Perfluorooctane sulfonate (PFOS) Affects Immunity through PPAR-alpha.

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DESCRIPTION (provided by applicant): Perfluorinated hydrocarbon compounds such as - perfluorooctane sulfonate (PFOS) are emerging contaminants of concern as concentrations of PFOS have been detected in surface water, house dust samples, processed milk, ground beef, and human serum, breast milk, and cord blood. Moreover they are persistent, bioaccumulative, and highly toxicity. Cause for concern is not only driven by the persistence and the documented toxicity, but by the uncertainty and data gaps including mechanisms of effects, exposure routes, kinetics in the body, under representation of populations in the current human biomonitoring data, and lack of understanding of sublethal exposure effects. Many compounds in this class, like PFOS, are PPAR-alpha ligands. We have shown that PFOS and compounds that degrade to PFOS modulate T- dependent antibody production. We speculate that this may occur through the known suppression on IL-6 production by such ligands. We speculate, that a plausible explanation related to PPAR-alpha ligation is through antagonism of NF-kappa B and c-Jun and the resultant inhibition of IL-6 production thereby resulting in inhibition of IL-6 stimulation of IgM production. Hypothesis: PFOS modulates antibody production through PPAR-alpha activation and subsequent suppression of B-cell IL-6 production.Aim 1. To determine the role of PPAR-alpha in the suppression of T-dependent antibody production by PFOS by assessing TNP-KLH antibody responses in wild type (control) and PPAR alpha null mice (129/SvlmJ &129S4/SvJae- Pparatm1Gonz/J mice; respectively). Mice will be treated with 0, 0.5 or 5 mg/kg PFOS over a 28-day period (total dose). Seven days prior to sacrifice mice will be injected with TNP-KLH and at the end of the study serum will be collected to assess TNP-specific IgM. Aim 2. To study possible modes of action of PFOS on T-dependent antibody production by assessing CD40 and CD154 expression, B-cell IL-6 production and T- cell cytokine production (IL-4, IL-5, and IL-6) in B6C3F1 mice. This will consist of two experimental sets where mice will be treated with 0, 0.5 or 5 mg/kg PFOS over a 28-day period (total dose). In Experiment A mice will be injected with TNP-KLH seven days prior to sacrifice. In Experiment B mice will not be immunized. The unimmunized and immunized experiments will be conducted to control for possible differences in response related to lymphocyte activation from the immunization.