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

全氟辛烷磺酸 (PFOS) 通过 PPAR-α 影响免疫力。

• 批准号: 7144523
• 负责人: MARGIE M PEDEN-ADAMS
• 金额: $ 6.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144523
• 关键词: B lymphocyte; CD40 molecule; T lymphocyte; antibody formation; biological signal transduction; environmental exposure; environmental toxicology; enzyme linked immunosorbent assay; gene expression; genetically modified animals; immunoglobulin M; immunosuppression; immunotoxicity; interleukin 4; interleukin 5; interleukin 6; laboratory mouse; peroxisome proliferator activated receptor; sulfonate

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.

描述（由申请方提供）：全氟辛烷磺酸（PFOS）等全氟碳氢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、人类血清、母乳和脐带血中检测到了PFOS的浓度。此外，它们具有持久性、生物累积性和高毒性。引起关注的原因不仅是持久性和记录的毒性，而且是不确定性和数据空白，包括影响机制、接触途径、体内动力学、目前人类生物监测数据中的人口代表性不足以及缺乏对亚致死接触影响的了解。这类化合物中的许多化合物，如全氟辛烷磺酸，都是PPAR-alpha配体。我们已经证明，PFOS和降解为PFOS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抑制IL-6的产生，这样的配体。我们推测，与PPAR-alpha连接相关的合理解释是通过NF-κ B和c-Jun的拮抗作用以及由此产生的IL-6产生的抑制，从而导致IL-6刺激IgM产生的抑制。假设：全氟辛烷磺酸通过激活PPAR-alpha并随后抑制B细胞产生IL-6来调节抗体的产生。通过评估野生型（对照）和无PPAR-alpha小鼠（分别为129/SvlmJ和129 S4/SvJae-Pparatm 1Gonz/J小鼠）的TNP-KLH抗体反应，确定PPAR-alpha在全氟辛烷磺酸抑制依赖T细胞的抗体产生中的作用。小鼠将在28天内接受0、0.5或5毫克/千克全氟辛烷磺酸的治疗（总剂量）。在处死前7天，将对小鼠注射TNP-KLH，并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B6 C3 F1小鼠的CD 40和CD 154表达、B细胞IL-6产生和T细胞因子（IL-4、IL-5和IL-6）产生，研究全氟辛烷磺酸对T细胞依赖性抗体产生的可能作用模式。这将包括两组实验，其中小鼠将在28天内接受0、0.5或5毫克/千克全氟辛烷磺酸的治疗（总剂量）。在实验A中，小鼠将在处死前7天注射TNP-KLH。在实验B中，小鼠将不进行免疫。将进行未免疫和免疫实验，以控制与免疫接种的淋巴细胞活化相关的应答的可能差异。