Effects of triphenyl phosphate on thyroid function and related mechanisms in zebrafish (Danio rerio) embryos/larvae and GH3 cells

Abstract

Triphenyl phosphate (TPP), one of the widely used organophosphorus flame retardants (OPFRs), has been frequently detected in environment and biota. However, knowledge on its toxicological effects is limited. The present study was conducted to investigate the thyroid hormone disruption potential of TPP and its underlying mechanisms using both in vivo and in vitro models. Zebrafish embryos/larvae were exposed to TPP until 7 days post-fertilization (dpf) to determine the changes in thyroid hormones and related gene transcriptions. After 7 d of zebrafish embryo/larval exposure, TPP significantly increased whole-body thyroid hormones, i.e., T3 and T4, concentrations. The up-regulation of the genes related to thyroid hormone synthesis (slc5a5, tg, and tpo) might be responsible for the increased whole-body T4 concentrations. TPP exposure also led to significant up-regulation the mRNA expression related to metabolism (deio1), transport (ttr), and elimination (ugt1ab) of thyroid hormones. Down-regulation of crh and tshb gene transcriptions indicates central regulatory feedback against increased levels of thyroid hormones in zebrafish larvae. To understand the direct interaction of TPP with central regulation, GH3 cell assay using rat pituitary gland cell was performed. In GH3 cells, TPP up-regulated the transcription of tshβ, trα, and trβ genes. TPP may interact with pituitary cells and increase tshb gene transcription as shown in GH3 cells, which was different from the observation in the fish larvae in vivo. The expressions of both deio1 and deio2 mRNA were not altered. Our observations clearly showed that TPP increases the thyroid hormone concentrations in early life stages of zebrafish through affecting the thyroid hormone synthesis, metabolism, transport, and elimination pathways. Later life implications of the thyroid hormone disruption deserve further investigations.