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 exp...