PROJECT SUMMARY/ABSTRACT – PROJECT 2 CRITICAL EFFECTS Metabolic diseases, including obesity and type 2 diabetes, are major public health problems of multifactorial etiology, in which early-life exposures to environmental pollutants, such as per- and polyfluoroalkyl substances (PFAS), appear to play a role. In parallel, a critical effect of PFAS exposure is immunotoxicity that paves the way for immune dysfunction and infectious disease. STEEP Project 2 (P2–Critical Effects) will examine the role of developmental exposure profiles for these high-priority environmental pollutants and determine outcomes up to ages 5 and 14 years to allow identification of windows of susceptibility. We will rely on two birth cohorts from the Faroe Islands (total N >1000) to prospectively explore the associations between exposure profiles of PFAS and outcomes, including immune deficiencies (suboptimal antibody production after vaccinations, and increased frequency of infectious disease) and metabolic abnormalities (excess adiposity, hyperlipidaemia, low bone mineral content, and prediabetes). P2–Critical Effects will further evaluate the possible usefulness of clinically relevant biomarkers in serum (such as cholesterol subfractions, adipocytokines, insulin-like growth factor-1). Exposure data are already available from analyses of maternal pregnancy, cord blood and postnatal serum at ages 18 months, 5 and 9 years from the oldest Cohort 5, and clinical data, including DXA scans, are available for comparisons with age 14 years. The youngest Cohort 6 is currently being formed, with blood samples and human milk being taken during infancy for PFAS analyses that will allow determination of PFAS transfer from lactation. Multiple regression analyses with adjustment for other environmental chemicals will be complemented by structural equation models and other advanced statistical methods. Thus, the proposed study will aim at providing prevention potentials and new insights into the pathogenesis of major public health problems that are associated with early-life exposures to high-priority environmental pollutants.

PROJECT NARRATIVE – PROJECT 2 CRITICAL EFFECTS STEEP achievements support the notion that PFAS exposures incurred during early development can affect immune system and metabolic functions and trigger potential vaccine failure and metabolic abnormalities that may lead to infections, obesity, and osteoporosis, all of which constitute important public health problems. This project is conducting prospective studies of about 1000 children from two birth cohorts generated in the Faroe Islands, where PFAS exposures are investigated prenatally, via breastfeeding, and beyond, and clinical features and blood biomarkers are assessed to determine adverse effects of profiles of PFAS exposures. The aim is to identify windows of vulnerability related to developmental pathways at ages 5 and 14 years and to determine exposure-related outcomes as a basis for improved risk assessment and protection against exposures to these persistent environmental contaminants.