Triclosan Disrupts Thyroid Hormones: Mode-of-Action, Developmental Susceptibility, and Determination of Human Relevance Public Deposited

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  • March 22, 2019
Creator
  • Paul, Katie B.
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Preliminary study demonstrated that triclosan (TCS), a bacteriostat in myriad consumer products, decreases serum thyroxine (T4) in rats. Adverse neurodevelopmental consequences result from thyroid hormone (TH) disruption; therefore determination of whether TCS disrupts THs during development, its mode-of-action (MOA), and the human relevance is critical. This research tested the hypothesis that TCS disrupts THs via activation of pregnane X and constitutive androstane receptors (PXR, CAR), mediating Phase I-II enzyme and hepatic transporter expression and protein changes, thereby increasing catabolism and elimination of THs, resulting in decreased TH concentrations. For Aim One, the hypothesized MOA was assessed using weanling female Long-Evans rats orally exposed to TCS (0-1000 mg/kg/day) for four days. Serum T4 decreased 35% at 300 mg/kg/day. Activity and expression of markers of Phase I (Cyp2b, Cyp3a1) and Phase II (Ugt1a1, Sult1c1) metabolism were moderately induced, consistent with PXR and/or CAR activation and increased hepatic catabolism. Susceptibility of dams and developing rats to TCS-induced hypothyroxinemia was determined for Aim Two. Long-Evans dams received TCS (0-300 mg/kg/day) orally from gestational day (GD) 6 to postnatal day (PND) 21; tissues were collected from fetuses (GD20), pups (PND4, 14, 21), and dams (GD20, PND22). Serum T4 decreased 30% in GD20 dams and fetuses, PND4 pups, and PND22 dams (300 mg/kg/day). Minor increases in activity and expression of markers of hepatic Phase I (Cyp2b, Cyp3a) and Phase II (T4-glucuronidation in PND22 dams) metabolism were consistent with PXR/CAR activation and concomitant minor decreases in T4. For Aim Three, cell-based rat and human PXR and CAR reporter assays were employed to evaluate the human relevance of the putative MOA. TCS (10-30 μM) demonstrated human receptor reporter activities: inverse agonism of CAR1 and agonism of CAR2 CAR3, and PXR. TCS was an inverse agonist of rat CAR, similar to compounds that increase Phase I-II metabolism downstream. Although the data indicate potential species differences in the initiating key event, downstream effects on hepatic catabolism may be similar due to overlapping transcriptional regulatory functions of PXR and CAR. These data establish a plausible MOA for TCS-induced hypothyroxinemia in rats and demonstrate initiation of the MOA in human models.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology.
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  • Crofton, Kevin Michael
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