Permethrin is a potential thyroid-disrupting chemical: In vivo and in silico envidence

• Thyroid endocrine disruption in zebrafish embryos was investigated following exposure to permethrin (PM).
• PM exposure significantly increased the levels of thyroid hormones in embryos.
• Both in vivo and in silico studies clearly disclosed that PM potentially disrupts the thyroid endocrine system in fish.
• PM markedly accumulated in larvae with a preference for cis-PM.

Permethrin (PM), one of the most heavily used synthetic pyrethroids, has the potential to interfere with thyroid hormones in mammals, however, the effect is poorly recognized in aquatic organisms. Herein, embryonic zebrafish were exposed to PM (0, 1, 3 and 10 μg/L) until 72 h post-fertilization. We demonstrated that PM readily accumulated in larvae with a preference for cis-PM, inhibited development and increased thyroxine and 3,5,3′-triiodothyronine levels accompanying increase in the transcription of most target genes, i.e., thyroid-stimulating hormone β, deiodinases, thyroid receptors, involved in the hypothalamic-pituitary-thyroid axis. Further Western blot analysis indicated that transthyretin (TTR) protein was significantly increased. Molecular docking analysis and molecular dynamics simulations revealed that PM fits into three hydrophobic binding pocket of TTR, one of the molecular targets of thyroid hormone disrupting chemicals (THDCs), and forms strong van der Waals interactions with six resides of TTR, including Leu8, Leu 101, Leu125, Thr214, Leu218 and Val229, thus altering TTR activity. Both in vivo and in silico studies clearly disclosed that PM potentially disrupts the thyroid endocrine system in fish. This study provides a rapid and cost-effective approach for identifying THDCs and the underlying mechanisms.

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