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.

全氟烷基物质和多氟烷基物质 (PFAS) 接触被普遍认为是主要的。 许多社区都发现了高浓度的 PFAS，引发了人们对健康的担忧 我们已经证明北卡罗来纳州皮茨伯勒的饮用水中 PFAS 含量很高。 该城市的居民目前正经历不同程度的 PFAS 暴露，但存在潜在的健康风险。 此外，人们对这些暴露的相关性知之甚少。 “新兴”PFAS，包括全氟丁烷磺酸 (PFBS)，其在环境中的检测量越来越多 我们已经证明了 PFBS 的生殖毒性。 毒理学研究结果支持的研究提供了强有力的证据，证明人类接触过 PFAS 遗留化合物面临免疫抑制风险，包括降低抗体对疫苗接种的反应 值得注意的是，缺乏评估接触新出现的 PFAS 的影响的相关数据。 化学品或 PFAS 混合物以及生命早期（例如怀孕和哺乳期间）的免疫毒性。 提议，我们将检验我们的假设，即母亲接触 PFAS 会导致免疫反应降低 通过细胞免疫和肠道在母鼠怀孕期间和出生后的后代中进行疫苗接种 微生物群；通过破坏胎盘和母乳减少抗体从母体转移到后代 我们的具体目标是：1) 研究母体 PFAS。 暴露及其对母鼠疫苗接种免疫反应和母体 IgG 胎盘转移的影响 2) 检查母亲通过母乳喂养和接触 PFAS 对后代的影响 抗体转移并确定潜在机制；3) 确定母体 PFAS 暴露对 这项研究是新颖的，因为肠道微生物群的建立和对疫苗接种的免疫反应。 我们将解决模仿高度污染的社区饮用水的 PFAS 混合物对健康的影响， 一种新兴的 PFAS 化合物，而之前的大多数研究都集中在传统化合物上，尽管是啮齿类动物； 是免疫毒性研究常用的模型，兔子是更适合的动物模型 研究母体抗体向后代的转移以及免疫系统的发育 这项研究将在生命早期进行，包括肠道微生物群的建立和对疫苗接种的免疫反应。 提供关于母乳喂养围产期 PFAS 暴露及其后续健康影响的新见解 对后代的影响：专业知识和初步研究的结合提供了坚实的基础。 针对该提案，冯博士实验室建立了围产期PFAS暴露兔子模型； Staats 博士和 Landon 博士拥有丰富的兔子研究经验，例如 芬顿博士在研究兔子对各种疫苗的免疫反应方面拥有三十年的经验。 动物模型中的乳腺发育、哺乳和毒性，其中大部分与 PFAS 暴露有关。 季博士是分析单细胞测序和宏基因组数据的专家，我们的研究将具有重大意义。 有助于我们了解 PFAS 对健康的影响，并为支持法规提供证据。