Perfluorooctane Sulfonate (PFOS) affects 1gM Production via IL-2

说明(申请人提供)：全氟辛烷磺酸(全氟辛烷磺酸)等全氟碳氢化合物是新出现的令人关注的污染物。已经在水、房屋灰尘和人血清中检测到全氟辛烷磺酸的浓度。全氟辛烷磺酸具有持久性、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激动剂。我们已经证明，全氟辛烷磺酸抑制T依赖(TDAR)和T非依赖(TI)抗体的产生，但在PPAR-α/-小鼠中这一点没有改变。我们还发现，IL-4、IL-5、IL-6和CD40、CD154的表达和信号的改变与抑制IgM的产生无关。我们推测，IgM抑制可能是通过已知PPAR-α配体抑制IL-2的产生而发生的，因为IL-2的产生对TDAR和TI抗体反应都很重要，而抗体产生的抑制在PPAR-α缺陷小鼠中没有发生。然而，为了更好地了解POFS对免疫系统的完整影响，应该评估与抗体产生相关的其他关键因素。假设：全氟辛烷磺酸通过改变T细胞IL-2的产生而抑制抗体的产生，但不会产生巨噬细胞细胞因子或改变CD25、CD27或CD70的表达。目的1.探讨T细胞IL-2、巨噬细胞IL-1、IL-10及CD25、CD27、CD70的表达在全氟辛烷磺酸抑制静息(未感染)免疫细胞产生抗体中的作用。目的：探讨T细胞IL-2、巨噬细胞IL-1和IL-10以及CD25、CD27和CD70的表达在全氟辛烷磺酸抑制绵羊红细胞攻击(活化)免疫细胞产生抗体中的作用。这项研究的数据将有助于这种化合物的危险评估，增加作用模式的信息，以便确定作用机制，并将导致关于PPAR-α激动剂在抗体产生中的作用的新信息。公共卫生相关性：确定全氟辛烷磺酸与抗体产生有关的模式和/或机制或作用对人类健康很重要，因为：1)在啮齿动物模型中，抗体产生的影响已被报告在人类体内；2)抑制IgM的产生与增加疾病的易感性有关，3)根据目前的数据进行危害和风险评估，而没有作用机制的信息将导致没有安全边际；因此，最有可能的是高估了接触所带来的人类健康风险。此外，了解影响的模式或机制还可以识别可以在人类身上评估的标记，以更好地确定真正的风险，而不是来自啮齿动物研究的相对风险。

DESCRIPTION (provided by applicant): Perfluorinated hydrocarbon compounds such as perfluorooctane sulfonate (PFOS) are emerging contaminants of concern. Concentrations of PFOS have been detected in water, house dust and in human serum. PFOS is persistent, bioaccumulative, and highly toxic. 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 agonists. We have shown that PFOS inhibits both T-dependent (TDAR) and T-independent (TI) antibody production but this is not altered in PPAR-alpha -/- mice. We have also shown that alterations in IL-4, IL-5, IL-6 and CD40, CD154 expression and signalling are not related to suppression of IgM production. We speculate that IgM suppression may occur through the known suppression of IL-2 production by PPAR-alpha ligands, since IL-2 production is important to both TDAR and TI antibody responses and suppression of antibody production does not occur in PPAR-alpha deficient mice. However, to better understand the complete effects POFS has on the immune system other critical factors associated with antibody production should be assessed. Hypothesis: PFOS suppresses antibody production via altered T-cell IL-2 production but not macrophage cytokine production or altered CD25, CD27, or CD70 expression. Aim 1. To determine the role of T-cell IL-2, Macrophage IL-1 and IL-10, and CD25, CD27, and CD70 expression in the suppression of antibody production by PFOS in resting (unchallegened) immune cells. Aim 2. To determine the role of T-cell IL-2, Macrophage IL-1 and IL-10, and CD25, CD27, and CD70 expression in the suppression of antibody production by PFOS in sheep red blood cell challenged (activated) immune cells The unimmunized and immunized experiments will be conducted to control for possible differences in responses related to lymphocyte activation from the immunization used to determine decreased antibody production. The data from this study will aid in hazard assessment of this compound, increase information on mode of action so that the mechanism of action can be determined, and will lead to new information on the role of PPAR-alpha agonists in antibody production. PUBLIC HEALTH RELEVANCE: Determination of the mode and or mechanism or action of PFOS in relation to antibody production is important to human health because: 1) effects on antibody production occur in rodent models at serum concentrations that have been reported in humans, 2) suppression of IgM production is related to increased disease susceptibility, and 3) basing hazard and risk assessments on current data without mechanism of action information would result in no margin of safety; thereby; most likely, overestimating human health risk from exposure. Moreover, understanding the mode or mechanism of effect may also allow identification of markers that can be assessed in humans to better determine true risk as opposed to relative risk derived from rodent studies.