NMR-based metabolomics to characterize naphthalene toxicity in mouse respiratory system
Date Issued
2010
Date
2010
Author(s)
Hong, Wan-Jen
Abstract
Pulmonary diseases have reached their transboundary properties and pose significant impact to human. Clara cell, a susceptible tracheobronchial epithelial cell type, is injured via CYP450-dependent metabolic activation when reactive intermediates of various environmental xenobiotics are produced. Naphthalene is a major polycyclic aromatic hydrocarbon in ambient polluted air, and has been demonstrated possible carcinogenic from animal investigations.
Metabolomics and histopathology approaches are applied to examine naphthalene toxicity in a susceptible species, mouse, using ip administration. Dose response and time course experiments were carried out in male ICR mice whose bronchoalveolar lavage fluid (BALF) and lung were then taken for metabolic analysis. BALF and the lung metabolomes were analyzed by using 1D 1H and 2D JRES NMR following principal component analysis (PCA). Mouse lung was embedded and examined by light and electron microscopes on morphologic changes.
Unsupervised PCA results of BALF and lung metabolomes noted a clear trend of naphthalene dose and time effects. Elevated ethane and acetone from BALF suggested a correlation between naphthalene-induced lipid peroxidation and loss of membrane integrity. Decreased glycerophosphocholine, result of higher dose effects, failed to serve as a pro-phospholipid source and an osmoregulator for cell membranes which eventually results in swollen and vacuolated Clara cells. Sphingomyeline in lung were found increased in 200 mg/kg dose and may be related to programmed cell death as a self-protection strategy. The amount of acetone in lung increased at 12 h post-dose has indicated the early initiation of lipid peroxidation before 12 h. It is postulated to accumulate in lung lipophilic layer in view of no huge difference from BALF investigation.
This study design can be used in investigating pathogenesis of diseases and related biomarker development. Non-invasive screening method can be further applied in human. Due to inadequate molecular information provided by epidemiology and histopathology, metabolomics hereby excavates correlated biochemical mechanisms. The underlying mechanisms will be very informative to disease prevention, therapy, or new drug design. Such breakthrough is as a milestone.
Subjects
naphthalene
Clara cell
lung disease
nuclear magnetic resonance(NMR)
metabolomics
metabonomics
bronchoalveolar lavage fluid
histopathology
SDGs
Type
thesis
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