Polychlorinated biphenyls (
PCBs) are persistent environmental toxicants, present in 100% of U.S. adults and dose-dependently associated with
obesity and
non-alcoholic fatty liver disease (
NAFLD).
PCBs are predicted to interact with receptors previously implicated in
xenobiotic/energy metabolism and
NAFLD. These receptors include the
aryl hydrocarbon receptor (AhR), pregnane
xenobiotic receptor (PXR),
constitutive androstane receptor (CAR),
peroxisome proliferator-activated receptors (PPARs),
liver-X-receptor (LXRα), and farnesoid-X-receptor (FXR). This study evaluates
Aroclor 1260, a PCB mixture with congener composition mimicking that of human adipose tissue, and selected congeners, as potential
ligands for these receptors utilizing human
hepatoma-derived (HepG2) and primate-derived (COS-1) cell lines, and primary human hepatocytes.
Aroclor 1260 (20 μg/ml) activated AhR, and
PCB 126, a minor component, was a potent inducer.
Aroclor 1260 activated PXR in a simple concentration-dependent manner at concentrations ≥10 μg/ml. Among the congeners tested,
PCBs 138, 149, 151, 174, 183, 187, and 196 activated PXR.
Aroclor 1260 activated CAR2 and CAR3 variants at lower concentrations and antagonize CAR2 activation by the CAR agonist, CITCO, at higher concentrations (≥20 μg/ml). Additionally,
Aroclor 1260 induced
CYP2B6 in primary hepatocytes. At subtoxic doses,
Aroclor 1260 did not activate LXR or FXR and had no effect on LXR- or FXR-dependent induction by the agonists
T0901317 or
GW4064, respectively.
Aroclor 1260 (20 μg/ml) suppressed PPARα activation by the agonist
nafenopin, although none of the congeners tested demonstrated significant inhibition. The results suggest that
Aroclor 1260 is a human AhR, PXR and CAR3 agonist, a mixed agonist/antagonist for CAR2, and an antagonist for human PPARα.