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

描述（由申请人提供）：由于在地表水、房屋灰尘样本、加工牛奶、碎牛肉、人血清、母乳和脐带血中检测到全氟辛烷磺酸（PFOS）等全氟烃化合物的浓度，它们是令人关注的新污染物。此外，它们具有持久性、生物蓄积性和高毒性。引起关注的原因不仅在于持久性和已记录的毒性，还在于不确定性和数据缺口，包括效应机制、暴露途径、体内动力学、当前人类生物监测数据中未代表的人群，以及缺乏对亚致死暴露效应的理解。这一类的许多化合物，如全氟辛烷磺酸，都是ppar - α配体。我们已经证明全氟辛烷磺酸和降解为全氟辛烷磺酸的化合物调节T依赖性抗体的产生。我们推测这可能是通过已知的这种配体对IL-6产生的抑制而发生的。我们推测，ppar - α连接的一个合理解释是通过NF-kappa B和c-Jun的拮抗以及由此产生的IL-6的抑制，从而抑制IL-6对IgM产生的刺激。假设：PFOS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PPAR α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PFOS抑制t依赖性抗体产生中的作用。小鼠将在28天内接受0、0.5或5 mg/kg全氟辛烷磺酸（总剂量）的治疗。在献祭前7天给小鼠注射TNP-KLH，在研究结束时收集血清以评估tnp特异性IgM。目标2。通过评估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PFOS对T依赖性抗体产生的可能作用模式。这将包括两组实验，小鼠将在28天内接受0、0.5或5 mg/kg全氟辛烷磺酸（总剂量）的治疗。在实验A中，在献祭前7天给小鼠注射TNP-KLH。实验B小鼠不免疫。将进行未免疫和免疫实验，以控制免疫引起的淋巴细胞活化反应的可能差异。

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.