Altered lipid metabolism as a possible mechanism in fumonisin-induced hepatocarcinogenesis in rats and investigations into risk assessment in humans

Burger, Hester Maria (2013-12)

Thesis (PhD)--Stellenbosch University, 2013.

Thesis

ENGLISH ABSTRACT: Exposure to food contaminates such as mycotoxins have been associated with a variety of animal and human diseases worldwide. In South Africa, maize is the most To further refine risk assessment in the socio-demographic heterogeneous population of South Africa, the development and evaluation of a sensitive and interactive model the Mycotoxin Risk Assessment Model (MYCORAM) proofed to be more sensitive compared to the classical probable daily intake (PDI). The development of the MYCORAM was based on mycotoxin distribution during dry milling of maize in milling fractions intended for human consumption which was superimposed on the maize intake profiles of the South African population. Although dry milling, including a degerming step, is an effective way to reduce mycotoxins, risk and exposure assessment are influenced by maize dietary intakes, gender and ethnicity. This became evident when considering FB dietary exposure in rural maize subsistence farming communities in the Eastern Cape Province, South Africa confirmed the vulnerability of this subpopulation to risk of fumonisin exposure. Specific maximum tolerated maximum levels (MTL) to safeguard these communities fall outside the international regulatory processes and need to be urgently addressed. With the complex nature of cancer development in mind, integration of basic science and nutritional epidemiology will be important to contribute to our understanding of the adverse effects of FB and to define relevant risk assessment parameters. important commercial grain crop not just economically but also as a local food commodity both commercially and in subsistence rural farming communities. In order to control and manage mycotoxin contamination in food, evidence-based risk assessment is needed that includes mechanistic and human exposure studies. From this perspective the current study was conducted and aimed in further unravelling fumonisin B1 (FB1) mycotoxin induced hepatocarcinogenesis via the disruption of the lipid metabolism. The study also critically evaluates aspects of human risk assessment due to its relevance and importance to food safety known to impact on food security. This entails mycotoxin distribution during maize dry milling and the assessment of mycotoxin exposure in the South African population and vulnerable rural communities at risk. Fumonisin B1 affects the integrity of biological membranes by altering key lipid and fatty acid parameter in plasma, microsomal, mitochondrial and nuclear subcellular membrane fractions in rat liver. Changes in the major lipid constituents entailing an increase in cholesterol (CHOL) and phosphatidylethanolamine (PE) whilst sphingomyelin (SM) and phosphatidylcholine (PC) tended to decrease. Isolated plasma membrane lipid rafts, from rat primary hepatocytes exposed to FB1 augments the intricate effects exerted on the lipid metabolism regarding CHOL, SM and PE. The disruption of lipid and fatty acid constituents, such as arachidonic acid and ceramide, are likely to be key determinants affecting growth regulatory signaling pathways relevant to the critical balance between cell proliferation and apoptosis during cancer promotion. These changes provide further evidence that FB1 induce cancer promotion by differential inhibition and/or stimulation process whereby a few resistant “initiated” hepatocytes proliferate in an environment where the growth of normal cells is inhibited. A specific lipogenic phenotype is effected by FB1 which is closely associated with cancer development and considered to occur via an epigenetic-type of mechanism. These effects are not adequately addressed in defining risk assessment parameters.

AFRIKAANSE OPSOMMING: Die blootstelling aan voedsel-kontaminante soos mikotoksienes word wêreldwyd met ‘n verskeidenheid van dierlike en menslike siektes geassosiseer. In Suid-Afrika word mielies as ‘n belangrike graanoes beskou, nie net vir die ekonomie nie maar ook as ‘n plaaslike voedselproduk beide kommersieel en vir bestaansboere in landelike gemeenskappe. Ten einde mikotoksien-kontaminasie van voedsel te kan beheer en bestuur, vereis bewys-gebaseerde risiko-evaluering wat insluit meganistiese en menslike blootstelling studies. Vanuit hierdie perspektief is die huidige studie uitgevoer en gemik op die verdere ontleding van die fumonisin B1 (FB1) mikotoksien geïnduseerde lewer-karsinogenese deur die ontwrigting van die lipiedmetabolisme. Die studie ondersoek terselfdetyd aspekte van menslike risiko-evaluering ingevolge die relevansie en belangrikheid hiervan in voedselveiligheid wat ook ‘n impak op voedselsekerheid sal maak. Dit sluit in die verspreiding van mikotoksiene gedurende die droëmaalproses van mielies en mikotoksien blootstelling in Suid-Afrika asook onder kwesbare landelike gemeenskappe. Fumonisin B1 beïnvloed die integriteit van biologiese membrane deur die modulasie van die belangrike lipied en vetsuur samestelling van plasma, mikrosomale, mitochondriale en kern subsellulêre membraan-fraksies in rot lewer. Veranderinge in die belangrike lipiedbestanddele, insluitende ‘n verhoging in cholesterol (CHOL) en phosphatidylethanolamine (PE), terwyl sphingomyelin (SM) en phosphatidylcholine (PC) geneig was om te verlaag. Geïsoleerde plasma membraan lipied vlotte (lipid rafts), vanaf primêre rot hepatosiete blootgestel aan FB1, versterk die ingewikkelde gevolge wat uitgeoefen word op die lipiedmetabolisme insluitende die voorgestelde veranderings in CHOL, SM en PE vlakke. Die versteuring van lipiede en vetsure soos aragidoonsuur (arachidonic acid) en ceramied kan beskou word as belangrike determinante wat inmeng in groei-regulerende seinbane verwant aan die kritiese balans tussen selgroei en seldood. Die versteurings verskaf verdere bewyse dat FB1 kanker bevorder deur ‘n seleksie proses wat onderskeidelike die onderdrukking en\of die stimulasie van ‘n paar weerstandige of geneties veranderde hepatosiete laat vermeerder in ‘n omgewing waar die groei van normale selle geïnhibeer word. Die spesifieke lipogeniese fenotipe wat FB1 versoorsaak hou ten nouste verband met kankerontwikkeling en die voorkoms van epigenetiese-soort meganismes word voorgestel. Hierdie oorsake word tans nie voldoende aangespreek tydens die bepaling van risiko-evaluerings limiete nie. Om risiko-bepaling verder te verbeter in die sosio-demografies heterogene populasie van Suid-Afrika, was die ontwikkeling en evalueering van ‘n sensitiewe en interaktiewe model, die “Mycotoxin Risk Assessment Model” (MYCORAM) meer doeltreffend vergeleke met die gewone waarskynlike daaglikse inname. Die ontwikkeling van die MYCORAM was gebaseer op die mikotoksien verspreiding tydens die droëmaalproses van mielies in fraksies wat vir menslike verbruik bedoel was tesame met mielie dieetinnames van die Suid-Afrikaanse populasie. Alhoewel, die droëmaalproses van mielies, insluitende die verwydering van die kiem doeltreffende maniere is om mikotoksienes te verminder, word risiko- en blootstellings evaluering beinvloed deur mielie dieetinnames, geslag en etnieseverbandskap. Hierdie was veral opmerklik gedurende blootstelling aan FB in die dieet van landelike mielie bestaansboer gemeenskappe in die Oos-Kaap van Suid- Afrika en bevestig hoe kwesbaar hierdie populasie is. Spesifieke maksimum toelaatbare vlakke om hierdie gemeenskappe te beskerm val buite die huidige internasionale regulatoriese prosesse en benodig dringende aandag. Met die ingewikkelde aard van kankerontwikkeling in gedagte, sal die integrasie van basiese wetenskappe en voedingsepidemiologie, ‘n belangrik bydrae lewer tot die kennis van die negatiewe eienskappe van FB om toepaslike risiko-evaluerings limiete te kan bepaal.

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