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Evaluating the additivity of perfluoroalkyl acids (PFAAs) in binary combinations on peroxisome proliferator-activated receptor-a(PPARa) activation
Citation:
Wolf, Cynthiaj, C. Ryder, C. Lau, AND B. Abbott. Evaluating the additivity of perfluoroalkyl acids (PFAAs) in binary combinations on peroxisome proliferator-activated receptor-a(PPARa) activation. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 316:43-54, (2014).
Impact/Purpose:
Humans are exposed to a multitude of environmental contaminants. Many environmental contaminants are found not as a single chemical, but as a group of chemicals of the same family. Perfluoroalkyl acids (PFAAs) are one such class of chemicals. Assessing the health risks of PFAAs must take into consideration the joint action of their mixtures.
Description:
Perfluoroalkyl acids (PFAAs) are found globally in the environment, detected in humans and wildlife, and are typically present as mixtures of PFAA congeners. Mechanistic studies have found that responses to PFAAs are mediated in part by PPARa. Our previous studies showed that individual PFAAs activate PPARa transfected into COS-1 cells. Here we evaluated whether the binary combinations of perfluorooctanoic acid (PFOA) and another PFAA act in an additive fashion to activate PPARa. COS-1 cells were transiently transfected with mouse PPARa luciferase reporter plasmid and exposed to either vehicle control (0.1% DMS0 or water), PPARa agonist (WY14643, 10uM), PFOA at 1- 128 uM, perfluorononanoic acid (PFNA) at 1- 128 uM, perfluorohexanoic acid (PFHxA) at 8—1024 uM, perfluorooctane sulfonate (PFOS) at 4—384 uM or perfluorohexane sulfonate (PFHxS) at 8—2048 uM to generate sigmoidal concentration-response curves. In addition, cells were exposed to binary combinations of PFOA + either PFNA, PFHxA, PFOS or PFHxS in an 8x8 factorial design. The concentration-response data for individual chemicals were fit to sigmoidal curves and analyzed with nonlinear regression to generate EC5Os and Hillslopes, which were used in response-addition and concentration-addition models to calculate predicted responses for mixtures in the same plate. All PFOA+PFAA combinations produced concentration-response curves that were closely aligned with the predicted curves for both response addition and concentration addition at low concentrations. However, at higher concentrations of all chemicals, the observed response curves deviated from the predicted models of additivity. We conclude that binary combinations of PFAAs behave additively at the lower concentration ranges in activating PPARa in the COS-1 cell system.