Ronald T. Riley

Sequential dietary exposure to aflatoxin B1 and fumonisin B1 in F344 rats increases liver preneoplastic changes indicative of a synergistic interaction

Dietary co-exposure to aflatoxin B1 (AFB1) and fumonisin B1 (FB1) and their interaction on hepatocellular carcinogenesis is of particular concern in toxicology and public health. In this study we evaluated the liver preneoplastic effects of single and sequential dietary exposure to AFB1 and FB1 in the F344 rat carcinogenesis model. Serum biochemical alterations, liver histopathological changes, and the formation of liver glutathione S transferase positive (GST-P+) foci were the major outcome parameters examined. Compared to the AFB1-only treatment, the FB1-only treatment induced less dysplasia, and more apoptosis and mitoses. Sequential AFB1 and FB1 treatment lead to increased numbers of dysplasia, apoptosis and foci of altered hepatocytes, as compared to either mycotoxin treatment alone. More importantly, sequential exposure to AFB1 and FB1 synergistically increased the numbers of liver GTP-P+ foci by approximately 7.3-and 12.9-fold and increased the mean sizes of GST-P+ foci by 6- and 7.5-fold, respectively, as compared to AFB1- or FB1-only treatment groups. In addition, liver ALT and AST levels were significantly increased after sequential treatment as compared to single treatment groups. The results demonstrate the interactive effect of dietary AFB1 and FB1 in inducing liver GST-P+ foci formation and provide information to model future intervention studies.

Chapter 53 – Fumonisins

Publisher Summary This chapter describes fumonisins in detail. The discovery of the fumonisins was a major breakthrough ending the search to identify the mycotoxin(s) causing the animal diseases associated with maize or feeds contaminated with Fusarium verticillioides. The bioavailability, distribution and toxicokinetics of fumonisins have been studied in multiple species. Horses are the most sensitive species to fumonisins. Horses ingesting contaminated feed develop a syndrome referred to as equine leukoencephalomalacia (ELEM). Like ELEM, porcine pulmonary edema is associated with the consumption of moldy feed. Poultry and ruminants are less sensitive. Interest in the potential adverse effects of fumonisins on reproduction and development began shortly after their discovery, suggesting that fumonisins are responsible for the reproductive effects of F. verticillioides. Results of experiments using Syrian hamsters suggested that fumonisins were fetotoxic at doses that did not elicit maternal toxicity. Toxicity was not a prerequisite for embryotoxicity. Neural tube defect, a relatively common birth defect, is associated with fumonisin exposure. Hydrolyzed fumonisin (HFB1) is produced during the cooking and steeping of fumonisin-contaminated maize in alkaline water. Popular snack foods are also made from alkaline cooked maize. It is important to understand how thermal processing affects fumonisins during the preparation of maize-based foods. The effect of alkaline cooking of maize, known as nixtamalization, is of particular interest. Fumonisin B1 has been designated as a possible human carcinogen. Much has been learned about the general toxicity and carcinogenicity of fumonisins in animals; however, their impact on human health remains unclear.

Modulation of pre-neoplastic biomarkers induced by sequential aflatoxin B 1 and fumonisin B 1 exposure in F344 rats treated with UPSN clay

Populations consuming aflatoxin (AF) and fumonisin (FN)-contaminated foods may be at increased risk for hepatocellular carcinoma (HCC) and developmental disorders; consequently, development of intervention strategies to reduce AF/FN-induced liver disease and adverse health effects in humans could be very useful. Calcium montmorillonite clay (NovaSil) has been shown to absorb AF in vitro, in multiple animal models, as well as in human studies. In the present study, we aimed to evaluate whether uniform particle size NovaSil (UPSN) possessed an ability to modulate the co-carcinogenic potentials of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) in F344 rats. Sequential treatment of FB1 following AFB1 synergistically induces preneoplastic alterations as well as liver damage, indicating that AFB1 acts as an initiator while FB1 as a promoter in the carcinogenesis model, confirming findings from previous studies. The enterosorbent agent UPSN clay at dose of up to 0.5% in diet was shown to be effective in modulating the toxicity and carcinogenicity of co-exposure to AFB1 and FB1, as demonstrated by significant reduction in number and size of hepatic GST-P+ foci, in alterations indicative of liver toxicity, and in levels of AFB1 and FB1 biomarkers.

Dietary Fumonisin and Growth Impairment in Children and Animals: A Review: Dietary fumonisin and growth impairment…

Fumonisins are mycotoxins produced primarily by the fungi Fusarium verticillioides and F. proliferatum, which colonize maize in tropical, subtropical, and temperate climates worldwide. Fumonisin exposure is the highest in rural populations that consume large amounts of maize and maize products. Among them, infants and young children are the most vulnerable when they are weaned onto maize-based foods. Therefore, it is critical to understand the impact of fumonisin on childrens health and growth. This review describes the evidence linking fumonisin exposure to child growth impairment. First, toxicological studies that attempt to elucidate the mechanism by which fumonisin may impair growth are discussed. Next, a description is given of candidate biomarkers for accurately capturing fumonisin exposure in humans. Potential human health effects of fumonisin exposure beyond growth impairment, including esophageal cancer and neural tube defects (NTDs), are briefly described. We review epidemiological studies that collectively show an increasing weight of evidence linking fumonisin exposure to growth impairment, particularly in world regions where young children consume maize-based weaning foods. Additionally, the evidence linking fumonisin exposure to growth impairment in plants and a variety of animal species are reviewed. Finally, we describe interventions to reduce fumonisin in parts of the world where dietary fumonisin exposure is high and is likely to predispose populations to increased health risk.

Chapter 47 – Fumonisins

Fumonisins are fungal toxins found in maize and maize-based foods. Fumonisins are toxic to animals but their impact on human health is uncertain. Epidemiological evidence suggests that fumonisins are potential risk factors for neural tube defects (NTDs) and for growth retardation of young children living in areas where large amounts of fumonisin-contaminated corn are consumed on a regular basis. Fumonisin B1 (FB1), the most common fumonisin, was not teratogenic in some animal studies although adverse embryonic and fetal affects secondary to maternal toxicity were found. These included generalized growth impairment and, at high doses, fetal death in utero. Other investigations have in contrast shown that FB1 induces NTDs in some mouse strains. The etiology of NTDs is complex and involves interactions between environmental, nutritional, and genetic factors. Reasons underlying differences in the sensitivity of mouse strains to NTD induction by fumonisins are not fully understood although they likely involve fumonisin-dependent disruption of sphingolipid biosynthesis and sphingolipid-dependent effects on folate utilization and uptake, diverse cell signaling pathways, and histone modification.