EFFECTS OF DIHYDROTESTOSTERONE AND ESTRADIOL ON EXPERIMENTAL IGA NEPHROPATHY INDUCED BY VOMITOXIN

Ingestion of the trichothecene vomitoxin (VT) by mice induces effects that mimic the common human glomerulonephritis, IgA nephropathy (IgAN). These include elevation of serum IgA, IgA immune complexes, and mesangial IgA deposition. Based on previous observations that male mice are more prone to VT-induced IgAN, the effects of castration of male and female B6C3F1 mice and sex hormone supplementation on several immunopathologic indicators of the disease were compared. In the first study, castrated and intact male and female mice were fed control AIN-76A diet or the same diet containing 10 ppm VT for 12 weeks. At Week 12, all but the intact female group fed VT exhibited increased serum IgA, with castrated female mice having greater levels than intact females. When microscopic hematuria was used as an indicator of disease severity in intact VT-fed mice, erythrocyte counts for males exceeded those for females at weeks 4 and 12. VT-fed, castrated females exhibited greater hematuria than intact counterparts, whereas VT-fed, castrated males had lower urinary erythrocyte counts than intact counterparts. In a second study, castrated male and female mice were implanted with controlled release pellets of placebo, 5 alpha-dihydrotestosterone (DHT), or 17 beta-estradiol (E(2)) and then were fed either control diet or a 10 ppm VT diet for 8 weeks. Castrated male and female mice treated with VT and DHT pellet exhibited more severe hematuria, higher IgA levels, and greater mesangial IgA deposition than mice exposed to the same diet with placebo or E(2) pellet at Week 8. While VT-fed animals with an E(2) pellet exhibited greater hematuria and mesangial IgA deposition at Week 8 than the placebo groups, their IgA levels were not significantly elevated over those for VT-fed mice with a placebo pellet. Relative to two other pathologic markers for IgAN, the aforementioned effects in both studies were generally consistent with mesangial deposition of complement component C-3 but not IgG. The results suggest that (I) enhanced male susceptibility to VT-induced IgAN may be related to modulation by the biologically active androgen DHT and (2) while castration of females increased severity of VT-induced IgAN, supplementation of castrated male or female mice with E(2) did not reverse this effect but rather increased disease severity. (C) 1995 Society of Toxicology.