Mycotoxin mixtures in food and feed: holistic, innovative, flexible risk assessment modelling approach: MYCHIF

Mycotoxins are toxic compounds mainly produced by fungi of the genera Aspergillus, Penicillium and Fusarium. They are present, often as mixtures, in many feed and food commodities including cereals, fruits and vegetables. Their ubiquitous presence represents a major challenge to the health and well being of humans and animals. Hundreds of compounds are listed as possible mycotoxins occurring in raw and processed materials destined for human food and animal feed. In this study, mycotoxins of major toxicological relevance to humans and target animal species were investigated in a range of crops of interest (and their derived products). Extensive Literature Searches (ELSs) were undertaken for data collection on: (i) ecology and interaction with host plants of mycotoxin producing fungi, mycotoxin production, recent developments in mitigation actions of mycotoxins in crop chains (maize, small grains, rice, sorghum, grapes, spices and nuts), (ii) analytical methods for native, modified and co-occurring mycotoxins (iii) toxicity, toxicokinetics, toxicodynamics and biomarkers relevant to humans and animals (poultry, suidae (pig, wild boar), bovidae (sheep, goat, cow, buffalo), rodents (rats, mice) and others (horses, dogs), (iv) modelling approaches and key reference values for exposure, hazard and risk modelling. Comprehensive databases were created using EFSA templates and were stored in the MYCHIF platform. A range of approaches were implemented to explore the modelling of external and internal exposure as well as dose-response of mycotoxins in chicken and pigs. In vitro toxicokinetic and in vivo toxicity databases were exploited, both for single compounds and mixtures. However, large data gaps were identified particularly with regards to absence of common statistical and study designs within the literature and constitute an obstacle for the harmonisation of internal exposure and dose-response modelling. Finally, risk characterisation was also performed for humans as well as for two animal species (i.e. pigs and chicken) using available tools for the modelling of internal dose and a component-based approach for selected mycotoxins mixtures

Mesalazine initiates an anti-oncogenic β-catenin / MUCDHL negative feed-back loop in colon cancer cells by cell-specific mechanisms

Chronic inflammation associated with intestinal architecture and barrier disruption puts patients with inflammatory bowel disease (IBD) at increased risk of developing colorectal cancer (CRC). Widely used to reduce flares of intestinal inflammation, 5-aminosalicylic acid derivatives (5-ASAs) such as mesalazine appear to also exert more direct mucosal healing and chemopreventive activities against CRC. The mechanisms underlying these activities are poorly understood and may involve the up-regulation of the cadherin-related gene MUCDHL (CDHR5). This atypical cadherin is emerging as a new actor of intestinal homeostasis and opposes colon tumorigenesis. Here, we showed that mesalazine increase mRNA levels of MUCDHL and of other genes involved in the intestinal barrier function in most intestinal cell lines. In addition, using gain / loss of function experiments (agonists, plasmid or siRNAs transfections), luciferase reporter genes and chromatin immunoprecipitation, we thoroughly investigated the molecular mechanisms triggered by mesalazine that lead to the up-regulation of MUCDHL expression. We found that basal transcription of MUCDHL in different CRC cell lines is regulated positively by CDX2 and negatively by β-catenin through a negative feed-back loop. However, mesalazine-stimulation of MUCDHL transcription is controlled by cell-specific mechanisms, involving either enhanced activation of CDX2 and PPAR-γ or repression of the β-catenin inhibitory effect. This work highlights the importance of the cellular and molecular context in the activity of mesalazine and suggests that its efficacy against CRC depends on the genetic alterations of transformed cells