Synergistic activation of pregnane X (PXR), peroxisome proliferator activated gamma (PPAR?) and aryl hydrocarbon (AHR) receptors by chemical mixtures – SYNERGY

Humans are chronically exposed to a broad mix of contaminants referred to as endocrine-disrupting chemicals (EDCs). Most of the reported harmful effects of these compounds are attributed to their interference with soluble receptors acting as ligand-regulated transcription factors controlling a plethora of biological processes. Our past work has contributed to increase our knowledge of the mechanisms by which EDCs can substitute for endogenous ligands and alter the functions of their target receptors. Beside their individual effects, we also reported on mechanisms whereby chemical mixtures can synergistically alter cell signaling. We showed a robust activation of the pregnane X receptor (PXR) by mixtures of chemicals exhibiting very low intrinsic activity. Decrypting the mechanisms contributing to the so-called “cocktail effect" is essential to understand the real impact of chemicals on human health.

In the SYNERGY project our aim will be to (1) get a deeper molecular understanding of these synergistic effects on PXR signaling, (2) explore if the underlying mechanisms can be operative in other EDC receptors such as PPAR? (peroxisome proliferator-activated-receptor gamma) and AHR (aryl hydrocarbon receptor), (3) identify EDCs targeting the overlooked receptor RXR which serves as an obligate heterodimerization partner of many nuclear receptors, including PXR and PPAR?, and (4) evaluate the toxicological outcome of synergic mixtures in vivo, and more specifically in the liver and adipose tissue where all receptors under study are known to play essential regulatory roles.

Our integrative approach will combine a set of cell-based, structural, biophysical, and in vivo assays. The knowledge gained from these studies, from the atomic to the whole organism scale, will have broad-reaching implications in the fields of toxicology, endocrine disruption, and pharmacology.