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

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.