Diethylene glycol produces nephrotoxic and neurotoxic effects in female rats

Abstract

Context

Diethylene glycol (DEG) is an organic compound found in household products but also as a counterfeit solvent in medicines. DEG poisonings are characterized by acute kidney injury (AKI) and by neurological sequelae such as decreased reflexes or face and limb weakness. Previous studies in male rats have demonstrated that neurotoxic effects develop only with the establishment of AKI, but the dose sensitivity of females to DEG toxicity is unknown.

Objectives

Assessing whether subacute administration of DEG in female rats would delineate any sex-differences in neuropathy or in kidney injury.

Methods

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

Results

Of 12 animals treated with DEG, 3 developed AKI as confirmed by increased BUN and creatinine concentrations. Renal and brain DGA contents were increased in animals that developed AKI compared to animals without AKI. Total CSF protein content in animals with AKI was markedly elevated compared to control and to treated animals without AKI. Decreases in forelimb grip strength and 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 a female model produced nephrotoxic effects at a dose similar to that in males. The decrease in motor function and increase in CSF protein were only present in females that developed AKI. However, kidney and neurologic effects were assessed only at the end of the treatments, thus limiting determination of which effect occurs first. Limb function and coordination were measured globally and more sensitive tests such as nerve conduction studies might offer a detailed neurotoxicity assessment of the effects of DEG.

Conclusions

These studies show that DEG toxicity does not appear to be sex-specific and that, in males and females, neurological symptoms are present only when DGA accumulation and kidney injury also occur.

Keywords:

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

Acknowledgements

The authors thank Mychal Grames for his assistance with animal training. Thanks to Julie Tobin and Noel Jacquet for their technical assistance during urine and 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 the NIH, grant R15 ES029704.