Abstract
Hexachlorobutadiene (HCBD), a by-product for the synthesis of perchloroethylene and trichloroethylene and a prominent environmental pollutant, is one of the most nephrotoxic chlorinated hydrocarbons in rodents. Its organ-specific toxicity is based on a bioactivation mechanism that includes hepatic conjugation to produce penta-chlorobutadienyl-glutathione followed by conversion to (penta-chlorobutadienyl)-cysteine and subsequent enzymatic degradation to toxic metabolites by the enzyme GTK/β-lyase. 28-day old male W/A rats received HCBD at 25mg /kg, ip (low dose) or 100mg/kg , ip (high dose). Other groups received probenecid, an organic anion transport inhibitor, (0. 5mmol/kg, 1ml/kg, i. p) before and after HCBD injection. Post mortem light microscopic examination of the kidney showed substantial renal tubular necrosis in HCBD treated rats compare to those which received HCBD plus probenecid and control groups. After 4 to 7 days of exposure, renal tubular damage was decreased, and regeneration in the damaged areas of the kidney was observed. Concentrations of blood urea nitrogen in HCBD treated rats were elevated in the short-term exposure groups. GTK/p-lyase specific activity was lower than control in all the HCBD treated groups. In the HCBD treated groups, apoptotic cell death was demonstrated after 2-3 days using a TUNEL assay and regeneration was demonstrated by immuno-staining for the antigen PCNA.Light microscopic examination of H&E stained brain sections showed extended damage in the choroid plexus of the lateral and third ventricles in rats which had received 100mg /kg dose of HCBD. In groups treated with 25mg /kg of HCBD there was minor damage (minor hemorrhage in the lateral ventricles with pyknotic and mitotic figures in coroidal cells). Brain GTK specific activity in the high dose treated groups was lower than control. Further experiments in which rats were allowed to recover from HCBD treatment before further challenge with HCBD, indicated that the kidney and possibly choroid plexus remained resistant to HCBD toxicity for up to 3 weeks. This period of resistance appeared to coincide with a prolonged reduction of GTK β-lyase activity in these tissues compared to control. The results of this work clearly show that the toxicity of HCBD towards GTK /β-lyase containing cells and subsequent replacement of the damaged cells with cells resistant to HCBD toxicity, is not restricted to the kidney in the young male rat. The choroid plexus of the CNS (a tissue related developmentally to the kidney proximal tubule) is also a target for site-specific toxicity following exposure to HCBD.