Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury
Background: Epidemiological studies have shown Per- and polyfluoroalkyl substances (PFAS) to be associated with diseases of dysregulated lipid and sterol homeostasis such as steatosis and cardiometabolic disorders. However, the majority of mechanistic studies rely on single chemical exposures instea...
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doaj-26b04211e64240c2ba52b30e3a54baa72021-10-01T04:47:28ZengElsevierEnvironment International0160-41202021-12-01157106843Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injuryKatherine Roth0Zhao Yang1Manisha Agarwal2Wendy Liu3Zheyun Peng4Ze Long5Johnna Birbeck6Judy Westrick7Wanqing Liu8Michael C. Petriello9Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USAInstitute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USAInstitute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USADepartment of Pathology, University Hospitals, Cleveland Medical Center, Cleveland, OH 44106, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USADepartment of Chemistry, Lumigen Instrumentation Center, Wayne State University, Detroit, MI 48202, USADepartment of Chemistry, Lumigen Instrumentation Center, Wayne State University, Detroit, MI 48202, USADepartment of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USAInstitute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA; Corresponding author at: 6135 Woodward Avenue, IBio 2128, Wayne State University, Detroit, MI 48202, USA.Background: Epidemiological studies have shown Per- and polyfluoroalkyl substances (PFAS) to be associated with diseases of dysregulated lipid and sterol homeostasis such as steatosis and cardiometabolic disorders. However, the majority of mechanistic studies rely on single chemical exposures instead of identifying mechanisms related to the toxicity of PFAS mixtures. Objectives: The goal of the current study is to investigate mechanisms linking exposure to a PFAS mixture with alterations in lipid metabolism, including increased circulating cholesterol and bile acids. Methods: Male and female wild-type C57BL/6J mice were fed an atherogenic diet used in previous studies of pollutant-accelerated atherosclerosis and exposed to water containing a mixture of 5 PFAS representing legacy, replacement, and alternative subtypes (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 12 weeks. Changes at the transcriptome and metabolome level were determined by RNA-seq and high-resolution mass spectrometry, respectively. Results: We observed increased circulating cholesterol, sterol metabolites, and bile acids due to PFAS exposure, with some sexual dimorphic effects. PFAS exposure increased hepatic injury, demonstrated by increased liver weight, hepatic inflammation, and plasma alanine aminotransferase levels. Females displayed increased lobular and portal inflammation compared to the male PFAS-exposed mice. Hepatic transcriptomics analysis revealed PFAS exposure modulated multiple metabolic pathways, including those related to sterols, bile acids, and acyl carnitines, with multiple sex-specific differences observed. Finally, we show that hepatic and circulating levels of PFOA were increased in exposed females compared to males, but this sexual dimorphism was not the same for other PFAS examined. Discussion: Exposure of mice to a mixture of PFAS results in PFAS-mediated modulation of cholesterol levels, possibly through disruption of enterohepatic circulation.http://www.sciencedirect.com/science/article/pii/S0160412021004682PFAS toxicityPer- and polyfluoroalkyl substancesLiver injuryCardiometabolic diseaseHyperlipidemiaCholesterol |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katherine Roth Zhao Yang Manisha Agarwal Wendy Liu Zheyun Peng Ze Long Johnna Birbeck Judy Westrick Wanqing Liu Michael C. Petriello |
spellingShingle |
Katherine Roth Zhao Yang Manisha Agarwal Wendy Liu Zheyun Peng Ze Long Johnna Birbeck Judy Westrick Wanqing Liu Michael C. Petriello Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury Environment International PFAS toxicity Per- and polyfluoroalkyl substances Liver injury Cardiometabolic disease Hyperlipidemia Cholesterol |
author_facet |
Katherine Roth Zhao Yang Manisha Agarwal Wendy Liu Zheyun Peng Ze Long Johnna Birbeck Judy Westrick Wanqing Liu Michael C. Petriello |
author_sort |
Katherine Roth |
title |
Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury |
title_short |
Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury |
title_full |
Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury |
title_fullStr |
Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury |
title_full_unstemmed |
Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury |
title_sort |
exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (pfas) results in sex-dependent modulation of cholesterol metabolism and liver injury |
publisher |
Elsevier |
series |
Environment International |
issn |
0160-4120 |
publishDate |
2021-12-01 |
description |
Background: Epidemiological studies have shown Per- and polyfluoroalkyl substances (PFAS) to be associated with diseases of dysregulated lipid and sterol homeostasis such as steatosis and cardiometabolic disorders. However, the majority of mechanistic studies rely on single chemical exposures instead of identifying mechanisms related to the toxicity of PFAS mixtures. Objectives: The goal of the current study is to investigate mechanisms linking exposure to a PFAS mixture with alterations in lipid metabolism, including increased circulating cholesterol and bile acids. Methods: Male and female wild-type C57BL/6J mice were fed an atherogenic diet used in previous studies of pollutant-accelerated atherosclerosis and exposed to water containing a mixture of 5 PFAS representing legacy, replacement, and alternative subtypes (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 12 weeks. Changes at the transcriptome and metabolome level were determined by RNA-seq and high-resolution mass spectrometry, respectively. Results: We observed increased circulating cholesterol, sterol metabolites, and bile acids due to PFAS exposure, with some sexual dimorphic effects. PFAS exposure increased hepatic injury, demonstrated by increased liver weight, hepatic inflammation, and plasma alanine aminotransferase levels. Females displayed increased lobular and portal inflammation compared to the male PFAS-exposed mice. Hepatic transcriptomics analysis revealed PFAS exposure modulated multiple metabolic pathways, including those related to sterols, bile acids, and acyl carnitines, with multiple sex-specific differences observed. Finally, we show that hepatic and circulating levels of PFOA were increased in exposed females compared to males, but this sexual dimorphism was not the same for other PFAS examined. Discussion: Exposure of mice to a mixture of PFAS results in PFAS-mediated modulation of cholesterol levels, possibly through disruption of enterohepatic circulation. |
topic |
PFAS toxicity Per- and polyfluoroalkyl substances Liver injury Cardiometabolic disease Hyperlipidemia Cholesterol |
url |
http://www.sciencedirect.com/science/article/pii/S0160412021004682 |
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