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Evaluation of additivity of binary mixtures of perfluoroalkyl acids (PFAAs) on peroxisome proliferator-activated receptor-alpha (PPARa) activation in vitro
Citation:
Wolf, Cynthiaj, C. Rider, C. Lau, AND B. Abbott. Evaluation of additivity of binary mixtures of perfluoroalkyl acids (PFAAs) on peroxisome proliferator-activated receptor-alpha (PPARa) activation in vitro. Presented at Society of Toxicology, March 10 - 14, 2013.
Impact/Purpose:
This abstract will be presented at the Society of Toxicology meeting March 10-14, 2013, San Antonio, TX
Description:
Perfluoroalkyl acids (PFAAs) are found globally in the environment and in animal tissues, and are present as mixtures of PFAA congeners. Mechanistic studies have found that in vivo effects of PFAAs are mediated by PPARL. Our previous studies showed that individual PFAAs activate PPARa transfected into COS- 1 cells. Here we evaluated whether binary combinations of perfluorooctanoic acid (PFOA, C8) and other PFAAs interact in an additive fashion to activate PPARa. COS-1 cells in 96 well plates were transiently transfected with mouse PPARcL luciferase reporter plasmid. After 24 hours, cells were exposed to either vehicle control (0.1 % DMSO or water), PPARa agonist (WY14643, 10 1iM), C8 or perfluorononanoic acid (C9) at I - 128 jiM, perfluorohexanoic acid (C6) at 8 — 1024 jiM, or perfluorooctane sulfonate (C8S) at 4 — 384 jiM to generate sigmoidal dose-response curves. In addition, cells in the same plate were exposed to binary combinations of C8 + either C6, C9, or C8S, in an 8x8 factorial design. After 24 hours of exposure, cells were lysed and luciferase activity was measured. Data were transformed on a fold-induction and % maximal response basis. The dose-response data for individual chemicals were fit to sigmoidal curves and analyzed with nonlinear regression to generate EC5Os and Hilislopes, which were used in response-addition and dose-addition models to calculate predicted responses for mixtures. All PFOA±PFAA combinations produced dose- response curves that were closely aligned with the predicted curves for both response addition and dose addition. However, at higher concentrations of all chemicals, the observed response curves deviated upward from the predicted models of additivity, although with more variability. We conclude that at the lower concentration ranges, binary combinations of PFAAs behave additively in activating PPARa in the COS-1 cell system. This abstract does not reflect USEPA policy.