CYP450-Dependent Biotransformation of the Insecticide Fipronil into Fipronil Sulfone Can Mediate Fipronil-Induced Thyroid Disruption in Rats (Full paper and erratum)

Béatrice Roques (1) , Marlène Z. Lacroix (1) , Sylvie Puel (2) , Véronique V. Gayrard-Troy (3) , Nicole Picard-Hagen (3) , Isabelle Jouanin (4) , Elisabeth Perdu (1) , Pascal G.P. Martin (1) , Catherine Viguié (3)

1 ToxAlim - ToxAlim
2 ToxAlim-BioToMyc - Biosynthèse & Toxicité des Mycotoxines
3 ToxAlim-EXPER - Exposition, Perturbation Endocrino-métabolique et Reproduction
4 E20 - MetaToul AXIOM

In rats, the widely used insecticide fipronil increases the clearance of thyroxine (T-4). This effect is associated with a high plasma concentration of fipronil sulfone, the fipronil main metabolite in several species including rats and humans. In sheep, following fipronil treatment, fipronil sulfone plasma concentration and thyroid disruption are much lower than in rats. We postulated that fipronil biotransformation into fipronil sulfone by hepatic cytochromes P450 (CYP) could act as a potential thyroid disruptor. The aim of this study was to determine if fipronil sulfone treatment could reproduce the fipronil treatment effects on T-4 clearance and CYP induction in rats. Fipronil and fipronil sulfone treatments (3.4 mu mol/kg/day per os, 14 days) increased total and free T-4 clearances to the same extent in THX + T-3, euthyroid-like rats. Both treatments induced a 2.5-fold increase in Ugt1a1 and Sult1b1 messenger RNA (mRNA) expressions and a twofold increase in UGT1A activity suggesting that T-4 elimination was mediated, at least in part, by hepatic uridine 5'-diphospho-glucuronosyltransferases (UGT) and/or sulfotransferases (SULT) induction. Both treatments induced a 10-fold increase in Cyp3a1 and Cyp2b2 mRNA expressions concomitant with a threefold increase in CYP3A immunoreactivity and a 1.7-fold increase in antipyrine clearance, a biomarker of CYP3A activity. All these results showed that fipronil sulfone treatment could reproduce the fipronil treatment effects on T-4 clearance and hepatic enzyme induction in rats. The potential of fipronil sulfone to act as a thyroid disruptor is all the more critical because it persists much longer in the organism than fipronil itself.

Mots clés: clearance; fipronil; fipronil sulfone; metabolism; rat; thyroid disruption

Domaines: Sciences du Vivant [q-bio]

Béatrice Roques, Marlène Z. Lacroix, Sylvie Puel, Véronique V. Gayrard-Troy, Nicole Picard-Hagen, et al.. CYP450-Dependent Biotransformation of the Insecticide Fipronil into Fipronil Sulfone Can Mediate Fipronil-Induced Thyroid Disruption in Rats (Full paper and erratum). Toxicological Sciences, 2012, 127 (1) 130 (2), pp.29-41 et 444-445. ⟨10.1093/toxsci/kfs094⟩. ⟨hal-01191244⟩