Les fumonisines (FBs) sont les principales mycotoxines produites par Fusarium verticillioides et Fusarium proliferatum, qui se retrouvent partout dans le monde dans le maïs et ses produits dérivés. Les doses toxiques et les signes cliniques de toxicité provoqués par les FBs varient dune espèce à lautre. La toxicité des FBs est généralement liée à leur capacité à bloquer le métabolisme des sphingolipides chez les espèces animales, y compris chez les espèces aviaires. De précédentes études ont démontré que les canards présentent une plus grande sensibilité à la toxicité des FBs que les dindes, alors que laccumulation de sphinganine (Sa) dans les tissues est plus importante chez les dindes que chez les canards. Lobjectif de nos travaux était de comprendre les différences de toxicité entre les dindes et les canards los dune exposition aux FBs. Les trois hypothèses suivantes ont été explorées : i) La toxicocinétique de la fumonisine B2 chez les dindes et les canards. ii) La capacité des cellules aviaires à se protéger de limportante accumulation de sphingolipides libres en augmentant leur catabolisme (phosphorylation). iii) Des mécanismes de toxicité des FBs autre que leur altération via le métabolisme des sphingolipides (stress oxydatif et les réponses inflammatoires). Lanalyse des paramètres de toxicocinétique de la fumonisine B2 na pas mis en évidence de différence significative entre les dindes et les canards. Les mesures de la toxicité simultanée de plusieurs FBs chez les dindes et les canards ont confirmé la forte sensibilité des canards. Laccumulation de shingasine-1-phosphate (Sa1P) dans le foie a également été corrélée avec la quantité de Sa mais pas avec les paramètres hépatiques de toxicité. De plus cette étude a mis en évidence que la quantité de Sa dans le foie était fortement dépendante de la teneur en FBs. Cependant les FBs nont eu aucun effet sur les paramètres de stress oxydatif pour les deux espèces. De manière intéressante, les FBs ont eu une légère réponse inflammatoire chez les canards mais pas chez les dindes. Des investigations plus poussées sur les effets des FBs sur le métabolisme des céramides et sur les processus inflammatoires seraient nécessaires pour comprendre les différences de toxicité entre les dindes et les canards exposés aux FBs. / Fumonisins (FBs) are the major mycotoxins produced by Fusarium verticillioides and Fusarium proliferatum, which are found worldwide in maize and maize products. FBs toxic dose and clinical signs of toxicity vary from one species to another. FBs toxicity is commonly linked to their ability on blocking sphingolipids metabolism in all animal species, including avian species. Previous studies have demonstrated that ducks exhibit higher sensitivity to FBs toxicity than turkeys, whereas, the accumulation of sphinganine (Sa) in tissues is more pronounced in turkeys than in ducks. The objectives of our works were to investigate the causes which lead to different toxicity between ducks and turkeys to FBs exposure. The following three hypotheses were investigated: i) Toxicokinetics of fumonisin B2 in ducks and turkeys. ii) Ability of bird cells to protect themselves against high accumulation of free sphingolipids by increasing their catabolism (phosphorylation). iii) Other toxicity mechanisms of FBs rather than their alteration of sphingolipids metabolism (oxidative stress damage and inflammatory responses). The analysis of toxicokinetic parameters of fumonisin B2 did not provide a significant difference between ducks and turkeys. The measurement of simultaneous toxicity of FBs in ducks and turkeys confirmed higher sensibility of ducks. Also the accumulation of Sphingasine-1-Phosphate (Sa1P) in the liver correlated with the amount of Sa but not parameters of hepatic toxicity. Moreover, this study revealed that the amount of Sa in the liver was strongly dependent on the amount of FBs. On the other hand, FBs had no effect on oxidative damages parameters in both species. Interestingly, FBs had mild inflammatory response effect in ducks but not in turkeys. Further investigation on the effects of FBs on ceramide metabolism and inflammatory processes would be necessary to understand the different toxicity between ducks and turkeys to FBs exposure.

Thesis (PhD (MedSc))--University of Stellenbosch, 2011. / ENGLISH ABSTRACT: Fumonisins are carcinogenic mycotoxins which occur world-wide in maize and maize-based products intended for human consumption. Consumption of fumonisin contaminated maize as a staple diet has been associated with oesophageal and liver cancer incidence as well as neural tube defects. This study has confirmed the State of Santa Catarina, Brazil as another region where the consumption of maize contaminated with fumonisins and high oesophageal cancer incidence co-occur. Since fumonisins exert their main biochemical effect by disruption of the sphingolipid biosynthetic pathway and are implicated in cancer, the role of fumonisin B1 (FB1) in FB1–induced rat hepatocyte nodules was investigated. The current study showed that FB1 exposure activated sphingosine accumulation in the nodules which could induce the bio-active sphingosine 1-phosphate to provide a selective growth stimulus on subsequent FB1 exposure. Since the FB1-induced hepatocyte nodules were not resistant to the disruption of sphingolipid biosynthesis, it was not the mechanism whereby the altered hepatocytes escaped the mitoinhibition of FB1 and selectively proliferated into hepatocyte nodules. A study in maize subsistence farming communities investigated the sphingosine and sphinganine levels in blood and urine of participants. Fumonisin exposure was assessed in these communities based on fumonisin levels in maize that was concurrently collected from the areas where the participants resided. Subsequently fumonisin exposure was assessed in individuals based on the fumonisin levels in maize collected from each household and by acquiring weighed food records for each member of the household. It was confirmed in both these studies that communities are chronically exposed to fumonisin levels well above the provisional maximum tolerable daily intake determined by the Joint FAO/WHO Expert Committee on Food Additives. Since the sphinganine and sphingosine levels in blood and urine of the participants exposed to various levels of fumonisin were not significantly different, the sphingoid bases and their ratios could not be established as a biomarker of fumonisin exposure. Therefore, an alternative biomarker of exposure was investigated during studies into a practical cost effective method to reduce fumonisin. The customary maize food preparation practices were assessed in a maize subsistence farming community and subsequently optimised to reduce the fumonisin levels in the maize under laboratory-controlled conditions. Implementation of this optimised and culturally acceptable intervention method of sorting and washing maize in a rural community reduced fumonisin contamination in home-grown maize by 84%. The intervention study attained a 62% reduction in fumonisin exposure based on fumonisin levels in maize-based food and consumption as assessed by 24-h dietary recall questionnaires. The alternative biomarker of fumonisin exposure, urinary FB1, was investigated during the intervention study. The FB1 urinary biomarker measured fumonisin intake at the individual level and confirmed the reduction achieved as assessed by food analysis and food intake data. The biomarker was thus well correlated with fumonisin exposure and confirmed the efficacy of the simple and culturally acceptable intervention method. Utilisation of the urinary FB1 biomarker and the customised hand-sorting and washing of maize to reduce fumonisin exposures has the potential to improve food safety and health in subsistence maize farming communities. / AFRIKAANSE OPSOMMING: Fumonisien is kankerverwekkende mikotoksiene wat wêreldwyd voorkom op mielies en mielie-verwante produkte bestem vir menslike verbruik. Daar is ‘n verband tussen die voorkoms van slukderm en lewer kanker, sowel as neuraalbuisdefekte, in gemeenskappe waar fumonisien-gekontamineerde mielies die stapel voedsel is. Die Brasiliaanse Staat, Santa Catarina is uitgewys as nog 'n area waar hoë voorkoms van slukdermkanker en hoë fumonisin vlakke in mielies gesamentlik voorkom. Aangesien fumonisien verbind word met van kanker en die hoof biochemiese effek die ontwrigting van die sfingolipiedbiosintese weg is, is die rol van fumonisien B1 (FB1) in FB1-geinduseerde rot hepatosietnodules ondersoek. Die studie het getoon dat FB1 blootstelling aktiveer sfingosien ophoping in die hepatosietnodules wat moontlik die bio-aktiewe sfingosien 1-fosfaat aktiveer om op daaropvolgende FB1 blootstellings geselekteerde groei stimulasie te ondergaan. Die FB1-geïnduseerde hepatosietnodules was nie bestand teen die inhibisie van die sfingolipied biosintese nie en dus nie die meganisme waardeur die veranderde hepatosiete mito- inhibisie van FB1 vryspring, en selektief ontwikkel in hepatosietnodules nie. ‘n Studie in bestaansboerdery gemeenskappe het die sfingosien en sfinganien vlakke in bloed en uriene vergelyk met individuele fumonisien blootstelling. Laasgenoemde is gebaseer op fumonisien vlakke in gekolleekterde mielies vanuit die deelnemers se huise en aannames vanuit die literatuur. Die opvolg studie in die areas het individuele fumonisien blootstelling bepaal gebaseer op fumonisien vlakke in die mielies van elke huishouding en die inname van mielies deur die voedsel van elke individu te weeg. Albei hierdie studies het bevestig dat die gemeenskappe blootgestel is aan kroniese fumonisien vlakke wat die maksimum toelaatbare daaglikse inname wat deur die gesamentlike FAO/WHO deskundige komitee op voedsel toevoegsels vasgestel is, oorskei. Aangesien die sfingosien en sfinganien vlakke nie beduidend verskil in bloed of uriene van mense wat aan verskillende fumonisien-kontaminasie vlakke blootgestel is nie, kan die lipiedbasisse en hul verhouding nie as ‘n biologiese merker vir fumonisien blootstelling bevestig word nie. Dus is ‘n alternatiewe biologiese merker vir fumonisien blootstelling ondersoek gedurende ‘n studie oor praktiese bekostigbare maniere om fumonisin blootstelling te verlaag. Die tradisionele voedsel voorbereidingspraktyke in ‘n bestaansboerdery gemeenskap is bestudeer en onder laboratorium-gekontroleerde toestande aangepas om fumonisien vlakke in die mielies optimaal te verlaag. Die kultureel aanvaarbare intervensie metode, sortering en was van die mielies, is in ‘n bestaansboerdery gemeenskap toegepas waar ‘n 84% verlaging in fumonisien vlakke van die mielies verkry is. Die intervensie metode het ‘n 62% verlaging in fumonisien blootstelling te weeggebring deur fumonisien vlakke in die mieliegebasserde disse te meet en inname daarvan deur die deelnemers met 24-h diëetkundige vraelyste vas t e stel. Gedurende die intervensie studie is urienêre FB1, die alternatiwe biologiese merker van fumonisien blootstelling, ondersoek. Individuele fumonisien blootstelling data, bepaal met die urienêre FB1 biomerker, het goed ooreengestem met die voedsel analise en voedsel inname data en het dus die doeltreffendheid van die praktiese kultuur aanvaarbare intervensie metode bevestig. Benutting van die FB1 urienêre biologies merker en die optimale sortering en was van die mielies om die fumonisien blootstelling te verlaag het die potensiaal om voedselveiligheid en gesondheid in hierdie bestaansboerdery gemeenskappe aansienlik te verbeter.