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

[摘要] ENGLISH ABSTRACT: Exposure to food contaminates such as mycotoxins have been associated with avariety of animal and human diseases worldwide. In South Africa, maize is the mostTo further refine risk assessment in the socio-demographic heterogeneouspopulation of South Africa, the development and evaluation of a sensitive andinteractive model the Mycotoxin Risk Assessment Model (MYCORAM) proofed to bemore sensitive compared to the classical probable daily intake (PDI). Thedevelopment of the MYCORAM was based on mycotoxin distribution during drymilling of maize in milling fractions intended for human consumption which wassuperimposed on the maize intake profiles of the South African population. Althoughdry milling, including a degerming step, is an effective way to reduce mycotoxins, riskand exposure assessment are influenced by maize dietary intakes, gender andethnicity. This became evident when considering FB dietary exposure in rural maizesubsistence farming communities in the Eastern Cape Province, South Africaconfirmed the vulnerability of this subpopulation to risk of fumonisin exposure.Specific maximum tolerated maximum levels (MTL) to safeguard these communitiesfall outside the international regulatory processes and need to be urgentlyaddressed. With the complex nature of cancer development in mind, integration ofbasic science and nutritional epidemiology will be important to contribute to ourunderstanding of the adverse effects of FB and to define relevant risk assessmentparameters.important commercial grain crop not just economically but also as a local foodcommodity both commercially and in subsistence rural farming communities. In orderto control and manage mycotoxin contamination in food, evidence-based riskassessment is needed that includes mechanistic and human exposure studies. Fromthis perspective the current study was conducted and aimed in further unravellingfumonisin B1 (FB1) mycotoxin induced hepatocarcinogenesis via the disruption of thelipid metabolism. The study also critically evaluates aspects of human riskassessment due to its relevance and importance to food safety known to impact onfood security. This entails mycotoxin distribution during maize dry milling and theassessment of mycotoxin exposure in the South African population and vulnerablerural communities at risk.Fumonisin B1 affects the integrity of biological membranes by altering key lipid andfatty acid parameter in plasma, microsomal, mitochondrial and nuclear subcellularmembrane fractions in rat liver. Changes in the major lipid constituents entailing anincrease in cholesterol (CHOL) and phosphatidylethanolamine (PE) whilstsphingomyelin (SM) and phosphatidylcholine (PC) tended to decrease. Isolatedplasma membrane lipid rafts, from rat primary hepatocytes exposed to FB1augments the intricate effects exerted on the lipid metabolism regarding CHOL, SMand PE. The disruption of lipid and fatty acid constituents, such as arachidonic acidand ceramide, are likely to be key determinants affecting growth regulatory signalingpathways relevant to the critical balance between cell proliferation and apoptosisduring cancer promotion. These changes provide further evidence that FB1 inducecancer promotion by differential inhibition and/or stimulation process whereby a fewresistant 'initiated hepatocytes proliferate in an environment where the growth ofnormal cells is inhibited. A specific lipogenic phenotype is effected by FB1 which isclosely associated with cancer development and considered to occur via anepigenetic-type of mechanism. These effects are not adequately addressed indefining risk assessment parameters.

[发布机构] Stellenbosch University