Neurotoxic effects of nephrotoxic compound diethylene glycol

Abstract

Context

Diethylene glycol (DEG) is an organic compound found in household products but also as an adulterant in medicines by acting as a counterfeit solvent. DEG poisonings have been characterized predominately by acute kidney injury (AKI), but also by delayed neurological sequelae such as decreased reflexes or face and limb weakness.

Objectives

Characterizing the neurological symptoms of DEG poisoning in a subacute animal model would create a clearer picture of overall toxicity and possibly make mechanistic connections between kidney injury and neuropathy.

Methods

Male Wistar-Han rats were orally administered doses of 4 − 6 g/kg DEG every 12 or 24 h and monitored for 7 days. Urine was collected every 12 h and endpoint blood and cerebrospinal fluid (CSF) were collected for a renal plasma panel and total protein estimation, respectively. Motor function tests were conducted before and after treatment. Kidney and brain tissue was harvested for metabolic analysis.

Results

Of the 43 animals treated with DEG, 11 developed AKI as confirmed by increased BUN and creatinine levels. Renal and brain DGA accumulation was markedly increased in animals that developed AKI compared to animals without AKI. The total protein content in CSF in animals with kidney injury was markedly elevated compared to control and to treated animals without AKI. Significant decreases in forelimb grip strength and decreases in locomotor and rearing activity were observed in animals with AKI compared to control and to animals without AKI.

Discussion

Repeated dosing with DEG in an animal model produced nephrotoxic effects like those in studies with acute DEG administration. The decrease in motor function and increase in CSF protein were only present in animals that developed AKI.

Conclusions

These studies show development of neurotoxicity in this DEG animal model and suggest that neurological symptoms are observed only when DGA accumulation and kidney injury also occur.

Keywords:

• Diethylene glycol
• diglycolic acid
• nephrotoxicity
• neurotoxicity
• cerebrospinal fluid
• motor function
• metabolite toxicity

Acknowledgements

The authors would like to thank Mychal Grames for his assistance with animal training. Thanks to Julie Tobin, Noel Jacquet, and Jacqueline Baines for their technical assistance during urine and tissue collection.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the NIH, grant R15 ES029704.