Dataset of medium throughput (96 well plate) in vitro nuclear receptor activation assays for peroxisome proliferator activated receptor alpha (PPARa), PPAR gamma (PPARg), and estrogen receptor (ER) across a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals. This dataset is associated with the following publication: Evans, N., J. Conley, M. Cardon, P. Hartig, E. Medlock Kakaley, and L. Gray. In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, USA, 449(116136): 1, (2022).

Production of per- and polyfluoroalkyl substances (PFAS) has shifted from long-chain perfluoroalkyl acids to short-chain compounds and those with ether bonds in the carbon chain. Next-generation perfluoroalkylether PFAS include HFPO-DA (“GenX chemicals”), Nafion Byproducts, and the PFOx homologous series that includes perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). PFO4DA and PFO5DoA have been detected in serum and/or tissues from humans and wildlife proximal to contamination point sources. However, toxicity data are extremely limited, with no animal developmental toxicology data. To address these data gaps, pregnant Sprague-Dawley rats were exposed via oral gavage to vehicle, PFO4DA, or PFO5DoA across a series of doses (0.1 to 62.5 mg/kg/day) from gestation day (GD) 18–22. Hepatic transcriptomics were assayed in dams and fetuses, and serum metabolomics in dams. These data were overlaid with serum PFO4DA and PFO5DoA concentrations to perform dose-response modeling. Both dams and fetuses exhibited dose-responsive disruption of hepatic gene expression in response to PFO4DA or PFO5DoA, with fetal expression disrupted at lower doses than dams. Several differentially expressed genes were upregulated by every dose of PFO5DoA in both maternal and fetal samples, including genes encoding enzymes that hydrolyze acyl-coA to free fatty acids. Maternal serum metabolomics revealed PFO4DA exposure did not induce significant changes at any tested dose, whereas PFO5DoA exposure resulted in dose-dependent differential metabolite abundance for 149 unique metabolites. Multi-omics pathway analyses of integrated maternal liver transcriptomics and serum metabolomics revealed significant convergent changes as low as 3 mg/kg/d PFO4DA and 0.3 mg/kg/d PFO5DoA exposure. Overall, transcriptomic and metabolomic effects of PFO4DA and PFO5DoA appear consistent with other carboxylic acid PFAS, with primary changes related to lipid metabolism, bile acids, cholesterol, and cellular stress. Importantly, PFO5DoA exposure more potently induced changes in maternal and fetal hepatic gene expression and maternal circulating metabolites, despite high structural similarity. Further, we report in vitro PPARα and PPARγ receptor activation for both compounds as putative molecular mechanisms. This work demonstrates the potential developmental toxicity of alternative moiety perfluoroethers and highlights the developing liver as particularly vulnerable to transcriptomic disruption. This dataset is associated with the following publication: Jackson, T., C. Lambright, N. Evans, L. Wehmas, D. Macmillan, J. Bangma, L. Gray, and J. Conley. Exploring maternal and developmental toxicity of perfluoroalkyl ether acids PFO4DA and PFO5DoA using hepatic transcriptomics and serum metabolomics. SCIENCE OF THE TOTAL ENVIRONMENT. Elsevier BV, AMSTERDAM, NETHERLANDS, 953(2): 175978, (2024).

Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα). In the current study, we used PPARα knockout (KO) and 129S1/SvlmJ wild-type (WT) mice to investigate the role of PPARα in mediating PFNA-induced in vivo effects. Pregnant KO and WT mice were dosed orally with water (vehicle control: 10 ml/kg), 0.83, 1.1, 1.5, or 2mg/kg PFNA on gestational days (GDs) 1−18 (day of sperm plug = GD 0). Maternal weight gain, implantation, litter size, and pup weight at birth were unaffected in either strain. PFNA exposure reduced the number of live pups at birth and survival of offspring to weaning in the 1.1 and 2 mg/kg groups in WT. Eye opening was delayed (mean delay 2.1 days) and pup weight at weaning was reduced inWT pups at 2mg/kg. These developmental endpoints were not affected in the KO. Relative liver weight was increased in a dose-dependent manner in dams and pups of theWT strain at all dose levels but only slightly increased in the highest dose group in the KO strain. In summary, PFNA altered liver weight of dams and pups, pup survival, body weight, and development in the WT, while only inducing a slight increase in relative liver weight of dams and pups at 2mg/kg in KO mice. These results suggest that PPARα is an essential mediator of PFNA-induced developmental toxicity in the mouse. This dataset is associated with the following publication: Abbott, B., C. Wolf, J. Schmid, C. Lau, and R. Zehr. Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-alpha.. PPAR research. Hindawi Publishing Corporation, New York, NY, USA, 1-11, (2010).

Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα). In the current study, we used PPARα knockout (KO) and 129S1/SvlmJ wild-type (WT) mice to investigate the role of PPARα in mediating PFNA-induced in vivo effects. Pregnant KO and WT mice were dosed orally with water (vehicle control: 10 ml/kg), 0.83, 1.1, 1.5, or 2mg/kg PFNA on gestational days (GDs) 1−18 (day of sperm plug = GD 0). Maternal weight gain, implantation, litter size, and pup weight at birth were unaffected in either strain. PFNA exposure reduced the number of live pups at birth and survival of offspring to weaning in the 1.1 and 2 mg/kg groups in WT. Eye opening was delayed (mean delay 2.1 days) and pup weight at weaning was reduced inWT pups at 2mg/kg. These developmental endpoints were not affected in the KO. Relative liver weight was increased in a dose-dependent manner in dams and pups of theWT strain at all dose levels but only slightly increased in the highest dose group in the KO strain. In summary, PFNA altered liver weight of dams and pups, pup survival, body weight, and development in the WT, while only inducing a slight increase in relative liver weight of dams and pups at 2mg/kg in KO mice. These results suggest that PPARα is an essential mediator of PFNA-induced developmental toxicity in the mouse. This dataset is associated with the following publication: Abbott, B., C. Wolf, J. Schmid, C. Lau, and R. Zehr. Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-alpha.. PPAR research. Hindawi Publishing Corporation, New York, NY, USA, 1-11, (2010).

Dataset for journal article 'Evaluation of 147 Perfluoroalkyl Substances for Immunosuppressive and other Activities Through Phenotypic Screening of Human Primary Cells'. Per- and polyfluoroalkyl substances (PFAS) are a large class of chemicals in widespread use for diverse applications in commerce resulting in significant presence in the environment. Extensive studies of several of the highly produced members of the class have demonstrated potential for adverse health consequences to humans and the environment as well as highly pervasive and persistent exposures. Here we report testing results of 147 PFAS substances in a phenotypic screening platform of primary human cell co-culture systems, the BioMAP® Diversity PLUS panel, used to model complex tissue and disease biology of organs (vasculature, immune system, skin, lung) and general tissue biology. PFAS were tested at four concentrations ranging from approximately 0.06 to 60 micromolar in order to minimize influence from confounding effects of polypharmacology resulting from qualitatively different activities at higher concentrations. We also compared response profiles for all PFAS with an existing database of responses for the BioMAP assays to identify other potential mechanisms of activity for this diverse chemical family. This dataset is associated with the following publication: Houck, K., K. Friedman, M. Feshuk, G. Patlewicz, M. Smeltz, M. Clifton, B. Wetmore, S. Velichko, A. Berenyi, and E. Berg. Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells. ALTEX. Society ALTEX Edition, Kuesnacht, SWITZERLAND, 40(2): 248-270, (2023).

Dataset for journal article 'Evaluation of 147 Perfluoroalkyl Substances for Immunosuppressive and other Activities Through Phenotypic Screening of Human Primary Cells'. Per- and polyfluoroalkyl substances (PFAS) are a large class of chemicals in widespread use for diverse applications in commerce resulting in significant presence in the environment. Extensive studies of several of the highly produced members of the class have demonstrated potential for adverse health consequences to humans and the environment as well as highly pervasive and persistent exposures. Here we report testing results of 147 PFAS substances in a phenotypic screening platform of primary human cell co-culture systems, the BioMAP® Diversity PLUS panel, used to model complex tissue and disease biology of organs (vasculature, immune system, skin, lung) and general tissue biology. PFAS were tested at four concentrations ranging from approximately 0.06 to 60 micromolar in order to minimize influence from confounding effects of polypharmacology resulting from qualitatively different activities at higher concentrations. We also compared response profiles for all PFAS with an existing database of responses for the BioMAP assays to identify other potential mechanisms of activity for this diverse chemical family. This dataset is associated with the following publication: Houck, K., K. Friedman, M. Feshuk, G. Patlewicz, M. Smeltz, M. Clifton, B. Wetmore, S. Velichko, A. Berenyi, and E. Berg. Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells. ALTEX. Society ALTEX Edition, Kuesnacht, SWITZERLAND, 40(2): 248-270, (2023).

Data for "Smeltz MG, Clifton MS, Henderson WM, McMillan L, Wetmore BA. Targeted Per- and Polyfluoroalkyl substances (PFAS) assessments for high throughput screening: Analytical and testing considerations to inform a PFAS stock quality evaluation framework. Toxicol Appl Pharmacol. 2023 Jan 15;459:116355. doi: 10.1016/j.taap.2022.116355. Epub 2022 Dec 16. PMID: 36535553". This dataset is associated with the following publication: Smeltz, M., M. Clifton, W. Henderson, L. McMillan, and B. Wetmore. Targeted Per- and Polyfluoroalkyl substances (PFAS) assessments for high throughput screening: Analytical and testing considerations to inform a PFAS stock quality evaluation framework. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, USA, 459: 116355, (2023).

Data for "Smeltz MG, Clifton MS, Henderson WM, McMillan L, Wetmore BA. Targeted Per- and Polyfluoroalkyl substances (PFAS) assessments for high throughput screening: Analytical and testing considerations to inform a PFAS stock quality evaluation framework. Toxicol Appl Pharmacol. 2023 Jan 15;459:116355. doi: 10.1016/j.taap.2022.116355. Epub 2022 Dec 16. PMID: 36535553". This dataset is associated with the following publication: Smeltz, M., M. Clifton, W. Henderson, L. McMillan, and B. Wetmore. Targeted Per- and Polyfluoroalkyl substances (PFAS) assessments for high throughput screening: Analytical and testing considerations to inform a PFAS stock quality evaluation framework. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, USA, 459: 116355, (2023).

Maternal and fetal liver gene expression and pathway changes following exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide-dimer acid (HFPO-DA) during gestation. This dataset is associated with the following publication: Blake, B., C. Miller, H. Nguyen, V. Chappell, T. Phan, D. Phadke, M. Balik-Meisner, D. Mav, R. Shah, and S. Fenton. Transcriptional pathways linked to fetal and maternal hepatic dysfunction caused by gestational exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) in CD-1 mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY. Elsevier Science Ltd, New York, NY, USA, 248: 114314, (2022).

General aggregate PFOS and PFOA exposure estimates are based on reported summary statistics from concentration studies by media, i.e. into indoor air, outdoor air, food, water, dust and soil, and published contact rates. These values were entered into a first-order PK model to estimate PFOS and PFOA blood serum concentrations. which were then compared measured concentrations reported by the 2013-2014 National Health and Nutrition Examination Survey (NHANES) measured concentrations. These methods are an expansion of the process taken by two previous studies, which predicted body burden from aggregate route intakes for PFOA and for PFOS, respectively. This dataset is associated with the following publication: East, A., P. Egeghy, E. Hubal, R. Slover, and D. Vallero. Computational estimates of daily aggregate exposure to PFOA/PFOS from 2011 to 2017 using a basic intake model. Journal of Exposure Science and Environmental Epidemiology. Nature Publishing Group, London, UK, 33: 56-68, (2023).