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Naphthalene, the most common polyaromatic hydrocarbons, exists widely in the
environment with significant human exposure. Naphthalene has been demonstrated
possible carcinogenic from animal investigations. Previous studies have also
demonstrated that naphthalene causes bronchiolar epithelial necrosis in mouse
distal airway, after parenteral administration. The toxic effects are species
and site selective. Formation of reactive metabolites and depletion of
glutathione have been correlated with naphthalene-induced cell injury in mice.
Our hypothesis is that naphthalene disrupts intracellular homeostasis and causes
metabolic turbulences which can be monitored and associated with cell injury in
urine. Metabolomic measurements from non-invasive samples can be applied in
exposed human populations to assess the health effects of exposure to
environmental toxicants in the future.
High-resolution 1H nuclear magnetic resonance (NMR) followed by principal
component analysis (PCA) was applied to characterize metabolic effects of
naphthalene in leading to cell injury in a susceptible species, mouse.
Dose-response (0, 100, 200mg/kg) and time course (12, 24, 36, 48 hrs)
experiments were conducted in mice, after parenteral administration. Urine
samples were collected for NMR-based metabolomic analysis. Both naphthalene
metabolites and endogenous metabolites were examined and correlated to the
progress of cell injury.
Most of naphthalene metabolites including N-acetyl cysteine naphthalene diol
epoxide conjugate and N-acetyl cysteine naphthalene conjugate were appeared in
the NMR spectra of urine at the first 12 hours. Results of PCA from 1H NMR
spectra of urine samples demonstrated dose-response relationship between
naphthalene concentration and urine metabolome at early time points. Partially
recovery of urine metabolome was observed at the late time point. Several
selected metabolites were semi-quantified by comparing to the control group.
Significantly decrease of endogenous metabolites including citrate and
2-oxoglutarate were found from urine of mice treated with high concentration of
naphthalene for 12 hours. In addition, the amount of taurine from urine of mice
was significantly decreased despite naphthalene doses and time periods after
doses.
In conclusion, metabolic effects of naphthalene to mice are dose- and
time-dependent. We suggest that the decrease of taurine may be due to
consumption of glutathione to conjugate to naphthalene electrophilic
metabolites. Therefore, little amount of cysteine was available to synthesize
taurine.
The research was supported by National Health Research Institutes
(NHRI-EX100-9915EC) in Taiwan.