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

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

Toxicol Appl Pharmacol

Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.

Published: October 2019

AI Article Synopsis

  • Environmental exposure to PCBs, specifically PCB153, disrupts retinoid (vitamin A) homeostasis, which may increase metabolic disease risk.
  • The study identifies the constitutive androstane receptor (CAR) as a key mediator in this disruption, particularly through the activation of liver enzymes that affect retinoid metabolism.
  • Dietary retinoids can reverse the changes caused by PCB153, suggesting that CAR activation and subsequent retinoid imbalance could play a significant role in the obesogenic effects of PCBs.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750730PMC
http://dx.doi.org/10.1016/j.taap.2019.114731DOI Listing

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