Back to search

BEDREHELSE-Bedre helse og livskvalitet

Effects of realistic mixtures of mould and mycotoxins on the immune system and assessment of human exposure

Awarded: NOK 5.0 mill.

Project Number:


Application Type:

Project Period:

2012 - 2016


Partner countries:

-Monocytes are immune cells that may be differentiated into macrophages or dendritic cells (DC), depending on environmental conditions. Macrophages exist in minimum two different forms, proinflammatory M1 and anti-inflammatory M2 cells and the functioning of the immune system is dependent on the balance between the forms. We have shown that the mycotoxin enniatin B trigger a differentiation from mouse monocytes (RAW264.7) to M2 macrophages, while another mycotoxin alternariol (AOH) triggers a differentiation into M1/DC like immune cells. DON did not trigger any differentiation of these cells. Enniatin B1 also triggered the macrophages secretion of the proinflammatory signal molecule IL-1beta, a molecule that stimulates the immune system. Previous exposure of the cells to LPS, a marker of infection by gram-negative bacteria, had a potentiating effect on enniatin B1s ability to increase the production of IL-1beta. LPS had no effect on the LPS had no such potentiating effect on DON in this model. Similar studies where done using macrophages from human blood donors to confirm the relevance of these findings to humans. Non-differentiated cells exposed to AOH differentiated into DC-like cells, while enniatin B and DON did not have any effect in this model. But in contrast to the findings from mouse cells, DON triggered an increase in IL-1 beta production in LPS treated cells. Enniatin B did not have any effect in these cells. The findings demonstrate the importance of conducting such studies in a model representing the species of interest. We have also found that AOH increase autophagy in RAW cells. Autophagy is a strictly regulated degradation of cell components like proteins and organelles, and mostly proteins and organelles that are not functional any more. A tight regulation of this process is needed to maintain the function and control of the cells, and any disturbances in the regulation of this process may have serious effects. Due to the different response in mouse and human immune cells, further studies of the mycotoxins ability to alter the differentiation of immune cells and their effect on the production of signal molecules that are vital for the functioning of the immune system were conducted using the human THP-1 monocyte cell line. These studies were conducted with and without activation of the immune cells using LPS. The studies indicated that mycotoxins normally present in grain may affect the differentiation processes in different ways, leading to different pattern of immune cells. Furthermore, some mycotoxins trigger the production of specific signal molecules in the immune system, while other mycotoxins have no effect of affect the production of other signal molecules with different effects on the immune system. Finally, we studied the effects of mixtures of low and realistic concentrations of mycotoxins on the differentiation of immune cells and the production of signal molecules. We have found that the differentiation process is the most sensitive step and further studies of mixtures were therefore focused on this process. The findings indicated that the mixtures mainly have an additive effect, but a weak synergistic effect was observed of the combination of zearalenone and AOH. Finally we have analysed the occurrence of DON and its metabolites in human urine samples. Almost all samples contains detectable levels of DON and its metabolites. Furthermore, we have compiled data for the occurrence of DON in Norwegian flour and a database With the dietary consumption of the individuals donating urine samples. Estimations of dietary intake and correlations With the urinary DON levels will be finalised this automn. Finally a paper summarizing the findings and assessing the risk Associated With the dietary exposure to mycotoxins from grain will be finalised.

Cereals are infected by a range of biological and chemical contaminants, including fungi, mycotoxins such as DON and HT-2 toxin, bacteria and protozoa. Humans ingesting cereals are therefore exposed to a mixture of contaminants. DON is present in almost a ll samples of cereal-based food. Previous estimations of the dietary exposure in Norway indicate that groups of the population may have an intake close to or exceeding the Tolerable Daily Intake; and the levels in grains seems to increase. An improved est imate of the human exposure is therefore needed to ensure that the levels are safe. Samples of human blood and urine from individuals with a known diet will be analysed for mycotoxins. A database on trichothecenes in food will be made. The intake of trich othecenes will be estimated from both biomonitoring and food data and major sources of trichothecenes in the diet identified. The estimated intake will be compared with the TDIs. The effects of DON and the sum of T-2 toxin and HT-2 toxins occurring at dos es realistic for humans are feed refusal, gastrointestinal disturbances, impairment of the immune system and the reduced formation of blood cells. Naturally infected grains are more toxic than feed with the corresponding levels of pure toxin, suggesting s ynergistic effects. Here we will explore the possible role of other biological agents, infections for mycotoxin-induced inflammatory effects in primary human immune cells. The effects of priming immune cells with various biological relevant components (re ceptor ligands) before exposure to selected Fusarium and Alternaria mycotoxins on cytokine production in will be examined. The effects of the most interesting single contaminants and component will be examined in a model on the interaction between the ep ithelial layer and immune cells will be explored in in vitro and the effects of mixtures will be characterized in the most sensitive model.

Publications from Cristin

No publications found

Funding scheme:

BEDREHELSE-Bedre helse og livskvalitet