Affordable Access

deepdyve-link
Publisher Website

Constitutive androstane receptor mediates PCB-induced disruption of retinoid homeostasis.

Authors
  • Shmarakov, Igor O1
  • Lee, Yun Jee2
  • Jiang, Hongfeng2
  • Blaner, William S2
  • 1 Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. Electronic address: [email protected]
  • 2 Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Type
Published Article
Journal
Toxicology and Applied Pharmacology
Publisher
Elsevier
Publication Date
Oct 15, 2019
Volume
381
Pages
114731–114731
Identifiers
DOI: 10.1016/j.taap.2019.114731
PMID: 31449830
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Environmental exposure to polychlorinated biphenyls (PCBs) is associated with an increased risk of incidence of metabolic disease, however the molecular mechanisms underlying this phenomenon are not fully understood. Our study provides new insights into molecular interactions between PCBs and retinoids (vitamin A and its metabolites) by defining a role for constitutive androstane receptor (CAR) in the disruption of retinoid homeostasis by non-coplanar 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153). Administration of four weekly 50 mg/kg doses of PCB153 to C57BL/6 male mice resulted in a significant decline in the tissue concentrations of retinyl esters, retinol and all-trans-retinoic acid (atRA), while no decline in hepatic and adipose tissue retinoid levels were detected in Car-null littermates. Our data imply that disrupted retinoid homeostasis occurs as a consequence of PCB153-induced activation of CAR, and raise the possibility that CAR signaling can affect atRA homeostasis in vivo. A strong correlation between the changes in retinoid metabolism and extensive upregulation of hepatic CAR-driven Cyp2b10 expression implicates this CYP isoform as contributing to retinoid homeostasis disruption via atRA oxidation during PCB153 exposure. In response to PCB153-induced CAR activation and disruption of retinoid homeostasis, expression of hepatic Pepck, Cd36 and adipose tissue Pparγ, Cd36, Adipoq, and Rbp4 were altered; however, this was reversed by administration of exogenous dietary retinoids (300 IU daily for 4 weeks). Our study establishes that PCB153 exposure enables a significant disruption of retinoid homeostasis in a CAR-dependent manner. We propose that this contributes to the obesogenic properties of PCB153 and may contribute to the predisposition to the metabolic disease. Copyright © 2019 Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times