Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes

J. A. Bjork, J. L. Butenhoff, Kendall B Wallace

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are surface active fluorochemicals that, due to their exceptional stability to degradation, are persistent in the environment. Both PFOA and PFOS are eliminated slowly in humans, with geometric mean serum elimination half-lives estimated at 3.5 and 4.8 years, respectively. The biological activity of PFOA and PFOS in rodents is attributed primarily to transactivation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARA), which is an important regulator of lipid and carbohydrate metabolism. However, there are significant species-specific differences in the response to PFOA and PFOS exposure; non-rodent species, including humans, are refractory to several but not all of these effects. Many of the metabolic effects have been attributed to the activation of PPARA; however, recent studies using PPARα knockout mice demonstrate residual PPARA-independent effects, some of which may involve the activation of alternate nuclear receptors, including NR1I2 (PXR), NR1I3 (CAR), NR1H3 (LXRA), and NR1H4 (FXR). The objective of this investigation was to characterize the activation of multiple nuclear receptors and modulation of metabolic pathways associated with exposure to PFOA and PFOS, and to compare and contrast the effects between rat and human primary liver cells using quantitative reverse transcription PCR (RT-qPCR). Our results demonstrate that multiple nuclear receptors participate in the metabolic response to PFOA and PFOS exposure resulting in a substantial shift from carbohydrate metabolism to fatty acid oxidation and hepatic triglyceride accumulation in rat liver cells. This shift in intermediary metabolism was more pronounced for PFOA than PFOS. Furthermore, while there is some similarity in the activation of metabolic pathways between rat and humans, particularly in PPARA regulated responses; the changes in primary human cells were more subtle and possibly reflect an adaptive metabolic response rather than an overt metabolic regulation observed in rodents.

Original languageEnglish (US)
Pages (from-to)8-17
Number of pages10
JournalToxicology
Volume288
Issue number1-3
DOIs
StatePublished - Oct 9 2011

Fingerprint

perfluorooctanoic acid
Cytoplasmic and Nuclear Receptors
Hepatocytes
Rodentia
Chemical activation
PPAR alpha
Rats
Carbohydrate Metabolism
Metabolic Networks and Pathways
Liver
Peroxisome Proliferator-Activated Receptors
Transcription
Bioactivity
perfluorooctane sulfonic acid
Lipid Metabolism
Metabolism
Knockout Mice
Refractory materials
Transcriptional Activation
Reverse Transcription

Keywords

  • CAR
  • LXR
  • Metabolic regulation
  • PPARA
  • PXR
  • Perfluoroalkyl acids
  • Species specificity

Cite this

Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes. / Bjork, J. A.; Butenhoff, J. L.; Wallace, Kendall B.

In: Toxicology, Vol. 288, No. 1-3, 09.10.2011, p. 8-17.

Research output: Contribution to journalArticle

@article{bf299895761f435291260a233e201827,
title = "Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes",
abstract = "Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are surface active fluorochemicals that, due to their exceptional stability to degradation, are persistent in the environment. Both PFOA and PFOS are eliminated slowly in humans, with geometric mean serum elimination half-lives estimated at 3.5 and 4.8 years, respectively. The biological activity of PFOA and PFOS in rodents is attributed primarily to transactivation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARA), which is an important regulator of lipid and carbohydrate metabolism. However, there are significant species-specific differences in the response to PFOA and PFOS exposure; non-rodent species, including humans, are refractory to several but not all of these effects. Many of the metabolic effects have been attributed to the activation of PPARA; however, recent studies using PPARα knockout mice demonstrate residual PPARA-independent effects, some of which may involve the activation of alternate nuclear receptors, including NR1I2 (PXR), NR1I3 (CAR), NR1H3 (LXRA), and NR1H4 (FXR). The objective of this investigation was to characterize the activation of multiple nuclear receptors and modulation of metabolic pathways associated with exposure to PFOA and PFOS, and to compare and contrast the effects between rat and human primary liver cells using quantitative reverse transcription PCR (RT-qPCR). Our results demonstrate that multiple nuclear receptors participate in the metabolic response to PFOA and PFOS exposure resulting in a substantial shift from carbohydrate metabolism to fatty acid oxidation and hepatic triglyceride accumulation in rat liver cells. This shift in intermediary metabolism was more pronounced for PFOA than PFOS. Furthermore, while there is some similarity in the activation of metabolic pathways between rat and humans, particularly in PPARA regulated responses; the changes in primary human cells were more subtle and possibly reflect an adaptive metabolic response rather than an overt metabolic regulation observed in rodents.",
keywords = "CAR, LXR, Metabolic regulation, PPARA, PXR, Perfluoroalkyl acids, Species specificity",
author = "Bjork, {J. A.} and Butenhoff, {J. L.} and Wallace, {Kendall B}",
year = "2011",
month = "10",
day = "9",
doi = "10.1016/j.tox.2011.06.012",
language = "English (US)",
volume = "288",
pages = "8--17",
journal = "Toxicology",
issn = "0300-483X",
publisher = "Elsevier Ireland Ltd",
number = "1-3",

}

TY - JOUR

T1 - Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes

AU - Bjork, J. A.

AU - Butenhoff, J. L.

AU - Wallace, Kendall B

PY - 2011/10/9

Y1 - 2011/10/9

N2 - Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are surface active fluorochemicals that, due to their exceptional stability to degradation, are persistent in the environment. Both PFOA and PFOS are eliminated slowly in humans, with geometric mean serum elimination half-lives estimated at 3.5 and 4.8 years, respectively. The biological activity of PFOA and PFOS in rodents is attributed primarily to transactivation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARA), which is an important regulator of lipid and carbohydrate metabolism. However, there are significant species-specific differences in the response to PFOA and PFOS exposure; non-rodent species, including humans, are refractory to several but not all of these effects. Many of the metabolic effects have been attributed to the activation of PPARA; however, recent studies using PPARα knockout mice demonstrate residual PPARA-independent effects, some of which may involve the activation of alternate nuclear receptors, including NR1I2 (PXR), NR1I3 (CAR), NR1H3 (LXRA), and NR1H4 (FXR). The objective of this investigation was to characterize the activation of multiple nuclear receptors and modulation of metabolic pathways associated with exposure to PFOA and PFOS, and to compare and contrast the effects between rat and human primary liver cells using quantitative reverse transcription PCR (RT-qPCR). Our results demonstrate that multiple nuclear receptors participate in the metabolic response to PFOA and PFOS exposure resulting in a substantial shift from carbohydrate metabolism to fatty acid oxidation and hepatic triglyceride accumulation in rat liver cells. This shift in intermediary metabolism was more pronounced for PFOA than PFOS. Furthermore, while there is some similarity in the activation of metabolic pathways between rat and humans, particularly in PPARA regulated responses; the changes in primary human cells were more subtle and possibly reflect an adaptive metabolic response rather than an overt metabolic regulation observed in rodents.

AB - Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are surface active fluorochemicals that, due to their exceptional stability to degradation, are persistent in the environment. Both PFOA and PFOS are eliminated slowly in humans, with geometric mean serum elimination half-lives estimated at 3.5 and 4.8 years, respectively. The biological activity of PFOA and PFOS in rodents is attributed primarily to transactivation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARA), which is an important regulator of lipid and carbohydrate metabolism. However, there are significant species-specific differences in the response to PFOA and PFOS exposure; non-rodent species, including humans, are refractory to several but not all of these effects. Many of the metabolic effects have been attributed to the activation of PPARA; however, recent studies using PPARα knockout mice demonstrate residual PPARA-independent effects, some of which may involve the activation of alternate nuclear receptors, including NR1I2 (PXR), NR1I3 (CAR), NR1H3 (LXRA), and NR1H4 (FXR). The objective of this investigation was to characterize the activation of multiple nuclear receptors and modulation of metabolic pathways associated with exposure to PFOA and PFOS, and to compare and contrast the effects between rat and human primary liver cells using quantitative reverse transcription PCR (RT-qPCR). Our results demonstrate that multiple nuclear receptors participate in the metabolic response to PFOA and PFOS exposure resulting in a substantial shift from carbohydrate metabolism to fatty acid oxidation and hepatic triglyceride accumulation in rat liver cells. This shift in intermediary metabolism was more pronounced for PFOA than PFOS. Furthermore, while there is some similarity in the activation of metabolic pathways between rat and humans, particularly in PPARA regulated responses; the changes in primary human cells were more subtle and possibly reflect an adaptive metabolic response rather than an overt metabolic regulation observed in rodents.

KW - CAR

KW - LXR

KW - Metabolic regulation

KW - PPARA

KW - PXR

KW - Perfluoroalkyl acids

KW - Species specificity

UR - http://www.scopus.com/inward/record.url?scp=79961024699&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79961024699&partnerID=8YFLogxK

U2 - 10.1016/j.tox.2011.06.012

DO - 10.1016/j.tox.2011.06.012

M3 - Article

VL - 288

SP - 8

EP - 17

JO - Toxicology

JF - Toxicology

SN - 0300-483X

IS - 1-3

ER -