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

描述(由申请人提供)：全氟辛烷磺酸(全氟辛烷磺酸)等全氟化烃化合物是新出现的令人关注的污染物，因为在地表水、室内灰尘样本、加工牛奶、碎牛肉、以及人血清、母乳和脐带血中检测到全氟辛烷磺酸的浓度。此外，它们具有持久性、生物蓄积性和高度毒性。令人担忧的原因不仅是持久性和有据可查的毒性，而且是不确定性和数据差距，包括影响机制、接触途径、体内动力学、当前人体生物监测数据中种群的代表性不足以及对亚致死剂量暴露影响缺乏了解。这一类中的许多化合物，如全氟辛烷磺酸，都是PPAR-α配体。我们已经证明了全氟辛烷磺酸及其降解为全氟辛烷磺酸的化合物能够调节T依赖抗体的产生。我们推测，这可能是通过这些配体对IL-6产生的已知抑制而发生的。我们推测，与PPAR-α连接有关的一个合理的解释是通过拮抗核因子-kappaB和c-jun，从而抑制IL-6的产生，从而抑制IL-6刺激IgM的产生。假设：全氟辛烷磺酸通过激活PPAR-α和随后抑制B细胞IL-6的产生来调节抗体的产生。目的1.通过评估野生型(对照)和PPARα缺失小鼠(分别为129/SvlmJ和129S4/SvJae-Pparatm1Gonz/J小鼠)的TNP-KLH抗体反应，确定PPAR-α在抑制全氟辛烷磺酸产生T依赖抗体中的作用。小鼠将在28天内接受0、0.5或5 mg/kg全氟辛烷磺酸的治疗(总剂量)。在牺牲前7天，小鼠将被注射TNP-KLH，在研究结束时，将收集血清以评估TNP特异性IgM。目的2.通过检测B6C3F1小鼠CD40和CD154的表达、B细胞IL-6的产生和T细胞细胞因子(IL-4、IL-5和IL-6)的产生，研究全氟辛烷磺酸对T依赖抗体产生的可能作用方式。这将由两组实验组成，在这两组实验中，小鼠将在28天内接受0、0.5或5 mg/kg全氟辛烷磺酸的治疗(总剂量)。在实验A中，小鼠在处死前7天注射TNP-K1H。在实验B中，小鼠将不会被免疫。将进行未免疫和免疫实验，以控制免疫后与淋巴细胞激活相关的反应可能存在的差异。

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.