Three typical organophosphorus flame retardants trigger thyroid hormone synthesis by inducing oxidative stress or inflammation reactions in Nthy-ori 3‑1 cells

Abstract

Accumulating evidence shows that organophosphorus flame retardants (OPFRs) can interfere with thyroid function in animals. However, studies on the effect of OPFR exposure on human thyroid hormone (TH) synthesis remain limited and controversial. In this study, we sought to investigate the effects and mechanisms of three typical OPFRs, including Tris (2-chloroethyl) phosphate (TCEP), tris (2-butoxyethyl) phosphate (TBEP), and triphenyl phosphate (TPHP), on TH synthesis using human thyroid follicular epithelial Nthy-ori 3–1 cells. The results showed that the cytotoxicity trend toward Nthy-ori 3–1 cells was TPHP > TBEP > TCEP. Moreover, TPHP significantly increased thyroxine levels and mRNA expression of thyroid-related functional proteins including thyroid peroxidase, thyrotropin receptor, and thyroglobulin at lower concentrations compared with TCEP and TBEP. Further analysis indicated that TBEP and TCEP caused mitochondrial dysfunction and impairment of oxidative phosphorylation, thereby elevating oxidative stress, as demonstrated by increases in reactive oxygen species and lipid peroxidation. In contrast, TPHP triggered TH synthesis by mediating inflammation reactions via activation of the TNF/IL-17/MAPK signaling pathway. In conclusion, this study revealed that the three OPFRs triggered TH synthesis to varying degrees by inducing oxidative stress or inflammation reactions, providing new insights into the mechanisms of action of OPFRs on the human thyroid.