Neuro- and Immunotoxic Effects of Fumonisin B1 in Cells

Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species can also be found in moisture-damaged buildings, and therefore there may also be human exposure to Fusarium mycotoxins, including FB1. FB1 is known to affect the metabolism of sphingolipids by inhibiting the enzyme ceramide synthase. It is neuro-, hepatoand nephrotoxic, and it is classified as possibly carcinogenic to humans. This study aimed to clarify the mechanisms behind FB1-induced neuroand immunotoxicity. Four neural and glial cell lines of human, rat and mouse origin were exposed to graded doses of FB1. The effects on the production of reactive oxygen species, lipid peroxidation, intracellular glutathione levels, cell viability and apoptosis were investigated at different time points (0.5-144 h). Furthermore, the effects of FB1, alone or together with lipopolysaccharide (LPS), on the mRNA and protein expression levels of different cytokines and chemokines were studied in human dendritic cells (DC), differentiated from peripheral blood mononuclear cells. FB1 induced oxidative stress and cell death in all cell lines studied. However, the sensitivities of the cell lines varied depending on which parameter was being studied. Generally, the effects were only seen after prolonged exposure at 10 and 100 μM of FB1. Signs of apoptosis, reflected as increased caspase-3-like protease activity and internucleosomal DNA fragmentation, were also seen in all four cell lines. The results provide evidence that FB1 is a potential neurotoxin in vitro, but that the magnitude of the toxic effects is cell line dependent. The sensitivities of the cell lines used in this study towards FB1 may be classified as human U-118MG glioblastoma > mouse GT1-7 hypothalamic > rat C6 glioblastoma > human SH-SY5Y neuroblastoma cells. When comparing cell lines of human origin, it can be concluded that glial cells seem to be more sensitive towards FB1 toxicity than those of neural origin. After exposure to 100 μM FB1 for 6 or 24 h, significantly increased mRNA levels of the cytokine interferon-γ (IFNγ) were detected in human DC. This observation was further confirmed by FB1-induced mRNA levels of the chemokine CXCL9, which is known to be regulated by IFNγ. During co-exposure of DC to both LPS and FB1, significant inhibitions of the LPS-induced levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1β, and their regulatory chemokines CCL3 and CCL5 were observed. The results show that FB1 has the capacity to modulate the immune responses in DC. Therefore, it is rather likely that it also affects other types of cells participating in the immune defence system. When evaluating the toxicity potential of FB1, it is important to consider the effects on different cell types and cell-cell interactions. The results of this study represent new information, especially about the mechanisms behind FB1-induced oxidative stress, apoptosis and immunotoxicity, as well as the varying sensitivities of different cell types towards FB1.