You are here:
EVALUATION OF PERFLUOROALKYL ACID ACTIVITY USING PRIMARY MOUSE AND HUMAN HEPATOCYTES
Citation:
ROSEN, M. B., K. DAS, C. R. WOOD, C. J. WOLF, B. D. ABBOTT, AND C. LAU. EVALUATION OF PERFLUOROALKYL ACID ACTIVITY USING PRIMARY MOUSE AND HUMAN HEPATOCYTES. Presented at Society of Toxicology (SOT) Annual meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Here we use both mouse and human primary heptatocytes to further assess the biological activity ofa similar group of PFAAs using custom designed Taqman Low Density Arrays.
Description:
While perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been studied at length, less is know about the biological activity of other environmental perfluoroalkyl acids (pFAAs). Using a transient transfection assay developed in COS-l cells, our group has previously evaluated a variety of PFAAs for activity associated with activation of peroxisome proliferator-activated receptor alpha (PPARa). Here we use both mouse and human primary heptatocytes to further assess the biological activity of a similar group of PFAAs using custom designed Taqman Low Density Arrays. Commercially available primary mouse and human hepatoyctes were cultured for 48 hours in the presence of varying concentrations of 12 different PFAAs or WyI4,643, a known activator of PPARa. Total RNA was collected and the expression of 48 mouse or human genes was evaluated. Gene selection was based on either in house liver microarray data (mouse) or published data using primary hepatocytes (human). Gene expression in primary mouse hepatocytes was more restricted than expected. The expression of genes typically regulated in whole tissue by PPARα agonists, such as Acox1, Me1, Acaa1a, Hmgcsl, and Slc72al was not altered in mouse cells. Cyp2bl0, a gene regulated by the constitutive androstane receptor and a transcript normally up-regulated by in-vivo exposure to PFAAs, was also unchanged in mouse cells. CYP4all, Ehhadh, Pdk4, Cptlb, and Fabpl were regulated as expected in mouse cells. In human primary hepatocytes, changes in gene expression were not robust making the determination of dose response across a wide group of genes and compounds difficult. This likely reflects weaker activation of PPARa in human versus rodent cells. Unlike mouse cells, CYP2B6 was up-regulated in human primary hepatocytes by certain PFAAs as was PPARα. Ranking of biological activity was determined based on a limited list of responsive genes and contrasted to data collected from COS-l cells. (This abstract does not necessarily reflect EPA policy.)