Dm. Greene et al., EFFECTS OF DIHYDROTESTOSTERONE AND ESTRADIOL ON EXPERIMENTAL IGA NEPHROPATHY INDUCED BY VOMITOXIN, Fundamental and applied toxicology, 26(1), 1995, pp. 107-116
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 mesa
ngial IgA deposition. Based on previous observations that male mice ar
e more prone to VT-induced IgAN, the effects of castration of male and
female B6C3F1 mice and sex hormone supplementation on several immunop
athologic indicators of the disease were compared. In the first study,
castrated and intact male and female mice were fed control AIN-76A di
et 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, wit
h castrated female mice having greater levels than intact females. Whe
n microscopic hematuria was used as an indicator of disease severity i
n 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 h
ad lower urinary erythrocyte counts than intact counterparts. In a sec
ond study, castrated male and female mice were implanted with controll
ed release pellets of placebo, 5 alpha-dihydrotestosterone (DHT), or 1
7 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 V
T and DHT pellet exhibited more severe hematuria, higher IgA levels, a
nd 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 significant
ly 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) en
hanced male susceptibility to VT-induced IgAN may be related to modula
tion by the biologically active androgen DHT and (2) while castration
of females increased severity of VT-induced IgAN, supplementation of c
astrated male or female mice with E(2) did not reverse this effect but
rather increased disease severity. (C) 1995 Society of Toxicology.