The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism.
Résumé
Fipronil is described as a thyroid disruptor in rat. Based on the hypothesis that this results from a perturbation of hepatic thyroid hormone metabolism, our goal was to investigate the pathways involved in fipronil-induced liver gene expression regulations. First, we performed a microarray screening in the liver of rats treated with fipronil or vehicle. Fipronil treatment led to the upregulation of several genes involved in the metabolism of xenobiotics, including the cytochrome P450 Cyp2b1, Cyp2b2 and Cyp3a1, the carboxylesterases Ces2 and Ces6, the phase II enzymes Ugt1a1, Sult1b1 and Gsta2, and the membrane transporters Abcc2, Abcc3, Abcg5, Abcg8, Slco1a1 and Slco1a4. Based on a large overlap with the target genes of constitutive androstane receptor (CAR) and pregnane X receptor (PXR), we postulated that these two nuclear receptors are involved in mediating the effects of fipronil on liver gene expression in rodents. We controlled that liver gene expression changes induced by fipronil were generally reproduced in mice, and then studied the effects of fipronil in wild-type, CAR- and PXR-deficient mice. For most of the genes studied, the gene expression modulations were abolished in the liver of PXR-deficient mice and were reduced in the liver of CAR-deficient mice. However, CAR and PXR activation in mouse liver was not associated with a marked increase of thyroid hormone clearance, as observed in rat. Nevertheless, our data clearly indicate that PXR and CAR are key modulators of the hepatic gene expression profile following fipronil treatment which, in rats, may contribute to increase thyroid hormone clearance.
Mots clés
Rodents
Slco
Sult
T3
T4
TATA-box binding protein
TSH
TT3
TT4
Tbp
Thyroid hormone metabolism
Thyroxine (PubChem CID: 5819)
Triiodothyronine (PubChem CID: 5920)
Ugt
carboxylesterase
cytochrome P450
electrospray ionization mode
free thyroxine
free triiodothyronine
gene expression omnibus
gene ontology
glutathione S-transferase
multidrug resistance-associated protein
multiple reaction monitoring
organic anion-transporting polypeptide
phenobarbital
pregnenolone-16alpha-carbonitrile
quality control
real-time quantitative polymerase chain reaction
solute carrier organic anion transporter
sulfotransferase
thyroid-stimulating hormone
thyroxine
total thyroxine
total triiodothyronine
triiodothyronine
(13)C(6)-levothyroxine (PubChem CID: 53442260)
5′-diphospho (UDP)-glucuronosyltransferase
ATP-binding cassette
Abc
CAR
Cyp
FT3
FT4
Fipronil (PubChem CID: 3352)
GEO
GO
Gst
Hepatic metabolism
MRM
MRP
OATP
RNA polymerase II polypeptide A
Domaines
Sciences du Vivant [q-bio]
Fichier principal
The nuclear receptors pregnane X receptor and constitutive_1.pdf (1.96 Mo)
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