Partho Sen1, Sami Qadri2, Panu K Luukkonen3, Oddny Ragnarsdottir4, Aidan McGlinchey5, Sirkku Jäntti6, Anne Juuti7, Johanna Arola8, Jennifer J Schlezinger9, Thomas F Webster9, Matej Orešič10, Hannele Yki-Järvinen11, Tuulia Hyötyläinen12. 1. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; School of Medical Sciences, Örebro University, Örebro, Sweden. 2. Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland. 3. Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Internal Medicine, Yale University, New Haven, Connecticut, USA. 4. MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden. 5. School of Medical Sciences, Örebro University, Örebro, Sweden. 6. Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. 7. Department of Gastrointestinal Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 8. Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 9. Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA. 10. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; School of Medical Sciences, Örebro University, Örebro, Sweden. Electronic address: matej.oresic@oru.se. 11. Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland. Electronic address: hannele.yki-jarvinen@helsinki.fi. 12. MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden. Electronic address: tuulia.hyotylainen@oru.se.
Abstract
BACKGROUND & AIMS: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. METHODS: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. RESULTS: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. CONCLUSIONS: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. LAY SUMMARY: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males.
BACKGROUND & AIMS: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. METHODS: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. RESULTS: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. CONCLUSIONS: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. LAY SUMMARY: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males.
Authors: Elizabeth Costello; Sarah Rock; Nikos Stratakis; Sandrah P Eckel; Douglas I Walker; Damaskini Valvi; Dora Cserbik; Todd Jenkins; Stavra A Xanthakos; Rohit Kohli; Stephanie Sisley; Vasilis Vasiliou; Michele A La Merrill; Hugo Rosen; David V Conti; Rob McConnell; Leda Chatzi Journal: Environ Health Perspect Date: 2022-04-27 Impact factor: 9.031
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