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• Exposure to PFOS and EtFOSAA affects urea cycle metabolism in maternal serum of pregnant women. • PFOS and EtFOSAA exhibit different association with key amino acid metabolites. • PFOS, but not EtFOSAA, activates energy metabolism pathways. High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk. [ABSTRACT FROM AUTHOR]

• Hierarchical community network to integrate exposome and metabolome. • Fatty acid and mitochondria related pathways are among associations with DDTs and PFASs. • Breast cancer risk in offspring positively associated with PCB compounds, negatively with PFASs. • Small number of metabolic phenotypes may account for large number of exposures. Even though the majority of population studies in environmental health focus on a single factor, environmental exposure in the real world is a mixture of many chemicals. The concept of "exposome" leads to an intellectual framework of measuring many exposures in humans, and the emerging metabolomics technology offers a means to read out both the biological activity and environmental impact in the same dataset. How to integrate exposome and metabolome in data analysis is still challenging. Here, we employ a hierarchical community network to investigate the global associations between the metabolome and mixed exposures including DDTs, PFASs and PCBs, in a women cohort with sera collected in California in the 1960s. Strikingly, this analysis revealed that the metabolite communities associated with the exposures were non-specific and shared among exposures. This suggests that a small number of metabolic phenotypes may account for the response to a large class of environmental chemicals. [ABSTRACT FROM AUTHOR]

• Exposure to PFOS and EtFOSAA affects urea cycle metabolism in maternal serum of pregnant women. • PFOS and EtFOSAA exhibit different association with key amino acid metabolites. • PFOS, but not EtFOSAA, activates energy metabolism pathways. High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk. [ABSTRACT FROM AUTHOR]