Sex-related differences and segmentary damage of proximal tubule due to hexachloro-1:3-butadiene in rats

Hexachloro-1:3-butadiene (HCBD) is known to cause kidney damage, in particular on pars recta of the proximal tubule. Recently, glutamine synthetase in urine (GSU) and renal tissue (GSK) was determined as early and segment-specific marker of pars recta involvement after treatment of rats with the solvent. The present research studied the sex-related differences in rats concerning pars recta after treatment with HCBD. Male and female (20010 g) Wistar rats were treated with a single i.p. injection of 0, 50, 100 or 200 mg/kg (five animals each group) of HCBD. Urines were collected every 14 (nocturnal) or 10 (diurnal) hours along the experimental period (48 hours), and rats were sacrificed 24 or 48 hours after treatment. GSU and GSK were determined according to (2) and related to creatinine (GSU) or tissue proteins (GSK). Light microscopy was performed 24 and 48 hours after treatment. The dose-dependent urinary profile of GSU excretion appeared similar in both sexes, with a peak after 24 hours in rats treated with 50 or 100 mg/kg, and after 10 hours with 200 mg/kg. On the other hand, female rats showed a higher excretion of the enzyme than male ones, at a significant level (p<0.001) for the lower dose. GSK showed a significant, dose-dependent decrease in both sexes, but female rats had a significant decrease 48 hours after treatment of GSK (p<0.001) at the all doses, and 24 hours after treatment at 50 mg/kg (p<0.001) relative to male ones. Light microscopy confirmed that only pars recta is affected by HCBD, the lesion ranging from focal to diffuse necrosis, according to the dose; female rats show an earlier and larger damage. The data confirm that 1) HCBD effects are specific on pars recta of the proximal tubule, and that 2) GSU and GSK are early, sensitive and specific markers of damage of this segment. In addition, female rats show a significantly higher susceptibility to HCBD, as demonstrated by higher enzyme excretion in urine, higher enzyme decrease in renal tissue, earlier and larger necrosis of the tubule. The data are in contrast with other previous researches that found a higher susceptibility in male rats.