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

描述（由申请人提供）：全氟辛烷磺酸（PFOS）等全氟烃化合物是令人关注的新兴污染物。在水、室内灰尘和人类血清中都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。这类化合物中的许多化合物，如全氟辛烷磺酸，都是ppar - α激动剂。我们已经证明，PFOS抑制t依赖性（TDAR）和t非依赖性（TI）抗体的产生，但这在ppar - α -/-小鼠中没有改变。我们还表明，IL-4、IL-5、IL-6和CD40、CD154表达和信号传导的改变与抑制IgM的产生无关。我们推测IgM抑制可能是通过ppar - α配体对IL-2产生的已知抑制而发生的，因为IL-2的产生对TDAR和TI抗体应答都很重要，而在ppar - α缺陷小鼠中不会发生抗体产生的抑制。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：PFOS通过改变t细胞IL-2的产生抑制抗体的产生，而不是通过改变巨噬细胞细胞因子的产生或CD25、CD27或CD70的表达来抑制抗体的产生。目的1。确定t细胞IL-2、巨噬细胞IL-1和IL-10以及CD25、CD27和CD70表达在PFOS抑制静息（未挑战）免疫细胞抗体产生中的作用。目标2。为了确定t细胞IL-2、巨噬细胞IL-1和IL-10以及CD25、CD27和CD70表达在PFOS在绵羊红细胞挑战（激活）免疫细胞中抑制抗体产生的作用，将进行未免疫和免疫实验，以控制与免疫有关的淋巴细胞激活反应的可能差异，用于确定抗体产生的减少。这项研究的数据将有助于对该化合物进行危害评估，增加作用方式的信息，从而确定作用机制，并将导致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相关的模式和/或机制或作用对人类健康至关重要，因为：1)对抗体产生的影响发生在啮齿动物模型中，其血清浓度已在人类中报道过，2)抑制IgM产生与疾病易感性增加有关，以及3)根据当前数据进行危害和风险评估，而没有作用机制信息将导致没有安全边际；因此;最有可能的是，高估了暴露对人类健康的风险。此外，了解作用的模式或机制也可能有助于识别可在人类中评估的标记物，从而更好地确定真实风险，而不是从啮齿动物研究中得出的相对风险。

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.