Nephrotoxicity of hexachloro-1:3-butadiene in the male Hanover Wistar rat; correlation of minimal histopathological changes with biomarkers of renal injury

ABSTRACT Hexachloro‐1:3‐butadiene (HCBD) causes damage specifically to the renal proximal tubule in rats. In the present study, injury to the nephron of male Hanover Wistar rats was characterized at 24 h following dosing with HCBD in the range 5–90 mg kg−1 to determine the most sensitive biomarkers of damage, that is, the biomarkers demonstrating significant changes at the lowest dose of HCBD, using a range of measurements in serum and urine, renal histopathology, and renal and hepatic gene expression. Histologically, kidney degeneration was noted at doses as low as 10 mg kg−1 HCBD. Significant changes in the hepatic and renal gene expression categories of xenobiotic metabolism and oxidative stress were observed at 5 mg kg−1 HCBD, and in the kidney alone, evidence of inflammation at 90 mg kg−1 HCBD. Increases in the urinary excretion of α‐glutathione S‐transferase (α‐GST) and kidney injury molecule‐1 (KIM‐1) were seen at 10 mg kg−1 HCBD, and increases in urinary excretion of albumin and total protein were evident at 15 mg kg−1 HCBD. The most sensitive, noninvasive biomarkers of HCBD‐induced renal toxicity in Hanover Wistar rats were urinary α‐GST and KIM‐1. Urinary albumin measurement is also recommended as, although it is not the most sensitive biomarker, together with α‐GST, albumin showed the largest relative increase of all the biomarkers investigated, and the protein is easily measured. Copyright © 2011 John Wiley & Sons, Ltd. Hexachloro‐1:3‐butadiene (HCBD)‐induced renal proximal tubule injury in male Hanover Wistar rats was characterized at 24 h following dosing with 5‐90 mg kg−1 HCBD. Onset of kidney degeneration and changes in urinary biomarkers occurred at 10 mg kg−1 HCBD; xenobiotic metabolism and oxidative stress gene expression changed at 5 mg kg−1 HCBD. The most sensitive noninvasive biomarkers were urinary α‐glutathione S‐transferase and kidney injury molecule‐1, with urinary albumin measurement recommended owing to ease of measurement and amplitude of biomarker signal.