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Joint Effects of Heterogeneous Estrogenic Chemicals in the E-Screen-Exploring the Applicability of Concentration Addition

Journal article
Authors Elisabete Silva
Nissanka Rajapakse
Martin Scholze
Thomas Backhaus
Sibylle Ermler
Andreas Kortenkamp
Published in Toxicological Sciences
Volume 122
Issue 2
Pages 383-394
ISSN 1096-6080
Publication year 2011
Published at Department of Plant and Environmental Sciences
Pages 383-394
Language en
Keywords endocrine disrupters, mixtures, xenoestrogens, E-Screen, cytochrome P450, BREAST-CANCER CELLS, ESTRADIOL METABOLITES, MIXTURES, MCF-7, PROLIFERATION, XENOESTROGENS, RECEPTOR, ASSAY, EXPRESSION, 1A1
Subject categories Biological Sciences


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.

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