The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

Beggs, Kevin M.; McGreal, Steven R.; McCarthy, Alex J.; Gunewardena, Sumedha; Lampe, Jed N.; Lau, Christoper; Apte, Udayan

doi:10.1016/j.taap.2016.05.001

Cited by 77 publications

(77 citation statements)

References 77 publications

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“…Recently, the European Food Safety Authority (EFSA) reported that the positive association of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), the two most common PFASs, with total cholesterol serum levels, as observed in several studies, may result from a possible common reabsorption of bile acids, PFOS, and PFOA from the gut and shared membrane transport pathways into the liver (https:// www.efsa.europa.eu/sites/default/files/news/efsa-contam-3503.pdf). Interestingly, it has been hypothesized that 7-alphahydroxylase (CYP7A1), which catalyzes the first and ratelimiting step in the formation of BAs from cholesterol, may be downregulated by PFASs [9,10]. This may lead to increased re-uptake of BAs, which would generate negative feedback loops via the farnesyl-X-receptor and subsequently reduce their de novo synthesis.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of perfluoroalkyl substances and bile acids in human serum using ultra-high-performance liquid chromatography–tandem mass spectrometry

et al. 2019

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There is evidence of a positive association between per-and polyfluoroalkyl substances (PFASs) and cholesterol levels in human plasma, which may be due to common reabsorption of PFASs and bile acids (BAs) in the gut. Here we report development and validation of a method that allows simultaneous, quantitative determination of PFASs and BAs in plasma, using 150 μL or 20 μL of sample. The method involves protein precipitation using 96-well plates. The instrumental analysis was performed with ultraperformance liquid chromatography-tandem mass spectrometry (UHPLC-MS), using reverse-phase chromatography, with the ion source operated in negative electrospray mode. The mass spectrometry analysis was carried out using multiple reaction monitoring mode. The method proved to be sensitive, robust, and with sufficient linear range to allow reliable determination of both PFASs and BAs. The method detection limits were between 0.01 and 0.06 ng mL −1 for PFASs and between 0.002 and 0.152 ng mL −1 for BAs, with the exception of glycochenodeoxycholic acid (0.56 ng mL −1). The PFAS measured showed excellent agreement with certified plasma PFAS concentrations in NIST SRM 1957 reference serum. The method was tested on serum samples from 20 healthy individuals. In this proof-of-concept study, we identified significant associations between plasma PFAS and BA levels, which suggests that PFAS may alter the synthesis and/or uptake of BAs.

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Section: Introductionmentioning

confidence: 99%

Simultaneous determination of perfluoroalkyl substances and bile acids in human serum using ultra-high-performance liquid chromatography–tandem mass spectrometry

et al. 2019

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“…The method presented here is suitable for fast, automated analysis of PFAS and BAs from human serum, and the sample amount can be reduced to 20 µL, however, with some loss of sensitivity. and NTCP are based on literature [12,8,26,19]. Fig.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Determination of Per- and Polyfluoroalkyl Substances and Bile Acids in Human Serum Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Salihović¹,

Dickens²,

Schoultz³

et al. 2019

Preprint

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There is evidence of a positive association between per-and polyfluoroalkyl substances (PFAS) and cholesterol levels in human plasma, which may be due to common reabsorption of PFAS and bile acids (BAs) in the gut. Here we report development and validation of a method that allows simultaneous, quantitative determination of PFAS and BAs in plasma, using 150 µl or 20 µl of sample. The method involves protein precipitation using 96-well plates. The instrumental analysis was performed with ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS), using reverse-phase chromatography, with the ion source operated in negative electrospray mode. The mass spectrometry analysis was carried out using multiple reaction monitoring mode. The method proved to be sensitive, robust and with sufficient linear range to allow reliable determination of both PFAS and BAs. The method detection limits were between 0.01 and 0.06 ng⋅mL-1 for PFAS and between 0.002 and 0.152 ng⋅mL-1 for BAs, with the exception of glycochenodeoxycholic acid (0.56 ng⋅mL-1). The PFAS measured showed excellent agreement with certified plasma PFAS concentrations in NIST SRM 1957 reference plasma. The method was tested on serum samples from 20 healthy individuals. In this proof-of-concept study, we identified significant associations between plasma PFAS and BA levels, which suggests that PFAS may alter the synthesis and/or uptake of BAs.

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“…Multiple MDCs can disrupt hepatic function, leading to toxicity, altered gluconeogenesis, and impaired glycogen storage, including POPs [62], BPA [63,64], PCBs [65], perfluorooctanoic acid (PFOA) [66], atrazine [67], arsenic [68], and DEHP [69]. For example, rats exposed to lipophilic POPs contained in dietary fish oil exhibited insulin resistance, abdominal obesity, and hepatosteatosis [62].…”

Section: Disruption Of Insulin Actionmentioning

confidence: 99%

“…TCDD), and polyphenols [70]; thus, it is a likely mediator of MDC toxicity. Interestingly, RNA-Seq analysis of human hepatocytes exposed to PFOA and PFOS demonstrate altered expression of lipid metabolism genes, possibly by direct interference with and downregulation of hepatocyte nuclear factor 4α (HNF4α), a master regulator of hepatocyte development and metabolism [66]. Mutations in HNF4α also cause a form of familial diabetes, maturity onset diabetes of the young type 1 (MODY1), which is uniquely responsive to the insulin augmenting class of sulfonylurea drugs.…”

Section: Disruption Of Insulin Actionmentioning

confidence: 99%

Polluted Pathways: Mechanisms of Metabolic Disruption by Endocrine Disrupting Chemicals

Mimoto

Nadal

Sargis

2017

Curr Envir Health Rpt

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Purpose of review Environmental toxicants are increasingly implicated in the global decline in metabolic health. Focusing on diabetes, herein the molecular and cellular mechanisms by which metabolism disrupting chemicals (MDCs) impair energy homeostasis are discussed. Recent findings Emerging data implicate MDC perturbations in a variety of pathways as contributors to metabolic disease pathogenesis, with effects in diverse tissues regulating fuel utilization. Potentiation of traditional metabolic risk factors, such as caloric excess, and emerging threats to metabolism, such as disruptions in circadian rhythms, are important areas of current and future MDC research. Increasing evidence also implicates deleterious effects of MDCs on metabolic programming that occur during vulnerable developmental windows, such as in utero and early post-natal life as well as pregnancy. Summary Recent insights into the mechanisms by which MDCs alter energy homeostasis will advance the field’s ability to predict interactions with classical metabolic disease risk factors and empower studies utilizing targeted therapeutics to treat MDC-mediated diabetes.

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The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

Cited by 77 publications

References 77 publications

Simultaneous determination of perfluoroalkyl substances and bile acids in human serum using ultra-high-performance liquid chromatography–tandem mass spectrometry

Simultaneous determination of perfluoroalkyl substances and bile acids in human serum using ultra-high-performance liquid chromatography–tandem mass spectrometry

Simultaneous Determination of Per- and Polyfluoroalkyl Substances and Bile Acids in Human Serum Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Polluted Pathways: Mechanisms of Metabolic Disruption by Endocrine Disrupting Chemicals

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