3,3',4,4',5-pentachlorobiphenyl (PCB 126) decreases hepatic and systemic ratios of epoxide to diol metabolites of unsaturated fatty acids in male rats

Xianai Wu, Jun Yang, Christophe Morisseau, Larry W. Robertson, Bruce Hammock, Hans Joachim Lehmler

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3- month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 μg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention.

Original languageEnglish (US)
Pages (from-to)309-322
Number of pages14
JournalToxicological Sciences
Volume152
Issue number2
DOIs
StatePublished - 2016

Fingerprint

3,4,5,3',4'-pentachlorobiphenyl
Epoxy Compounds
Metabolites
Unsaturated Fatty Acids
Rats
Oxylipins
Liver
Epoxide Hydrolases
Plasmas
Weights and Measures
Thymus
Aryl Hydrocarbon Receptors

Keywords

  • CYP1A
  • Oxylipin
  • Persistent organic pollutants
  • Polychlorinated biphenyls
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Toxicology

Cite this

3,3',4,4',5-pentachlorobiphenyl (PCB 126) decreases hepatic and systemic ratios of epoxide to diol metabolites of unsaturated fatty acids in male rats. / Wu, Xianai; Yang, Jun; Morisseau, Christophe; Robertson, Larry W.; Hammock, Bruce; Lehmler, Hans Joachim.

In: Toxicological Sciences, Vol. 152, No. 2, 2016, p. 309-322.

Research output: Contribution to journalArticle

Wu, Xianai ; Yang, Jun ; Morisseau, Christophe ; Robertson, Larry W. ; Hammock, Bruce ; Lehmler, Hans Joachim. / 3,3',4,4',5-pentachlorobiphenyl (PCB 126) decreases hepatic and systemic ratios of epoxide to diol metabolites of unsaturated fatty acids in male rats. In: Toxicological Sciences. 2016 ; Vol. 152, No. 2. pp. 309-322.
@article{c65ab34d03324a52bfa7e4adcf9ec35f,
title = "3,3',4,4',5-pentachlorobiphenyl (PCB 126) decreases hepatic and systemic ratios of epoxide to diol metabolites of unsaturated fatty acids in male rats",
abstract = "Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3- month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 μg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention.",
keywords = "CYP1A, Oxylipin, Persistent organic pollutants, Polychlorinated biphenyls, Soluble epoxide hydrolase",
author = "Xianai Wu and Jun Yang and Christophe Morisseau and Robertson, {Larry W.} and Bruce Hammock and Lehmler, {Hans Joachim}",
year = "2016",
doi = "10.1093/toxsci/kfw084",
language = "English (US)",
volume = "152",
pages = "309--322",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - 3,3',4,4',5-pentachlorobiphenyl (PCB 126) decreases hepatic and systemic ratios of epoxide to diol metabolites of unsaturated fatty acids in male rats

AU - Wu, Xianai

AU - Yang, Jun

AU - Morisseau, Christophe

AU - Robertson, Larry W.

AU - Hammock, Bruce

AU - Lehmler, Hans Joachim

PY - 2016

Y1 - 2016

N2 - Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3- month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 μg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention.

AB - Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3- month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 μg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention.

KW - CYP1A

KW - Oxylipin

KW - Persistent organic pollutants

KW - Polychlorinated biphenyls

KW - Soluble epoxide hydrolase

UR - http://www.scopus.com/inward/record.url?scp=84992731346&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992731346&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfw084

DO - 10.1093/toxsci/kfw084

M3 - Article

VL - 152

SP - 309

EP - 322

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 2

ER -