- (KO) mice were exposed to the real-ambient system for six weeks. After PM_2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2^-/- mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM_2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM_2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM_2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM_2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM_2.5 exposure. Nrf2 facilitates lung injury during PM_2.5 exposure and CYP2E1 metabolism is involved in this process.

SUBMITTER: Ding H

PROVIDER: S-EPMC8104929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundStudies suggested that PM2.5 exposure could lead to adverse reproductive effects on male animals. However, the underlying mechanism is still not clear. Besides, animals in the majority of previous studies were exposed to PM2.5 through intratracheal instillation which should be improved. In addition, limited amount of research has been conducted in China where the PM2.5 concentration is higher and the PM2.5 components are different. The aim of this work is to explore the effects of concentrated ambient PM2.5 (CAP) on mice sperm quality and testosterone biosynthesis.MethodsA total of 12 male C57BL/6 mice were exposed to filtered air (FA) or CAP for 125 days using the Shanghai Meteorological and Environmental Animal Exposure System. The mice sperm concentration, sperm motility, DNA fragmentation index, high DNA stainability and plasma testosterone were analyzed. Testicular histology and sperm morphology were observed through optical microscope. Testosterone biosynthesis related gene expressions were analyzed using real-time PCR, including cytochrome P450 CHOL side-chain cleavage enzyme (P450scc), steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β HSD), 17β-hydroxysteroid dehydrogenase, cytochrome P450 aromatase (P450arom), estrogen receptor (ER), androgen receptor (AR) and follicle stimulating hormone receptor (FSHR).ResultsExposure to CAP resulted in disturbance of various stages of spermatogenesis and significant higher percentage of abnormal sperm (FA vs. CAP: 24.37% vs. 44.83%) in mice testis. CAP exposure significantly decreased sperm concentration (43.00 × 106 vs. 25.33 × 106) and motility (PR: 63.58% vs. 55.15%; PR + NP: 84.00% vs. 77.08%) in epididymis. Plasma testosterone concentration were significantly declined (0.28 ng/ml vs. 0.69 ng/ml) under CAP exposure. Notably, the levels of testosterone biosynthesis related genes, StAR, P450scc, P450arom, ER and FSHR were significantly decreased with CAP exposure.ConclusionConcentrated ambient PM2.5 exposure altered mice sperm concentration, motility and morphology, which might be mediated primarily by the decline in testosterone concentration and testosterone biosynthesis process.

Project description:BackgroundThe metabolomic signatures of short- and long-term exposure to PM2.5 have been reported and linked to inflammation and oxidative stress. However, little is known about the relative contribution of the specific PM2.5 species (hence sources) that drive these metabolomic signatures.ObjectivesWe aimed to determine the relative contribution of the different species of PM2.5 exposure to the perturbed metabolic pathways related to changes in the plasma metabolome.MethodsWe performed mass-spectrometry based metabolomic profiling of plasma samples among men from the Normative Aging Study to identify metabolic pathways associated with PM2.5 species. The exposure windows included short-term (one, seven-, and thirty-day moving average) and long-term (one year moving average). We used linear mixed-effect regression with subject-specific intercepts while simultaneously adjusting for PM2.5, NO2, O3, temperature, relative humidity, and covariates and correcting for multiple testing. We also used independent component analysis (ICA) to examine the relative contribution of patterns of PM2.5 species.ResultsBetween 2000 and 2016, 456 men provided 648 blood samples, in which 1158 metabolites were quantified. We chose 305 metabolites for the short-term and 288 metabolites for the long-term exposure in this analysis that were significantly associated (p-value < 0.01) with PM2.5 to include in our PM2.5 species analysis. On average, men were 75.0 years old and their body mass index was 27.7 kg/m2. Only 3% were current smokers. In the adjusted models, ultrafine particles (UFPs) were the most significant species of short-term PM2.5 exposure followed by nickel, vanadium, potassium, silicon, and aluminum. Black carbon, vanadium, zinc, nickel, iron, copper, and selenium were the significant species of long-term PM2.5 exposure. We identified several metabolic pathways perturbed with PM2.5 species including glycerophospholipid, sphingolipid, and glutathione. These pathways are involved in inflammation, oxidative stress, immunity, and nucleic acid damage and repair. Results were overlapped with the ICA.ConclusionsWe identified several significant perturbed plasma metabolites and metabolic pathways associated with exposure to PM2.5 species. These species are associated with traffic, fuel oil, and wood smoke. This is the largest study to report a metabolomic signature of PM2.5 species' exposure and the first to use ICA.

Project description:IntroductionLong-term exposure to ambient air pollution is related to major cardiovascular risk factors including diabetes, hypertension, hyperlipidemia and overweight, but with few studies in high-concentration nations like China so far. We aimed to investigate the association between long-term exposure to ambient fine particulate matter (particles with an aerodynamic diameter ≤ 2.5 μm, PM2.5) and major cardiovascular risk factors in China.MethodsAdult participants with selected biochemical tests were recruited from the Chinese Physiological Constant and Health Condition (CPCHC) survey conducted from 2007 to 2011. Gridded PM2.5 data used were derived from satellite-observed data with adjustment of ground-observed data. District-level PM2.5 data were generated to estimate the association using multivariate logistic regression model and generalized additive model.ResultsA total of 19,236 participants from the CPCHC survey were included with an average age of 42.8 ± 16.1 years, of which nearly half were male (47.0%). The annual average PM2.5 exposure before the CPCHC survey was 33.4 (14.8-53.4) μg/m3, ranging from 8.0 μg/m3 (Xiwuqi) to 94.7 μg/m3 (Chengdu). Elevated PM2.5 was associated with increased prevalence of hypertension (odds ratio (OR) =1.022, 95% confidence interval (95%CI): 1.001, 1.043) and decreased prevalence of overweight (OR = 0.926, 95%CI: 0.910, 0.942). Education significantly interacted with PM2.5 in association with all the interesting risk factors. Each 10 μg/m3 increment of PM2.5 was associated with increased prevalence of diabetes (OR = 1.118, 95%CI: 1.037, 1.206), hypertension (OR = 1.101, 95%CI: 1.056, 1.147), overweight (OR = 1.071, 95%CI: 1.030, 1.114) in participants with poor education, but not in well-educated population. PM2.5 exposure was negatively associated with hyperlipidemia in all participants (OR = 0.939, 95%CI: 0.921, 0.957). The results were robust in all the sensitivity analyses.ConclusionAssociation between long-term PM2.5 exposure and cardiovascular risk factors might be modified by education. PM2.5 was associated with a higher prevalence of diabetes, hypertension, and overweight in a less-educated population with time-expose dependency. Long-term exposure to PM2.5 might be associated with a lower prevalence of hyperlipidemia.

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Effects of Real-Ambient PM_2.5 Exposure on Lung Damage Modulated by Nrf2^-/.

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Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2-/.

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OmicsDI is part of the ELIXIR infrastructure

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Effects of Real-Ambient PM_2.5 Exposure on Lung Damage Modulated by Nrf2^-/.