Project description:PFAS are widely used in commercial products, and so humans have consistent exposure to them via oil- and water-resistant consumer products, fire- fighting foam, and industrial surfactants 1,2. The four PFASs commonly detected in blood, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS) 3,4, are present in drinking water supplies both in northern New England as well as in 27 states nationally 5-8. Animal models shows that PFASs have can have effects on both the endocrine system and on adiposity 9-12. Epidemiological evidence shows that the presence of PFASs in maternal serum is associated with changes in maternal serum lipid and cholesterol composition 13,14. Similarly, serum levels of PFAS in adolescents have been associated with increases in serum cholesterol 15. These findings raise interesting questions about the association of PFAS and lipids in human milk. Research has shown the PFASs are present in human milk 16-18, and human milk is composed primarily of lipids 19. However, the relation between PFAS in milk and milk composition is unclear. The chemical and compositional profiles of breast milk are important because of the potential effects on the developing infant. The developmental origins of health and disease hypothesis suggests that early life exposures, such as toxins and nutrients via breast milk, have lasting effects on health, particularly obesity outcomes 20. In fact, some studies have shown associations between PFAS in maternal serum and infant birth weight and later childhood BMI 14,21. Our study will help to better illuminate the potential effects of maternal exposure to PFASs on infant exposure, both through direct transmission into breast milk and indirectly via influence on the lipid profiles of milk. To investigate how early life exposure to perfluoroalkyl substances (PFAS) may affect childhood health outcomes as mediated through breast milk, we propose the following specific aims: 1. Characterize the levels of PFAS in breast milk samples (n=495) in the NHBCS; 2. Characterize the lipid profiles of breast milk samples (n=495) in the NHBCS; 3. Test the relation between PFAS concentration and breast milk lipid profiles; and 4. Test the association between PFAS concentrations in maternal plasma collected during pregnancy with paired breast milk samples (n=100).

Project description:Per- and polyfluoroalkyl substances (PFAS) are some of the most prominent organic contaminants in human blood that have the potential to disrupt biological processes and pathways in the liver. Although the toxicological implications from human exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are well established, data on other, lesser-understood PFAS are limited. A challenge for regulatory authorities is to determine acceptable levels of human exposure to large, diverse classes of environmental contaminants. New approach methodologies (NAMs) that apply bioinformatics tools to interpret biological data are being increasingly considered to inform risk assessment when traditional toxicology methodologies are not amenable. The aim of the current investigation was to identify the biological responses relevant to PFAS mode of action as the concentration (benchmark dose) that these effects take place in order to utililze this information to inform/facilitate read-across for risk assessment of data-poor PFAS. A TempO-Seq platform (BioSpyder) measured gene expression changes in human liver microtissues (i.e., spheroids) after 1-day and 10-day exposures to increasing concentrations of PFAS. A bioinformatics framework was applied to 23 PFAS sub-classed into carboxylates (PFCAs), sulfonates (PFSAs), or PFAS precursors that were analyzed for the total altered transcripts, the concentration where effects take place, and identifying target genes of interest. Both PFCAs and PFSAs exhibited a trend toward increased transcriptional changes with carbon chain-length. Specifically, longer-chain compounds (7 to 10 carbons) were more likely to surpass liver-toxic transcriptomic thresholds established from previous studies than shorter chain PFAS. Longer-chain PFAS were also more potent, inducing transcriptional effects at lower concentrations. However, PFOS was the most potent PFAS and of all precursors, only PFOSA (a PFOS precursor) induced a response. The combined high-throughput transcriptomic and bioinformatics analyses revealed the capability of NAMs to assess the effects of PFAS in liver microtissues; such data improves our understanding of PFAS-related effects in humans and facilitates the use of read-across in human health risk assessment for other data-poor chemicals.

Project description:Per- and polyfluoroalkyl substances (PFAS) are a very large (thousands of chemicals) category; these substances have important industrial and consumer product applications. PFAS are highly persistent in the environment, and some are known to pose human health hazard. Regulatory agencies worldwide are considering restrictions and outright bans of PFAS; however, little data exists to make informed decisions. Therefore, a prioritization strategy is urgently needed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist requires confirmation. We tested 26 structurally diverse PFAS from 8 groups in two human cell types from organs that are thought to be targets for PFAS. We used human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes and tested concentration-response effects on both cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed for 8 of 26 PFAS. Substance- and cell-dependent transcriptomic changes were more pronounced; however, little evidence of group-specific effects was observed. In hepatocytes, we found up-regulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractility-related pathways were most affected. Using these data, we derived phenotypic and transcriptomic point of departure estimates and compared them to predicted PFAS exposures. The conservative estimates for bioactivity and exposure were used to derive margin-of-exposure (MOE) for each PFAS. We found that most (23 of 26) PFAS had MOE>1. Overall, our data suggests that chemical structure-based grouping of PFAS may not be an appropriate strategy to predict their biological effects. This means that testing of the individual PFAS would be needed for confident decision-making. Our proposed strategy of using two human cell types and considering both phenotypic and transcriptomic effects, combined with dose-response analysis, may be used for prioritization of PFAS.

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Pesticides, Perfluorinated compounds and the development of adolescents in agricultural communities

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