fumonisin-b1 and Carcinoma--Hepatocellular

Fumonisins, fungal toxins produced by Fusarium moniliforme, contaminate maize based foods and feeds throughout the world. They cause liver and kidney toxicity in animals in addition to leukoencephalomalacia in horses and pulmonary edema in pigs. Fumonisin B(1) is carcinogenic in rats and mice. Ecological studies have linked consumption of fumonisin contaminated maize with oesophageal cancer in human populations in South Africa and China. This review discusses the potential health risks for people exposed to the fumonisins, and describes how mechanistic studies of toxicity in animal models have allowed the development of putative biomarkers of fumonisin exposure at the individual level. The requirements for an applicable biomarker include sample availability as well as a high specificity and sensitivity for the exposure of interest. Most environmental toxic insults involve complex exposures both to other toxins and to infections; these confounding factors need to be considered in assessing both the validity of the biomarker and the exposure-disease associations. Fumonisins can be detected in the urine of animals in feeding studies but the sensitivity of the current methodology means only highly exposed people could be monitored. Mechanistic studies indicate that ceramide synthase, an enzyme involved in sphingolipid synthesis, is one cellular target for fumonisin toxicity and carcinogenicity, and this disruption to sphingolipid metabolism increases the ratio of two sphingoid precursors, sphinganine and sphingosine. The altered ratio has been observed in tissues, serum and urine for a number of animal models suggesting it as a good candidate marker of fumonisin exposure. Despite development of analytical methods to measure this biomarker there have been no studies to date correlating it to fumonisin intake in people. Given the toxic effects of fumonisins in animals and the widespread human exposure, which has been calculated to reach 440 micrograms kg(-1) body weight day(-1) in a population consuming high quantities (460 g day(-1)) of contaminated maize, then the development of biomarkers and their application in epidemiological studies should be a priority for research on these toxins.

Topics: Animals; Biomarkers; Carboxylic Acids; Carcinogens, Environmental; Carcinoma, Hepatocellular; Esophageal Neoplasms; Female; Food Contamination; Food Microbiology; Fumonisins; Humans; Liver Neoplasms; Male; Mice; Neoplasms, Experimental; Rats; Risk Assessment; Sphingolipids; Sphingosine

Green tea polyphenols (GTP) are highly effective in inhibiting a variety of tumorigenic effects induced by carcinogens. In this study we assessed GTP mitigation on biomarkers of fumonisin B1 (FB1), a class 2B carcinogen, in blood and urine samples collected from an intervention trial. A total of 124 exposed people were recruited and randomly assigned to low-dose (GTP 500 mg, n = 42), high-dose (GTP 1,000 mg, n = 41) or placebo (n = 41) for 3 months. After one-month of intervention, urinary FB1 was significantly decreased in high-dose group compared to that of placebo group (p = 0.045), with reduction rates of 18.95% in the low-dose group and 33.62% in the high-dose group. After three-month intervention, urinary FB1 showed significant decrease in both low-dose (p = 0.016) and the high-dose (p = 0.0005) groups compared to that of both placebo group and baseline levels, with reduction rates of 40.18% in the low-dose group and 52.6% in the high-dose group. GTP treatment also significantly reduced urinary excretion of sphinganine (Sa), sphingosine (So), and Sa/So ratio, but had no effect on serum Sa, So, and Sa/So ratio. Analysis with mixed-effect model revealed significant interactions between time and treatment effects of GTP on both urinary free FB1 levels and Sa/So ratios.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Fumonisins; Humans; Liver Neoplasms; Male; Middle Aged; Polyphenols; Tea

FB

Topics: Adenosine; Carcinoma, Hepatocellular; Epigenesis, Genetic; Fumonisins; Hep G2 Cells; Humans; Kelch-Like ECH-Associated Protein 1; Liver Neoplasms; Methylation; NF-E2-Related Factor 2; Oxidative Stress; RNA; Signal Transduction

Fumonisin B₁ (FB₁), a common mycotoxin contaminant of maize, is known to inhibit sphingolipid biosynthesis and has been implicated in hepatocellular carcinoma promoting activity in humans and animals. MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression via translational repression. Human cytochrome P450 (CYP1B1) is highly expressed in oestrogen target tissues and catalyzes the metabolic activation of many procarcinogens. The aim of our study was to investigate the effect of FB₁ on miR-27b suppression and its effect on CYP1B1 modulation in a human hepatoma cell line (HepG2). MiR27b and CYP1B1 expressions were evaluated in HepG2 cells by quantitative PCR. In order to directly assess the effect of miR-27b on CYP1B1 mRNA levels, cells were transfected with the mimic to miR-27b. CYP1B1 protein expression was measured using Western blot. FB₁ significantly down-regulated (11-fold) expression of miR-27b in HepG2 cells; whilst CYP1B1 mRNA and protein expression was significantly upregulated by 1.8-fold and 2.6-fold, respectively. CYP1B1 is post-transcriptionally regulated by miR-27b after HepG2 exposure to FB₁. FB₁-induced modulation of miR-27b in hepatic cells may be an additional mode of hepatic neoplastic transformation.

Topics: Aryl Hydrocarbon Hydroxylases; Carcinogens, Environmental; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cluster Analysis; Cytochrome P-450 CYP1B1; Down-Regulation; Enzyme Induction; Fumonisins; Hep G2 Cells; Hepatocytes; Humans; Liver Neoplasms; MicroRNAs; Molecular Mimicry; Neoplasm Proteins; RNA, Messenger; Transfection

Fumonisin B1 (FB1), a mycotoxin that contaminates corn in certain climates, has been demonstrated to cause hepatocellular cancer (HCC) in animal models. Whether a relationship between FB1 and HCC exists in humans is not known. To examine the hypothesis, we conducted case-control studies nested within two large cohorts in China; the Haimen City Cohort and the General Population Study of the Nutritional Intervention Trials cohort in Linxian. In the Haimen City Cohort, nail FB1 levels were determined in 271 HCC cases and 280 controls. In the General Population Nutritional Intervention Trial, nail FB1 levels were determined in 72 HCC cases and 147 controls. In each population, odds ratios and 95% confidence intervals (95%CI) from logistic regression models estimated the association between measurable FB1 and HCC, adjusting for hepatitis B virus infection and other factors. A meta-analysis that included both populations was also conducted. The analysis revealed no statistically significant association between FB1 and HCC in either Haimen City (OR=1.10, 95%CI=0.64-1.89) or in Linxian (OR=1.47, 95%CI=0.70-3.07). Similarly, the pooled meta-analysis showed no statistically significant association between FB1 exposure and HCC (OR=1.22, 95%CI=0.79-1.89). These findings, although somewhat preliminary, do not support an associated between FB1 and HCC.

Topics: Carcinoma, Hepatocellular; China; Chromatography, High Pressure Liquid; Cohort Studies; Fumonisins; Humans; Liver Neoplasms; Risk Factors; Tandem Mass Spectrometry

Aflatoxin B(1) (AFB(1)) and fumonisin B(1) (FB(1)) are important food-borne mycotoxins. The co-contamination of food stuffs with these two mycotoxins is well known and has been possibly implicated in the development of human hepatocellular carcinoma in high risk regions around the world. In this study the acute and combinative toxicity of AFB(1) and FB(1) were tested in F-344 rats, mosquitofish (Gambusia affinis), immortalized human hepatoma cells (HepG2) and human bronchial epithelial cells (BEAS-2B). Preliminary experiments were conducted in order to assess the acute toxicity and obtain LD(50), LC(50) and IC(50) values for individual toxins in each model, respectively. This was followed by testing combinations of AFB(1) and FB(1) to obtain LD(50), LC(50) and IC(50) values for the combination in each model. All models demonstrated a significant dose response in relation to toxin treatment. The potency of the mixture was gauged through the determination of the interaction index metric. Results of this study demonstrate that these two toxins interacted to produce alterations in the toxic responses with a strong additive interaction noted in the cases of F344 rats and mosquitofish. It can be gathered that this combination may pose a significant threat to public health and further research needs to be completed addressing alterations in metabolism and detoxification that may influence the toxic manifestations in combination. These results will provide foundational knowledge for future studies on long-term combinative toxic and health effects of these mycotoxins.

Topics: Aflatoxin B1; Animals; Bronchi; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Cell Survival; Cyprinodontiformes; Drug Interactions; Epithelial Cells; Food Contamination; Fumonisins; Humans; Liver Neoplasms; Male; Mycotoxins; Rats; Rats, Inbred F344

Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced by Fusarium verticillioides. Dietary exposure to FB1 has been linked to human cancer in certain parts of the world, and treatment with FB1 causes oval cell proliferation and liver tumors in rats. To study the potential role of oval (liver progenitor) cells in the cellular pathogenesis of FB1-induced liver tumors, we gave male F344 rats prolonged treatment with FB1 for 25 weeks, followed by return to control diet until 50 weeks ('stop study'). The time course of FB1-induced liver lesions was followed by examination of serial liver biopsies at set time intervals and post-mortem liver tissue at the end of the study. The effects of different FB1 treatment regimens (5 versus 25 weeks), as well as the modulating effect of 2-acetylaminofluorene (2-AAF), on the kinetics of oval cell proliferation and development of liver tumors were compared. Prolonged treatment with FB1 in normal diet caused persistent oval cell proliferation and generation of both hepatic adenomas and cholangiofibromas (CFs). These liver lesions occurred in the setting of chronic toxic hepatitis and liver fibrosis/cirrhosis, similar to that seen in human hepatocarcinogenesis. Some adenomas and CFs were dysplastic, and one post-mortem liver contained a hepatocellular carcinoma. OV-6+ oval cells were noted in close relation to proliferative neoplastic liver lesions, and some of these lesions expressed OV-6, suggesting that all these cell types were derived from a common progenitor cell. 2-AAF enhanced the size of FB1-induced glutathione S-transferase pi+ hepatocellular lesions and the incidence of CFs in post-mortem liver specimens, but this was not statistically significant. In conclusion, this study supports the involvement of dietary FB1 in liver carcinogenesis in male F344 rats. Oval cells may be the source of both the hepatocellular and cholangiocellular tumors induced by prolonged treatment with FB1. 2-AAF appears to have an enhancing effect on FB1-induced liver tumors, presumably due to its potent inhibitory effects on hepatocyte regeneration.

Topics: 2-Acetylaminofluorene; Adenoma, Liver Cell; Animals; Carcinogens; Carcinogens, Environmental; Carcinoma, Hepatocellular; Cell Division; Fumonisins; Liver Neoplasms; Male; Rats; Rats, Inbred F344

Fumonisin B(1) (FB(1)), a widespread Fusarium toxin which is frequently found in corn, causes liver tumors in laboratory rodents and is a suspected human carcinogen. The compound was tested in micronucleus (MN) and single cell gel electrophoresis (SCGE) assays in human derived hepatoma (HepG2) cells and caused a pronounced dose-dependent genotoxic effect at exposure concentrations > or = 25 microg/ml. In contrast, no induction of his(+) revertants was found in Salmonella microsome assays with strains TA98, TA100, TA102, TA1535 and TA1537 upon addition of HepG2-derived enzyme (S9) mix in liquid incubation assays with identical exposure concentrations. Taken together, our results indicate that FB(1) is clastogenic in human derived cells. This observation supports the assumption that this compound may act as a genotoxic carcinogen in humans.

Topics: Carcinogens, Environmental; Carcinoma, Hepatocellular; Comet Assay; Dose-Response Relationship, Drug; Fumonisins; Humans; Kinetics; Micronucleus Tests; Models, Chemical; Mutagens; Time Factors; Tumor Cells, Cultured

A comparative study on the natural occurrence of aflatoxins and Fusarium toxins was conducted with corn samples from high- and low-incidence areas for human primary hepatocellular carcinoma (PHC) in Guangxi, China. In samples from the high-risk area, aflatoxin B(1) was the predominant toxin detected in terms of quantity and frequency, with its concentration ranging between 9 and 2496 microg/kg and an 85% incidence of contamination. Among the samples, 13 (76%) exceeded the Chinese regulation of 20 microg/kg for aflatoxin B(1) in corn and corn-based products intended for human consumption. Significant differences in aflatoxin B(1), B(2), and G(1) and total aflatoxin concentrations in corn between the areas were found (P < 0.05). The average daily intake of aflatoxin B(1) from corn in the high-risk area was 184.1 microg, and the probable daily intake is estimated to be 3.68 microg/kg of body weight/day, 3.20 times the TD(50) in rats. Corn samples from both areas were simultaneously contaminated with fumonisins B(1), B(2), and B(3). Aflatoxin B(1) may play an important role in the development of PHC in Guangxi.

Topics: Aflatoxin B1; Aflatoxins; Carboxylic Acids; Carcinoma, Hepatocellular; China; Food Contamination; Fumonisins; Fusarium; Humans; Incidence; Liver Neoplasms; Mycotoxins; Safety; Zea mays

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.

Topics: 3T3 Cells; Animals; Apoptosis; Carcinogens, Environmental; Carcinoma, Hepatocellular; Cell Cycle; Cell Division; Cell Survival; DNA; Epithelial Cells; Epithelium; Esophagus; Fumonisins; Humans; Keratinocytes; Liver Neoplasms; Mice; Microscopy, Electron; Mycotoxins; Tumor Cells, Cultured