Gender-related differences in subacute fumonisin B-1 hepatotoxicity in BALB/c mice

Fumonisin B-1 (FB1), a potent mycotoxin prevalent in corn, is a carcinogen and causative agent of various animal diseases. Species and sex variations to chronic FB1 toxicity have been reported. Free sphingoid bases and cytoki ne levels are the two major biochemical alterations of FB1 in vivo and may explain any sex differences in FB1 toxicity. Male and female BALB/c mice (5 /group) were injected subcutaneously with either saline vehicle or 2.25 mg/ kg/day of FB1 for 5 days. One day after the last injection females showed a greater increase in circulating alanine aminotransferase and greater numbe r of apoptotic cells in liver after FB1 treatment than males, indicating gr eater hepatotoxicity. Peripheral leukocytic counts, including neutrophils, were increased in females only after FB1 treatment. The increased toxicity in females correlated with a greater increase of sphinganine and sphingosin e levels in liver after FB1 treatment compared to males. No sex differences in kidney sphinganine or sphingosine levels were observed after FB1 treatm ent. Previously we have shown the induction of tumor necrosis factor alpha (TNF alpha) in FB1-induced hepatotoxicity. While in males FB1 treatment cau sed increased expression of TNF alpha, interleukin (IL)-12 p40, interferon gamma (IFN gamma), IL-1 beta, IL-6 and IL-10, females showed an increased e xpression of IL-6 only, and a downward modulation of IFN gamma, indicating gender differences in cytokine pathways in liver activated by FB1. The basa l expression of TNF alpha, IL-12 p40, IL-1 beta and IFN gamma in liver of f emales was higher compared to males. Gender differences in alterations of f ree sphingoid bases and cytokine modulation after FB1 treatment suggest the ir possible involvement in sex-dependent differential hepatotoxicity in mic e. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.