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

全氟烷基物质和多氟烷基物质(PFAS)的暴露很普遍。饮用水被认为是主要的 接触来源，在许多社区发现高水平的全氟辛烷磺酸，引发了对健康的担忧 对这些人群的影响。我们已经证明，在北卡罗来纳州皮茨伯勒的饮用水中存在高水平的全氟辛烷磺酸。这个 这座城市的居民目前正经历着不同的全氟辛烷磺酸暴露。然而，潜在的健康风险 与这些暴露相关的信息还不是很清楚。此外，人们对其毒性知之甚少。 正在出现的全氟辛烷磺酸，包括全氟丁烷磺酸(全氟丁烷磺酸)，在 环境和人类内部。我们已经证明了PFBS的生殖毒性。流行病学 在毒理学研究结果的支持下，研究提供了强有力的证据，表明人类接触到 全氟辛烷磺酸遗留化合物存在免疫抑制的风险，包括疫苗接种后抗体反应降低。 在孩子们身上。值得注意的是，缺乏评估暴露于新兴的全氟辛烷磺酸影响的相关数据。 化学品或全氟辛烷磺酸混合物和早期生命中的免疫毒性，如怀孕和哺乳期间。在这 提案中，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 通过改变细胞免疫和肠道，在母鸡怀孕期间和出生后的后代中接种疫苗 微生物区系；通过扰乱母鼠的胎盘和母乳，减少从母鼠到后代的抗体转移 内分泌信号和抗体转移受体。我们的具体目标是：1)调查产妇的PFAS 母体免疫及胎盘转移对母体免疫应答的影响 2)检查母亲通过母乳喂养接触PFAS对后代的影响，以及 抗体转移和确定潜在的机制；3)确定母亲接触全氟辛烷磺酸对 子代肠道微生物区系的建立及对接种疫苗的免疫应答。这项研究是新颖的，因为 我们将解决全氟辛烷磺酸混合物对健康的影响，模拟高污染的社区饮用水和 一种新兴的全氟辛烷磺酸化合物，而以前的大多数研究集中在遗留化合物上；尽管啮齿动物 是研究免疫毒性的常用模型，兔是更适合于 研究母体对后代的抗体转移和免疫系统的发育 在生命早期，包括肠道微生物区系的建立和对疫苗接种的免疫反应。这项研究将 为围产期母乳喂养中接触全氟辛烷磺酸及其对健康的影响提供新的见解 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 支持这项提议。冯博士的实验室已经建立了围产期PFAS暴露的兔模型；这一建议是一种 她的K01项目的延期。斯塔茨博士和兰登博士对兔子有丰富的工作经验，例如 兔对各种疫苗的免疫反应。芬顿博士有三十年的经验 动物模型中的乳腺发育、哺乳和毒性，其中大部分与全氟辛烷磺酸暴露有关。 纪万昌是分析单细胞测序和元基因组数据的专家。我们的研究将具有重要的意义 有助于我们理解全氟辛烷磺酸对健康的影响，并为支持法规提供证据。

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.