Deglucosylation of zearalenone-14-glucoside in animals and human liver leads to underestimation of exposure to zearalenone in humans

Zearalenone (ZEA) is a mycotoxin produced mainly by fungi belonging to the genus Fusarium in foods and feeds. It is frequently implicated in reproductive disorders of farm animals and occasionally in hyperoestrogenic syndromes in humans. There is evidence that ZEA and its metabolites possess oestrogenic activity in pigs, cattle and sheep. However, ZEA is of a relatively low acute toxicity after oral or interperitoneal administration in mice, rat and pig. The biotransformation for ZEA in animals involves the formation of two metabolites alpha-zearalenol (alpha-ZEA) and beta-zearalenol (beta-ZEA) which are subsequently conjugated with glucuronic acid. Moreover, ZEA has also been shown to be hepatotoxic, haematotoxic, immunotoxic and genotoxic. The exact mechanism of ZEA toxicity is not completely established. This paper gives an overview about the acute, subacute and chronic toxicity, reproductive and developmental toxicity, carcinogenicity, genotoxicity and immunotoxicity of ZEA and its metabolites. ZEA is commonly found on several foods and feeds in the temperate regions of Europe, Africa, Asia, America and Oceania. Recent data about the worldwide contamination of foods and feeds by ZEA are considered in this review. Due to economic losses engendered by ZEA and its impact on human and animal health, several strategies for detoxifying contaminated foods and feeds have been described in the literature including physical, chemical and biological process. Dietary intakes of ZEA were reported from few countries from the world. The mean dietary intakes for ZEA have been estimated at 20 ng/kgb.w./day for Canada, Denmark and Norway and at 30 ng/kgb.w./day for the USA. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established a provisional maximum tolerable daily intake (PMTDI) for ZEA of 0.5 microg/kg of body weight.

Fusarium mycotoxins are secondary metabolites produced by Fusarium spp. in cereals. Among them, deoxynivalenol (DON) and zearalenone (ZEN) are widespread worldwide contaminants of cereal commodities and are ranked as the most important chronic dietary risk factors. Their conjugates, known as masked mycotoxins, have been described but are still not accounted for in risk assessment studies. This study demonstrates for the first time that DON and ZEN are effectively deconjugated by the human colonic microbiota, releasing their toxic aglycones and generating yet unidentified catabolites. For this reason, masked mycotoxins should be considered when evaluating population exposure.

Zearalenone (ZEA), a Fusarium toxin, is frequently found in animal feed materials. It is known to exert oestrogenic effects in all animals tested but susceptibility varies between species, possibly reflecting differences in the metabolic processing of ZEA, which predominantly involves hydroxylations, assumed to be catalysed by 3alpha- and 3beta- hydroxysteroid dehydrogenases, as well as conjugation with glucuronic acid. In this study, the biotransformation of ZEA by hepatic subcellular fractions of various domestic animals was investigated and compared to the rat. Notable inter-species differences in terms of the rate of absolute and relative metabolite production in the different subcellular fractions were identified. The highest amount of alpha-zearalenol (alpha-ZOL) was produced by pig hepatic microsomes (V(max)=795.8+/-122.7pmol/mg/min), whereas in chicken microsomes the highest amounts of beta-zearalenol (beta-ZOL) (V(max)=1524+/-29.7pmol/mg/min) could be measured. Except for sheep and cattle, the efficiency of alpha-ZOL production (expressed as the ratio of apparent V(max)/k(m)) was higher in the microsomal fraction compared to the post-mitochondrial fraction. In contrast, the apparent efficiency of beta-ZOL production was high in pigs, cattle, chickens and rats, but very low in sheep. Conjugation of ZEA with glucuronic acid was investigated, and the results indicated significant inter-species differences in the rate of glucuronidation, which was saturable at low concentrations in all species tested, except pigs. The significant differences between the percentages of glucuronidation of ZEA, alpha-ZOL, and beta-ZOL suggest not only differences in the affinity of the individual substrate, but might also indicate the presence of different isoforms of uridine diphosphate glucuronyl transferases (UDPGTs). The results are of clinical relevance, as they contribute to the understanding of the species-specific susceptibility towards exposure to ZEA.