Gender-related differences in subacute fumonisin B1 hepatotoxicity in BALB/c mice

Fumonisin B1 (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 cytokine 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 number of apoptotic cells in liver after FB1 treatment than males, indicating greater 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 sphingosine levels in liver after FB1 treatment compared to males. No sex differences in kidney sphinganine or sphingosine levels were observed after FB1 treatment. Previously we have shown the induction of tumor necrosis factor alpha (TNFalpha) in FB1-induced hepatotoxicity. While in males FB1 treatment caused increased expression of TNFalpha, interleukin (IL)-12 p40, interferon gamma (IFNgamma), IL-1beta, IL-6 and IL-10, females showed an increased expression of IL-6 only, and a downward modulation of IFNgamma, indicating gender differences in cytokine pathways in liver activated by FB1. The basal expression of TNFalpha, IL-12 p40, IL-1beta and IFNgamma in liver of females was higher compared to males. Gender differences in alterations of free sphingoid bases and cytokine modulation after FB1 treatment suggest their possible involvement in sex-dependent differential hepatotoxicity in mice.