Summary of Study ST001919

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001210. The data can be accessed directly via it's Project DOI: 10.21228/M89D7G This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

Study ID	ST001919
Study Title	Exposure to environmental contaminants is associated with alterations in hepatic lipid metabolism in non-alcoholic fatty liver disease
Study Summary	Background & aims: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of 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 four 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 as regards bile acid metabolism. Specifically, we identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables in female subjects versus males. 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.
Institute	Örebro University
Department	Department of Medical Sciences
Last Name	McGlinchey
First Name	Aidan
Address	School of Medical Sciences, Örebro, Örebro, 70281, Sweden
Email	aidan.mcglinchey@oru.se
Phone	+46736485638
Submit Date	2021-09-07
Raw Data Available	Yes
Raw Data File Type(s)	mzdata.xml
Analysis Type Detail	LC-MS
Release Date	2021-11-03
Release Version	1

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Treatment:

Treatment ID:	TR002009
Treatment Summary:	Male and female, humanized PPARa mice (hPPARa) were generated from mouse PPARa-null, human PPARa-heterozygous breeding pairs (generously provided by Dr. Frank Gonzalez, NCI). At weaning, mice were provided a custom diet based on the What we eat in America (NHANES 2013/2014) analysis (Research Diets, New Brunswick, NJ) (USDA, 2018): 51.8% carbohydrate, 33.5% fat (soybean oil, lard and butter, with cholesterol at 224 mg/1884 kcal), and 14.7% protein, as a % energy intake. Fats are in the form of . Vehicle (VH) and treatment water were prepared from NERL High Purity water (23-249-589, Thermo Fisher Scientific), prepared with PFAS removal. Mice were administered vehicle (0.5% sucrose) drinking water or PFOA (8 mM +0.5% sucrose) drinking water ad libitum for 6-7 weeks. Food and water consumption were determined on a per cage basis each week and previously reported. Body weight was measured weekly. Aliquots of liver for lipidomics were flash frozen in liquid nitrogen and stored at -80?C. A total of 11 female mice (5 VH and 6 PFOA) and 12 male mice (7 VH and 5 PFOA) were analyzed.

Treatment ID:

TR002009

Treatment Summary:

Male and female, humanized PPARa mice (hPPARa) were generated from mouse PPARa-null, human PPARa-heterozygous breeding pairs (generously provided by Dr. Frank Gonzalez, NCI). At weaning, mice were provided a custom diet based on the What we eat in America (NHANES 2013/2014) analysis (Research Diets, New Brunswick, NJ) (USDA, 2018): 51.8% carbohydrate, 33.5% fat (soybean oil, lard and butter, with cholesterol at 224 mg/1884 kcal), and 14.7% protein, as a % energy intake. Fats are in the form of . Vehicle (VH) and treatment water were prepared from NERL High Purity water (23-249-589, Thermo Fisher Scientific), prepared with PFAS removal. Mice were administered vehicle (0.5% sucrose) drinking water or PFOA (8 mM +0.5% sucrose) drinking water ad libitum for 6-7 weeks. Food and water consumption were determined on a per cage basis each week and previously reported. Body weight was measured weekly. Aliquots of liver for lipidomics were flash frozen in liquid nitrogen and stored at -80?C. A total of 11 female mice (5 VH and 6 PFOA) and 12 male mice (7 VH and 5 PFOA) were analyzed.