title: In-vivo evidence of nephrotoxicity and altered hepatic function in rats following administration of diglycolic acid, a metabolite of diethylene glycol.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Pharmacology, Toxicology and Neuroscience , Louisiana State University Health Sciences Center - Shreveport , Shreveport , LA , USA.
authors.forename: Corie N
authors.initials: CN
authors.lastname: Robinson
authors.affiliation: a Department of Pharmacology, Toxicology and Neuroscience , Louisiana State University Health Sciences Center - Shreveport , Shreveport , LA , USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Latimer
authors.affiliation: b Department of Pathology , Louisiana State University Health Sciences Center - Shreveport , Shreveport , LA , USA.
authors.forename: Fleurette
authors.initials: F
authors.lastname: Abreo
authors.affiliation: c Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Kiera
authors.initials: K
authors.lastname: Broussard
authors.affiliation: a Department of Pharmacology, Toxicology and Neuroscience , Louisiana State University Health Sciences Center - Shreveport , Shreveport , LA , USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: McMartin
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006016:Glycolates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D006016:Glycolates; C571256:diglycolic acid
keywords: Diglycolic acid; diethylene glycol; hepatotoxicity; metabolite toxicity; nephrotoxicity