Apoptotic and anti-proliferative effects of fumonisin B₁ in human keratinocytes, fibroblasts, esophageal epithelial cells and hepatoma cells

Abstract

Fumonisin B1 is associated with various animal and human carcinomas and toxicoses, including leukoencephalomalacia, hepatocarcinoma, pulmonary edema and esophageal carcinoma. We have examined the cellular effects of fumonisin B1 in vitro using cellular model systems relevant to potential human target tissues. Although fumonisin B1 has been described as a mitogen in Swiss 3T3 cells based on stimulation of [3H]thymidine incorporation, in the current work it was found that fumonisin B1 inhibited incorporation of [3H]thymidine by cultured neonatal human keratinocytes and HepG2 human hepatocarcinoma cells at 10(-7) and 10(-4) M respectively. Fumonisin B1 also inhibited clonal expansion of normal human keratinocytes and HET-1A human esophageal epithelial cells at 10(-5) M and growth in mass culture of normal human fibroblasts at 10(-7) M. The clonogenicity of normal human keratinocytes decreased to 45.5% of controls after exposure to 10(-4) M fumonisin B1 for 2 days. However, no differences in the cell cycle distribution of cultured keratinocytes was noted after exposure to 10(-5) M fumonisin B1 for 40 h. The viability of normal human keratinocytes and HET-1A cells decreased as a result of fumonisin B1 treatment, as determined by a fluorescein diacetate/propidium iodide flow cytometric cell viability assay. Fumonisin B1-treated keratinocytes released nucleosomal DNA fragments into the medium 2-3 days after exposure to 10(-4) M fumonisin B1 and increased DNA strand breaks were detected in attached keratinocytes exposed to 0-10(-4) M fumonisin B1 using a terminal deoxynucleotidyl transferase-based immunochemical assay system. Furthermore, fumonisin B1-treated keratinocytes and HET-1A cells developed morphological features consistent with apoptosis, as determined by phase contrast microscopy, fluorescent microscopy of acridine orange stained cells and electron microscopy. These results are consistent with the occurrence of fumonisin B1-mediated apoptosis in vitro.

Fumonisins in Maize: Can We Reduce Their Occurrence?

“…Sphingolipids are structural components of eukaryotic cell membranes; however, there is increasing evidence that sphingolipids also affect cellular proliferation and differentiation, and that they regulate apoptosis, programmed cell death. Recent studies also demonstrate that treatment with FB 1 induces apoptosis and blocks cell proliferation in several types of cultured human and animal cells (56,61). The role of sphingolipids and the sphingolipid-analog mycotoxins in programmed cell death is a fast-developing field of research that should provide insights into the diseases caused by consumption of fumonisins.…”

Mycotoxins reveal connections between plants and animals in apoptosis and ceramide signaling

“…or greater (Nelson et al, 1993;Sydenham et al, 1991). Ingestion of fumonisin through contaminated feed, or as pure FB 1 , has been shown to induce a variety of responses in the challenged animals including neuro-, renal-or hepatoxicosis and neoplasms as well as cell death (Gelderblom et al, ,b, 1992Marasas et al, 1988a;Merrill et al, 1996;Nelson et al, 1993;Tolleson et al, 1996). Because of the frequency and level of contamination of maize and the toxicity of fumonisin to animals, serious concern exists over the dual roles involving proliferation and apoptosis these mycotoxins may play in animal and human disease.…”

Risk-Assessment Implications of Mechanistic Model's Prediction of Low-Dose Nonlinearity of Liver Tumor Risk for Mice FED Fumonisin B1

“…This nongenotoxic mechanism is believed to begin with the interruption of sphingolipid synthesis in cells due to the inhibition of ceramide synthase by fumonisin B 1 (Riley et al, 1998). The resulting increased intracellular levels of sphinganine are associated with increased apoptosis (Tolleson et al, 1996;Yoo et al, 1996;Delongchamp and Young, 2001). It is hypothesized that compensatory proliferation of cells in response to increased apoptosis puts more cells at risk of mutation to malignancy, hence increasing the risk of cancer.…”