In-vivo evidence of nephrotoxicity and altered hepatic function in rats following administration of diglycolic acid, a metabolite of diethylene glycol

Abstract

Context: Diglycolic acid (DGA) is one of the two primary metabolites of diethylene glycol (DEG). DEG is an industrial solvent that has been implicated in mass poisonings resulting from product misuse in the United States and worldwide, with the hallmark toxicity being acute kidney injury, hepatotoxicity, encephalopathy and peripheral neuropathy. Our laboratory has generated in-vitro evidence suggesting that DGA is the metabolite responsible for the proximal tubule necrosis and decreased kidney function observed following DEG ingestion. Furthermore, we have shown that DGA specifically accumulates in kidney tissues (100× higher than peak blood concentrations) following DEG administration.

Objective: To examine renal and hepatic accumulation and dysfunction following direct administration of DGA in-vivo. We hypothesize that administration of DGA will result in renal and hepatic DGA accumulation, as well as proximal tubular necrosis and liver injury.

Materials and methods: Adult male Wistar rats were divided into three groups dosed with 0, 100 or 300 mg/kg DGA via single oral gavage. Urine was collected every 6–12 h and blood, kidneys and liver were removed upon sacrifice at 48 h post-dosing for analysis.

Results: DGA accumulated significantly in both kidney and liver tissue only at 300 mg DGA/kg. DGA concentrations in the kidneys and liver correlated with renal and hepatic injury, respectively. Histopathological and clinical chemistry analysis revealed that DGA-treated animals exhibited moderate liver fatty accumulation and marked renal injury, again only at 300 mg/kg.

Discussion: DGA-induced kidney injury demonstrated a steep dose response threshold, where severe damage occurred only in animals given 300 mg/kg DGA, while no toxicity was observed at 100 mg/kg.

Conclusion: These results provide evidence for in-vivo toxicity following direct administration of DGA, a metabolite of DEG. The steep dose–response threshold for toxicity suggests mechanistically that there is likely a saturable step that results in DGA accumulation in target organs.

Keywords:

• Diglycolic acid
• diethylene glycol
• nephrotoxicity
• hepatotoxicity
• metabolite toxicity

Acknowledgements

The authors would like to thank Kimberly McCarter and Kasey Jackson for their assistance with animal handling. Thanks to Elliot Luttrell-Williams, Sam Crooks, Ashton Jorgensen and Cody Dunning for their technical assistance during tissue collection.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This research was supported by a research agreement with the Ethylene Glycol/Ethylene Oxide Panel of the American Chemistry Council. Members of the Panel include BASF Corporation, Dow Chemical Company, Eastman Chemical Company and Shell Chemical.