Thyroid disruption by triphenyl phosphate, an organophosphate flame retardant, in zebrafish (Danio rerio) embryos/larvae, and in GH3 and FRTL-5 cell lines

Abstract

Triphenyl phosphate (TPP), one of the most widely used organophosphate flame retardants (OPFRs), has frequently been detected in the environment and biota. However, knowledge of its toxicological effects is limited. The present study was conducted to determine the adverse effects of TPP on the thyroid endocrine system of embryonic/larval zebrafish, and the underlying mechanisms for these effects were studied using rat pituitary (GH3) and thyroid follicular (FRTL-5) cell lines. In the GH3 cells, TPP up-regulated the expression of the tshβ, trα, and trβ genes, while T3, a positive control, down-regulated the expression of these genes. In the FRTL-5 cells, the expression of the nis and tpo genes was significantly up-regulated, suggesting that TPP stimulates thyroid hormone synthesis in the thyroid gland. In zebrafish larvae at 7 days post-fertilization (dpf), TPP exposure led to significant increases in both T3 and T4 concentrations and expression of the genes involved in thyroid hormone synthesis. Exposure to TPP also significantly up-regulated the expression of the genes related to the metabolism (dio1), transport (ttr), and elimination (ugt1ab) of thyroid hormones. The down-regulation of the crh and tshβ genes in the zebrafish larvae suggests the activation of a central regulatory feedback mechanism induced by the increased T3 levels in vivo. Taken together, our observations show that TPP could increase the thyroid hormone concentrations in the early life stages of zebrafish by disrupting the central regulation and hormone synthesis pathways.