Résumé
Metabolic endocrine-disrupting chemicals (MDCs) contribute to the development andincreasing incidence of metabolic disorders, highlighting the need for relevant assays to identifythem. Several alternative models to mammals, notably the zebrafish, have been developed, butnone of these assays account for the mode of action and effects of MDCs on intestine. Thisstudy aimed to 1) establish and characterize a transgenic embryo model expressing GFP underthe control of the zebrafish cyp3a65 gene, ortholog of the human cyp3a4, 2) set-up an originalzebrafish embryo-based bioassay to study the Effects of Metabolic Endocrine disRuptors in Gutof zebrafish Embryos (EMERGE). Spatiotemporal expression of cyp3a65-GFP and temporalendogenous cyp3a65 was characterized using fluorescence imaging of GFP,immunohistochemistry and RT-qPCR, under both normal and exposed conditions toclotrimazole and TCDD (respectively zfPXR and zfAhR2 agonists). Then, twenty-twochemicals were screened for their potential activity using the EMERGE assay. We report anearly and dynamic expression of cyp3a65 in the developing intestine which is disrupted in atime and concentration dependent manner by zfPXR and zfAhR2 agonists. Using EMERGE,we report that various environmental chemicals can significantly up- or down regulate cyp3a65expression, most of them being newly identified as targeting the intestine and disrupt thiscritical metabolic enzyme. In conclusion, EMERGE represents a new easy to use assay to screenmetabolic disrupting activity of chemicals in a non-mammalian model. The data collectedsuggest it could provide valuable insights into the effects of substances on cyp3a4 in humansand may emerge as a valuable assay for assessing human-relevant effects.