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Modeling the interaction of binary and ternary mixtures of estradiol with bisphenol A and bisphenol A F in an in vitro estrogen mediated transcriptional activation assay (T47D-KBluc)
Citation:
Bermudez, D., L. E. GRAY, AND V. S. WILSON. Modeling the interaction of binary and ternary mixtures of estradiol with bisphenol A and bisphenol A F in an in vitro estrogen mediated transcriptional activation assay (T47D-KBluc). Presented at NC Society of Toxicology Regional Chapter Meeting, RTP, NC, October 07, 2010.
Impact/Purpose:
abstract submission for NCSOT PARC2010
Description:
Exposure to xenoestrogens occurs against a backdrop to physiological levels of endogenous estrogens. Endogenous estrogen levels vary from low levels in early childhood to high levels during pregnancy and in young women. For example, children have circulating E2concentrations ranging from 0.3-50 pM (0.08 -13 ng/L), while women in late pregnancy have circulating concentrations of' E2, are as high as 60-88 nM (16.35-24 ug/L). Therefore, data examining the interaction of environmental estrogens like BPA or its analogues with the ER when in concert with endogenous estrogens such as E2 are needed. However, few studies have addressed how xenoestrogens interact with endogenous estrogens. The current study was designed to characterize the individual dose-response curves of estradiol-l7B (E2), bisphenol A (BPA), tetrabromo-bisphenol A (TBBPA) and bisphenol AF (BPAF, 4,4'Hexafluoroisopropylidene diphenol) on estrogen-dependent luciferase expression in T47D-KBluc cells and to determine how binary (8x8 factorial) and ternary (4x4x4 factorial) mixtures of an endogenous estrogen (E2) interact with the ER in the presence of BPA and/or BPAF. The study was also designed to determine concentrations of BPA and BPAF that enhanced the response induced by increasing concentrations of E2, to simulate how these xenoestrogens might interact with physiological levels of estrogens during different life stages. Using a transcriptional-activation assay, individual compounds and binary and ternary mixtures of an endogenous estrogen (E2) with BPA or its analogues (TBBPA and BPAF) were tested. Dose-response parameters (EC50and Hillslope) obtained from individual chemical experiments were incorporated into a dose-addition model to predict the responses elicited by mixtures of E2 and BPA, E2 and BPAF and E2, BPA and BPAF in order to develop a predicted response surface plot. Additionally, EC50 values and mixture concentrations were incorporated into the toxic equivalence (TEQ) model of additivity to develop an estrogen equivalence (EEQ) model, to compare the EEQ predictions with those obtained with dose addition modeling. The TEQ model is a specific type of dose-addition model that assumes same slopes and requires less data to calculate.