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Lipid peroxidation: a possible mechanism of trichloroethylene-induced nephrotoxicity
Abstract:
The purpose of this study was to investigate whether lipid peroxidation plays a role in (TCE) trichloroethylene-induced nephrotoxicity in mice at different oxygen concentrations. Male NMRI mice (25-30 g) were treated i.p. with TCE in a dosage of 125-1000 mg/kg in sesame oil. To determine the TCE-induced depletion of reduced glutathione (GSH) in the kidney cortex and liver tissue, mice were given 1000 mg/kg TCE i.p., then killed between 0 and 6 h after TCE administration and GSH was measured was non-protein sulfhydryls. In another series of experiments, mice were administered 125 to 1000 mg/kg TCE i.p. with or without a 2 h i.p. pretreatment with 1500 mg/kg L-buthionine-S-R-sulfoximine (BSO). Mice were then exposed to a 10, 15, 20 or 100% oxygen atmosphere for 3 h and lipid peroxidation in vivo was measured as exhalation of ethane. Subsequently, mice were killed and malondialdehyde (MDA) generation was measured in the liver and kidney cortex. Ethane evolution was estimated by gas chromatography and MDA was determined as thiobarbituric acid reactive substances. In a further series of experiments mice were treated in the same manner as for ethane and MDA determination and the changes in blood urea nitrogen (BUN) and accumulation of the organic ion p-aminohippurate (PAH) were determined. PAH accumulation by renal cortical slices were measured as the slice to medium (S/M) ratio. Six hours after administration of 1000 mg/kg TCE to mice, GSH was significantly depleted to about 60% of control in the kidney cortex but not in the liver. Three hours after TCE administration, MDA content in the kidney cortex and ethane exhalation increased in a dose-dependent manner only under a 10% oxygen atmosphere. Under the same experimental conditions, MDA content remained unchanged in the liver. BSO depletion of GSH prior TCE administration induced an increase of the MDA content in the kidney cortex and an increase of the ethane exhalation in vivo. At 10% oxygen concentration, TCE induced a dose-dependent increase in BUN and a dose-dependent decrease of PAH accumulation by the renal cortical slices. Thus, the results of the present study suggest that, under hypoxic conditions, lipid peroxidation plays a role in TCE nephrotoxicity.
Insights
Trichloroethylene (TCE) causes kidney damage by increasing lipid peroxidation under low oxygen conditions. This study shows that reduced glutathione depletion exacerbates TCE-induced nephrotoxicity, highlighting the role of oxidative stress in hypoxic environments.
Area of Science:
- Toxicology
- Environmental Health
- Biochemistry
Background:
- Trichloroethylene (TCE) is a common environmental pollutant.
- TCE exposure can lead to kidney damage (nephrotoxicity).
- The role of oxidative stress, specifically lipid peroxidation, in TCE-induced nephrotoxicity is not fully understood, especially under varying oxygen concentrations.
Purpose of the Study:
- To investigate the role of lipid peroxidation in trichloroethylene (TCE)-induced nephrotoxicity in mice.
- To examine the influence of different oxygen concentrations on TCE-induced kidney damage.
- To assess the relationship between glutathione levels and TCE-induced oxidative stress.
Main Methods:
- Mice were administered varying doses of TCE (125-1000 mg/kg).
- Reduced glutathione (GSH) levels were measured in kidney and liver tissue.
- Lipid peroxidation was assessed by measuring ethane exhalation and malondialdehyde (MDA) generation.
- Kidney function was evaluated by measuring blood urea nitrogen (BUN) and p-aminohippurate (PAH) accumulation.
- Mice were exposed to different oxygen concentrations (10%, 15%, 20%, 100%).
- Some mice were pretreated with L-buthionine-S-R-sulfoximine (BSO) to deplete GSH.
Main Results:
- TCE significantly depleted kidney GSH levels but not liver GSH.
- Lipid peroxidation (ethane exhalation and MDA) and kidney damage (increased BUN, decreased PAH accumulation) were observed in a dose-dependent manner under hypoxic (10% oxygen) conditions.
- BSO pretreatment enhanced TCE-induced lipid peroxidation.
- MDA levels in the kidney cortex and ethane exhalation increased with BSO pretreatment.
- TCE-induced nephrotoxicity was more pronounced under hypoxic conditions.
Conclusions:
- Lipid peroxidation plays a significant role in trichloroethylene (TCE)-induced nephrotoxicity, particularly under hypoxic conditions.
- Reduced glutathione depletion exacerbates TCE-induced oxidative stress and kidney damage.
- These findings suggest that oxidative stress mechanisms are critical in the development of TCE nephrotoxicity in low-oxygen environments.