PKCα mediated by the PI3K/Akt-FOXA1 cascade facilitates cypermethrin-induced hyperthyroidism

Cypermethrin (CYP), a broad-spectrum pyrethroid insecticide is extensively used. CYP is also considered as a potential endocrine disruptor with the thyroid-disturbing property. Protein kinase C alpha (PKCα) is a pleiotropic signal transduction molecule that functions crucially in thyroid hormone (TH) homeostasis and thyroid functions. To explore underlying roles of PKCα in CYP-mediated disturbance of TH homeostasis, Sprague-Dawley rats and rat thyroid cells were used in this study. Results showed that β-CYP stimulated TH biosynthesis, as shown by the increase in plasma levels of TT4, FT4, TT3, FT3, and TSH. After β-CYP treatment, expressions of PKCα, three miRNAs (miR-17-5p, miR-330-3p, and miR-331-3p), thyroid transcription factor TTF-1, and thyroid-specific proteins (TSHr, TPO, and Tg) were significantly increased, while expressions of PI3K p110α, p-Akt, FOXA1, and thyroid transcription factors (TTF-2 and Pax8) were decreased. Further studies found that β-CYP induced PKCα translation by the miR-330-3p-targeted PI3K/Akt-FOXA1 cascade and then PKCα positively regulated TTF-1 to promote TPO and Tg expressions, which in turn facilitated TH biosynthesis. Likewise, PKCα positively modulated TSHr expressions to strengthen the TSH/TSHr signal in the HPT axis, thereby synergistically contributing to TH biosynthesis. Moreover, β-CYP also disturbed TH biotransformation and biotransport by inducing DIO1 and inhibiting DIO3 in thyroids and TTR expressions in livers. Taken together, β-CYP has the thyroid-disturbing effect and could promote TH biosynthesis, and PKCα plays vital roles in β-CYP-caused hyperthyroidism.