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: 7846832
• 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/7846832
• 关键词: Acids; Adult; Affect; Agonist; Antibody Formation; Antibody Suppression; Antigens; B-Lymphocytes; Biological Monitoring; Blood; Blood specimen; Cells; Centers for Disease Control and Prevention (U.S.); Child; Data; Disease susceptibility; Dose; Erythrocytes; Exhibits; Exposure to; Half-Life; Hazard Assessment; Health; House Dust; Human; Hydrocarbons; IL2RA gene; Immune; Immune system; Immunization; Immunoglobulin M; Immunologics; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-5; Interleukin-6; Kinetics; Lead; Ligands; Lymphocyte; Lymphocyte Activation; Mus; NOEL; National Health and Nutrition Examination Survey; Oral; PPAR alpha; Population; Process; Production; Relative Risks; Reporting; Rest; Risk; Risk Assessment; Rodent; Rodent Model; Role; Route; Safety; Serum; Sheep; Signal Transduction; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Toxic effect; Uncertainty; United States; United States Environmental Protection Agency; Water; base; cytokine; hazard; immunotoxicity; in vivo; macrophage; perfluorooctane sulfonate; public health relevance; research study; response

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（由申请人提供）： 全氟碳氢化合物，例如全氟辛烷磺酸 (PFOS) 是新出现的令人关注的污染物。水、室内灰尘和人血清中均检测到了 PFOS 浓度。全氟辛烷磺酸具有持久性、生物累积性和剧毒性。令人担忧的原因不仅是持久性和已记录的毒性，还包括不确定性和数据差距，包括影响机制、暴露途径、体内动力学、当前人类生物监测数据中人群的代表性不足，以及缺乏对亚致死暴露效应的了解。此类中的许多化合物（例如 PFOS）都是 PPAR-α 激动剂。我们已经证明，PFOS 抑制 T 依赖性 (TDAR) 和 T 不依赖性 (TI) 抗体产生，但在 PPAR-α -/- 小鼠中这一点没有改变。我们还表明，IL-4、IL-5、IL-6 和 CD40、CD154 表达和信号转导的改变与 IgM 产生的抑制无关。我们推测 IgM 抑制可能是通过已知的 PPAR-α 配体对 IL-2 产生的抑制而发生的，因为 IL-2 的产生对于 TDAR 和 TI 抗体反应都很重要，并且在 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 的产生而不是巨噬细胞细胞因子的产生或改变 CD25、CD27 或 CD70 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 CD25、CD27 和 CD70 表达在静息（未受攻击）免疫细胞中 PFOS 抑制抗体产生中的作用。目标 2. 确定 T 细胞 IL-2、巨噬细胞 IL-1 和 IL-10 以及 CD25、CD27 和 CD70 表达在抑制绵羊红细胞攻击（活化）免疫细胞中 PFOS 产生抗体中的作用。将进行未免疫和免疫实验，以控制与免疫接种中淋巴细胞活化相关的反应中可能存在的差异，以确定减少的免疫反应。 抗体的产生。这项研究的数据将有助于对该化合物进行危害评估，增加有关作用方式的信息，以便确定作用机制，并将带来有关 PPAR-α 激动剂在抗体生产中作用的新信息。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很重要，因为：1）在啮齿动物模型中，在人类血清浓度下，对抗体产生产生影响；2）IgM产生的抑制与疾病易感性增加有关；3）在没有作用机制信息的情况下根据当前数据进行危害和风险评估将导致没有安全边际；从而;最有可能的是，高估了暴露造成的人类健康风险。此外，了解效应的模式或机制还可以识别可在人类中评估的标记，以更好地确定真实风险，而不是啮齿动物研究得出的相对风险。