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

全氟辛烷磺酸 (PFOS) 通过 IL-2 影响 1gM 产量

• 批准号: 7984776
• 负责人: MARGIE M PEDEN-ADAMS
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984776
• 关键词: Affect; Interleukin-2; Production; perfluorooctane sulfonate

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.

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。已在水、室内灰尘和人类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、生物累积性和剧毒性。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激动剂。我们已经证明，全氟辛烷磺酸抑制T依赖性（TDAR）和T非依赖性（TI）抗体的产生，但在PPAR-alpha -/-小鼠中没有改变。我们还表明，IL-4，IL-5，IL-6和CD 40，CD 154表达和信号传导的改变与IgM产生的抑制无关。我们推测IgM抑制可能通过已知的PPAR-alpha配体抑制IL-2产生而发生，因为IL-2产生对TDAR和TI抗体应答都很重要，而抗体产生的抑制不会发生在PPAR-alpha缺陷小鼠中。然而，为了更好地了解POFS对免疫系统的完整影响，应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的产生来抑制抗体的产生，但不会通过改变巨噬细胞细胞因子的产生或CD 25、CD 27或CD 70的表达来抑制抗体的产生。目标1。确定T细胞IL-2、巨噬细胞IL-1和IL-10以及CD 25、CD 27和CD 70的表达在全氟辛烷磺酸抑制静息（未激发）免疫细胞产生抗体方面的作用。目标二。为了确定T细胞IL-2、巨噬细胞IL-1和IL-10以及CD 25、CD 27和CD 70的表达在绵羊红细胞激发（激活）免疫细胞中全氟辛烷磺酸抑制抗体产生中的作用，将进行未免疫和免疫实验，以控制与用于确定抗体产生减少的免疫中淋巴细胞激活相关的反应的可能差异。本研究的数据将有助于该化合物的危害评估，增加关于作用模式的信息，以便确定作用机制，并将导致关于PPAR-alpha激动剂在抗体产生中的作用的新信息。公共卫生关系：确定全氟辛烷磺酸与抗体产生有关的作用模式和/或机制对人类健康十分重要，因为：1）在啮齿动物模型中，在已报道的人类血清浓度下，对抗体产生产生的影响，2）IgM产生的抑制与疾病易感性增加有关，以及3）根据目前的数据进行危害和风险评估，而不提供作用机制信息，将导致没有安全边际;因此，很可能高估了接触的人类健康风险。此外，了解影响的模式或机制还可以识别可以在人类中评估的标记物，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。