title: A concentration addition model to assess activation of the pregnane X receptor (PXR) by pesticide mixtures found in the French diet.
abstract: French consumers are exposed to mixtures of pesticide residues in part through food consumption. As a xenosensor, the pregnane X receptor (hPXR) is activated by numerous pesticides, the combined effect of which is currently unknown. We examined the activation of hPXR by seven pesticide mixtures most likely found in the French diet and their individual components. The mixture's effect was estimated using the concentration addition (CA) model. PXR transactivation was measured by monitoring luciferase activity in hPXR/HepG2 cells and CYP3A4 expression in human hepatocytes. The three mixtures with the highest potency were evaluated using the CA model, at equimolar concentrations and at their relative proportion in the diet. The seven mixtures significantly activated hPXR and induced the expression of CYP3A4 in human hepatocytes. Of the 14 pesticides which constitute the three most active mixtures, four were found to be strong hPXR agonists, four medium, and six weak. Depending on the mixture and pesticide proportions, additive, greater than additive or less than additive effects between compounds were demonstrated. Predictions of the combined effects were obtained with both real-life and equimolar proportions at low concentrations. Pesticides act mostly additively to activate hPXR, when present in a mixture. Modulation of hPXR activation and its target genes induction may represent a risk factor contributing to exacerbate the physiological response of the hPXR signaling pathways and to explain some adverse effects in humans.
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), French National Institute for Agricultural Research (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, Sophia-Antipolis Cedex, France desousa@sophia.inra.fr rahmani@sophia.inra.fr.
authors.forename: Georges
authors.initials: G
authors.lastname: de Sousa
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), French National Institute for Agricultural Research (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, Sophia-Antipolis Cedex, France.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Nawaz
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), French National Institute for Agricultural Research (INRA), 180 chemin de Tournefeuille-BP 93173, Toulouse, Cedex 3, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cravedi
authors.affiliation: UMR 1331 TOXALIM (Research Centre in Food Toxicology), French National Institute for Agricultural Research (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, Sophia-Antipolis Cedex, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Rahmani
mesh_terms: D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D045424:Complex Mixtures / Q000032:analysis* / Q000633:toxicity; D004032:Diet; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000032:analysis* / Q000633:toxicity; D005506:Food Contamination / Q000032:analysis*; D005602:France; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008954:Models, Biological; D010573:Pesticide Residues / Q000032:analysis* / Q000633:toxicity; D011237:Predictive Value of Tests; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012044:Regression Analysis
chemical_list: D045424:Complex Mixtures; D052244:Endocrine Disruptors; D010573:Pesticide Residues; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D008156:Luciferases
keywords: concentration addition; exposure; hPXR; mixture; pesticides