Perinatal Per- and Polyfluoroalkyl Substances (PFAS) exposure and Immunotoxicity in early life

围产期全氟烷基物质和多氟烷基物质 (PFAS) 暴露与生命早期的免疫毒性

• 批准号: 10634382
• 负责人: Liping Feng
• 金额: $ 51.57万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634382
• 关键词: Address; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Birth; Blood; Blood specimen; Breast Feeding; Cells; Cellular Immunity; Chemical Exposure; Chemicals; Child; Childhood; Circulation; Cities; Clinical; Communities; Data; Development; Disease susceptibility; EGF gene; Endocrine; Endocrine disruption; Environment; Exposure disparity; Exposure to; Fc Receptor; Female; Fetal Weight; Fetus; Foundations; Gut associated lymphoid tissue; Health; Hormones; Human; Human Milk; Immune; Immune System Diseases; Immune response; Immune system; Immunoglobulin A; Immunoglobulin G; Immunosuppression; Individual; Industrialization; Interruption; Intervention; Lactation; Life; Mammary Duct; Mammary gland; Maternal Exposure; Measures; Metagenomics; Military Personnel; Milk; Modeling; Morphology; North Carolina; Oryctolagus cuniculus; Outcome; Oxytocin; Perinatal; Peripheral Blood Mononuclear Cell; Placenta; Play; Policies; Poly-fluoroalkyl substances; Population; Predisposition; Pregnancy; Progesterone; Prolactin; Recommendation; Regulation; Research; Risk; Rodent; Role; Route; Signal Transduction; Site; Somatotropin; Source; Spleen; Sulfonic Acids; Syncytiotrophoblast; System; Systems Development; Testing; Tissues; Toxic effect; Toxicology; Vaccinated; Vaccination; Vaccines; Weight; antibody transfer; consumer product; contaminated drinking water; design; drinking water; environmental health disparity; epidemiology study; experience; exposed human population; fetal; gut microbiota; hormonal signals; immune function; immunotoxicity; in utero; indexing; insight; mammary gland development; neonatal Fc receptor; novel; offspring; placental transfer; postnatal; public health relevance; receptor; reproductive toxicity; single cell sequencing

Per- and polyfluoroalkyl substances (PFAS) exposure is widespread. Drinking water is considered a primary source of exposure, and high levels of PFAS are found in many communities, sparking concerns about health impacts on these populations. We have demonstrated high PFAS levels in drinking water in Pittsboro, NC. The residents in this city are currently experiencing disparate exposures of PFAS. However, the potential health risks associated with these exposures are not well understood. In addition, very little is known about the toxicity of “emerging” PFAS, including perfluorobutane sulfonic acid (PFBS), which are increasingly detected in the environmment and within humans. We have demonstrated the reproductive toxicity of PFBS. Epidemiological studies, supported by findings from toxicological studies, provide strong evidence that humans exposed to the PFAS legacy compounds are at risk for immunosuppression, including reduced antibody response to vaccination in children. Notably, there are lack of relevant data assessing the effects of exposure to emerging PFAS chemicals or PFAS mixtures and immunotoxicity in early life such as during pregnancy and lactation. In this proposal, we will test our hypothesis that maternal PFAS exposure results in reduced immune response to vaccination, during pregnancy in dams and in offspring after birth through altered cellular immunity and gut microbiota; decreased antibody transfer from dams to offspring through placenta and breast milk by disrupting endocrine signaling and antibobdy transfer receptors. Our specific aims are to: 1) Investigate maternal PFAS exposure and its effects on immune response to vaccination in dams and placental transfer of IgG from maternal to fetal compartment; 2) Examine the effects of maternal PFAS exposure on offspring through breastfeeding and antibody transfer and identify underlying mechanisms; 3) Determine the impact of maternal PFAS exposure on the establishment of gut microbiota and immune response to vaccination in offspring. This study is novel because we will address health impacts of PFAS mixtures mimicking highly contaminated community drinking water and an emerging PFAS compound, whereas most previous studies focused on legacy compounds; Although rodents are a commonly used model for immunotoxicity studies, rabbits are a more suitable animal model for investigating both maternal transfer of antibodies to the offspring and the development of the immune system during early life, including establishment of gut microbiota and immune response to vaccination. This study will provide new insights into the impact of perinatal PFAS exposure from breast-feeding and the subsequent health effects in offspring. Feasibility: The combination of expertise and preliminary studies provide a strong foundation for this proposal. Dr. Feng’s lab has established the perinatal PFAS exposure rabbit model; this proposal is an extension of her K01 project. Drs. Staats and Landon have extensive experience working with rabbits, such as immune responses to a variety of vaccinations in rabbits. Dr. Fenton has three decades of experience with mammary gland development, lactation, and toxicity in animal models, most of which pertains to PFAS exposure. Dr. Ji is an expert in analyzing single-cell sequencing and metagenomics data. Our study will make significant contributions to our understanding of the health impacts of PFAS and provide evidence to support regulations.

全氟烷基和多氟烷基物质（PFAS）的暴露很普遍。饮用水被认为是主要的 在许多社区发现了高水平的PFAS，引发了对健康的担忧 对这些人群的影响。我们已经证明了高PFAS水平的饮用水在北卡罗来纳州的Bamboro。的 这个城市的居民目前正在经历不同的PFAS暴露。然而，潜在的健康风险 与这些暴露有关的问题还不太清楚。此外，对药物的毒性知之甚少。 “新出现的”全氟辛烷磺酸，包括全氟丁烷磺酸（PFBS）， 在人与人之间。我们已经证明了PFBS的生殖毒性。流行病学 毒理学研究结果支持的研究提供了强有力的证据，表明人类暴露于 PFAS遗留化合物存在免疫抑制风险，包括对疫苗接种的抗体反应降低 小儿值得注意的是，缺乏评估暴露于新出现的PFAS的影响的相关数据 化学品或PFAS混合物和免疫毒性在生命早期，如在怀孕和哺乳期。在这 我们将测试我们的假设，即母体PFAS暴露导致免疫反应降低， 通过改变细胞免疫和肠道，在母鼠怀孕期间和出生后的后代中接种疫苗 减少抗体通过胎盘和母乳从母体转移到后代， 内分泌信号和抗体转移受体。我们的具体目标是：1）调查产妇PFAS 暴露及其对母体免疫应答和母体IgG胎盘转移的影响 2）检查母体PFAS暴露对母乳喂养后代的影响， 抗体转移并确定潜在机制; 3）确定母体PFAS暴露对 肠道微生物群的建立和后代对疫苗接种的免疫反应。这项研究是新颖的，因为 我们将解决模拟高度污染的社区饮用水的PFAS混合物对健康的影响， 一种新出现的PFAS化合物，而以前的大多数研究都集中在传统化合物上;尽管啮齿动物 是免疫毒性研究的常用模型，家兔是更合适的动物模型， 研究母体向后代转移抗体和免疫系统的发育 在生命早期，包括肠道微生物群的建立和对疫苗接种的免疫反应。本研究将 为母乳喂养和随后的健康带来的围产期PFAS暴露的影响提供了新的见解 对后代的影响可行性：专业知识和初步研究的结合提供了坚实的基础 对于这个提议。冯博士的实验室建立了围产期PFAS暴露兔模型，该方案是一个 K 01项目的延伸。Staats和Landon博士有丰富的兔子工作经验，例如 免疫反应的各种疫苗接种在兔子。芬顿博士有三十年的经验， 乳腺发育、哺乳和动物模型中的毒性，其中大部分与PFAS暴露有关。 博士Ji是分析单细胞测序和宏基因组学数据的专家。我们的研究将使 有助于我们了解PFAS对健康的影响，并提供证据支持法规。