Growth and metabolic programming from prenatal PFAS exposure: examining the roles of placental functional genomics and protection by maternal exercise

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PROJECT SUMMARY Rates of childhood obesity have more than tripled over the last 40 years with 18.5% of children and adolescents classified as obese. Endocrine-disrupting chemicals, particularly environmentally ubiquitous obesogens such as per- and polyfluoroalkyl substances (PFAS), are thought to contribute to the rapid increases in obesity. Indeed, prenatal PFAS exposures have been shown to contribute to gender-specific obesity development in children. Interestingly, PFAS exposures that occur during pregnancy can cross the placenta leading to direct in utero exposure, and PFAS have been detected in placental tissues. In addition to supporting fetal growth, the placenta is likely involved in longer term persistent effects in the offspring. However, interrelationships between prenatal PFAS, impacts on the placenta, and postnatal growth and metabolic health are understudied. Additionally, a lifestyle intervention including dietary training, physical activity, and behavioral modifications has been shown to attenuate the association between higher PFAS to higher body weight. However, similar studies have not been performed in the context of prenatal exposure and children’s health outcomes. Thus, there are key gaps in our understanding of the impacts and preventive opportunities regarding prenatal PFAS exposure: whether the timing of exposure and/or tissue-specific concentrations are important; whether molecular activities of the placental are disrupted by PFAS; and whether physical activity during pregnancy may attenuate these effects. For this proposal, we have assembled a newly formed collaborative team of investigators with unique expertise in children’s growth and metabolic health (mPI Andres, Aim 1), environmental health and placental functional genomics (mPI Everson, Aim 2), and physical activity interventions (mPI Pearson, Aim 3) to address these knowledge gaps. Using an existing longitudinal cohort, we aim to quantify PFAS in maternal serum at each trimester as well as in umbilical cord serum and placental tissues to determine their associations with birth weight, placental functional genomics, as well as pediatric obesity. Additionally, because PFAS are pervasive and thus exposure avoidance can be difficult, we will also explore the role of maternal exercise in decreasing maternal PFAS burden during the pregnancy period as part of an ongoing exercise randomized control trial during pregnancy. We hypothesize that 1) prenatal PFAS burden will significantly affect birth weight, as well as child growth, and adiposity accretion; 2) prenatal PFAS exposure will influence placental epigenomic regulation, with impacts on transcription and metabolic features; and 3) exercise during pregnancy will decrease PFAS burden in maternal and umbilical serum. The proposed studies will offer innovative new insights to understanding the role of PFAS compounds as obesogens during human development, their impact on placental function which could lead to novel targets for intervention or prevention, and determine whether exercise mitigates the PFAS exposure risk.