title: Joint effects of heterogeneous estrogenic chemicals in the E-screen--exploring the applicability of concentration addition.
abstract: In the last few years, significant advances have been made toward understanding the joint action of endocrine disrupting chemicals (EDCs). A number of studies have demonstrated that the combined effects of different types of EDCs (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by the model of concentration addition (CA). However, there is still limited information on the effects of mixtures of large numbers of chemicals with varied structural features, which are more representative of realistic human exposure scenarios. The work presented here aims at filling this gap. Using a breast cancer cell proliferation assay (E-Screen), we assessed the joint effects of five mixtures, containing between 3 and 16 estrogenic agents, including compounds as diverse as steroidal hormones (endogenous and synthetic), pesticides, cosmetic additives, and phytoestrogens. CA was employed to predict mixture effects, which were then compared with experimental outcomes. The effects of two of the mixtures tested were additive, being accurately predicted by CA. However, for the three other mixtures, CA slightly overestimated the experimental observations. In view of these results, we hypothesized that the deviations were due to increased metabolism of steroidal estrogens in the mixture setting. We investigated this by testing the impact of two such mixtures on the activation and expression of steroidal estrogen metabolizing enzymes, such as cytochrome P450 (CYP) 1A1, CYP 1B1, and CYP 3A4. Activation of CYP 1B1 and, consequently, a reduction in the levels of steroidal estrogens in the mixture could contribute to the shortfall from the additivity prediction that we observed.
authors.affiliation: Centre for Toxicology, School of Pharmacy, University of London, London WC1N1AX, UK. elisabete.silva@pharmacy.ac.uk
authors.forename: Elisabete
authors.initials: E
authors.lastname: Silva
authors.forename: Nissanka
authors.initials: N
authors.lastname: Rajapakse
authors.forename: Martin
authors.initials: M
authors.lastname: Scholze
authors.forename: Thomas
authors.initials: T
authors.lastname: Backhaus
authors.forename: Sibylle
authors.initials: S
authors.lastname: Ermler
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortenkamp
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D045744:Cell Line, Tumor; D045424:Complex Mixtures / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D017711:Nonlinear Dynamics; D010575:Pesticides / Q000494:pharmacology*; D048789:Phytoestrogens / Q000494:pharmacology*; D012044:Regression Analysis; D018570:Risk Assessment
chemical_list: D045424:Complex Mixtures; D052244:Endocrine Disruptors; D004967:Estrogens; D010575:Pesticides; D048789:Phytoestrogens; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human