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Mechanisms of perfluoroalkyl acid (PFAA) toxicity: Involvement of peroxisome proliferator activator receptor alpha (PPAR) molecular signals.
Citation:
U.S. EPA, AND B. D. ABBOTT. Mechanisms of perfluoroalkyl acid (PFAA) toxicity: Involvement of peroxisome proliferator activator receptor alpha (PPAR) molecular signals. Presented at PFAA Days II, RTP, NC, June 03 - 04, 2008.
Impact/Purpose:
This research investigates the mode-of-action for perfluorinated compounds to support the risk assessment.
Description:
Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of environmentally persistent perfluorinated compounds and are found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in rats and mice. Exposure in utero reduces postnatal survival and growth and delays development. PFOS and PFOA are weak agonists of PPARα , a causal pathway for induction of hepatocellular carcinoma in rodents. This presentation addresses the question of whether PPARα is involved in the mode-of-action for PFOA and PFOS-induced developmental toxicity and discusses the potential for PFAA to activate PPARα in an in vitro model. In in vivo studies, WT and PPARα KO mice were exposed to PFOA at 0 – 20 mg/kg/day from GD1-17 or PFOS at 0-10.5 mg/kg/day from GD15-17. These studies demonstrated that PFOA-induced postnatal lethality, growth effects, and delayed eye opening were dependent on expression of PPARα , but that the effects on early pregnancy loss were independent of PPARα . However, PFOS-induced neonatal lethality and delayed eye opening were not dependent on activation of PPARα . Additional studies are required to further define the modes-of-action for PFOA and PFOS-induced developmental toxicity. In vitro transfected cell assays were used to evaluate the ability of PFAA of various carbon chain lengths, (both perfluoroalkyl and sulfonic acids), to activate the ligand binding domain (LBD) of mouse or human PPARα . Cos-1 cells were transfected with a plasmid containing either the mouse or human PPARα LBD and a luciferase reporter and incubated with perfluoroalkyl acids of 4, 6, 8, 9 or 10 carbon chain length or perfluorosulfonic acids of 4, 6, or 8 carbon chain length. The perfluoroalkyl acids were more active than the sulfonic acids. The activity generally increased with increasing chain length, and PFAAs generally activated plasmid containing the mouse LBD to a greater degree than the human LBD. While this model is useful for determining the potential for PFAA to activate mouse or human PPARα , it cannot address whether these compounds would activate PPARα in a physiological system. In summary, our in vitro studies indicate that the PFAAs examined have the potential to act via a PPARα mode-of-action and the in vivo studies confirmed that PFOA, but not PFOS, has a PPARα -dependent mode-of-action for developmental toxicity in the mouse. Thus, PFAAs with the ability to activate PPARα and produce similar outcomes, may or may not have the same mode-of-action. It may be necessary to determine for each PFAA, and possibly for each outcome, whether a PPARα mode-of-action exists. This abstract does not necessarily reflect US EPA policy.