Pentabromoethylbenzene Exposure Induces Transcriptome Aberration and Thyroid Dysfunction: In Vitro, in Silico, and in Vivo Investigations

Pentabromoethylbenzene (PBEB), as one of the novel brominated flame retardants (NFBRs), has caused increasing public concern for health risks. Till now, information regarding potential effects of PBEB on thyroid function remains unclear. Herein, we investigated thyroid disruption of PBEB in vitro and in silico and evaluated thyroid dysfunction induced by PBEB using Sprague-Dawley rats. PBEB showed thyroid receptor (TR) beta antagonistic activity with IC50 of 9.82 x 10(-7) M in the dual-luciferase reporter gene assay and induced relative reorientation of helix 11 (H11) and H12 of the TR ligand binding domain as revealed by molecular dynamics simulations. PBEB (0.2, 2, 20 mg/kg BW/d) markedly altered the transcriptome profile of thyroid with induction of 17, 42, and 119 differentially expressed genes (DEGs) involved in thyroid hormone signaling and synthesis pathway, of which transthyretin and albumin are common DEGs. The 28-d exposure to PBEB significantly decreased the triiodothyronine level (from 7.23 to 5.67 ng/mL) and increased the thyrotropin level (from 7.88 to 12.86 mU/L) for female rats. PBEB consequently reduced thyroid weight and altered its morphology with more depleted follicles. Overall, our study provides the first account of evidence on PBEB exerted thyroid disruption, transcriptome aberration, and morphological alteration, facilitating health risk assessment of PBEB and structurally related NBFRs.