Sex Differences in the Localization and Severity of Ferric Nitrilotriacetate‐induced Lipid Peroxidation in the Mouse Kidney

Male mice are much more susceptible than female mice to acute renal proximal tubular necrosis as well as the carcinogenic effect induced by an iron chelate, ferric nitrilotriacetate (Fe‐NTA). In the present study, iron‐promoted lipid peroxidation was analyzed histochemically in frozen kidney sections using cold Schiffs reagent and biochemically by measuring thiobarbituric acid‐reactive substance in the kidney. When untreated mouse frozen kidney sections were exposed to ascorbic acid‐Fe‐NTA (0.8 mM, 0.2 mM and 0.4 mM) in vitro for 40 min and washed, diffuse Schiff positivity was obtained along the proximal tubules, and no sex differences were evident. When non‐reduced Fe‐NTA (0.2 mM and 0.4 mM) was layered on untreated kidney sections from males, about half of the cortical proximal tubules showed a positive reaction with Schiffs reagent, whereas in females the proximal tubules of the outer stripe of the outer medulla were positive. In an ex vivo study, 30 to 40 min after i.p. injection of Fe‐NTA (5 mg Fe/kg), Schiff‐positive areas corresponded to those observed in the in vitro non‐reduced Fe‐NTA study in each sex. However, in males, the positive tubular cells gradually became necrotic, whereas in females the positivity disappeared with time and there was no tubular necrosis. Results of the thiobarbituric acid test were correlated with the above findings. In conclusion, the localization and severity of FeNTA induced lipid peroxidation in the tubules differed between the sexes. We suspect that these results reflect functional heterogeneity in the ability of the tubules to reduce iron.