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In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse
Published on: October 6, 2023
Novel brominated flame retardant TBPH upregulates thyroid synthesis markers via S1PR3 and involves IL-10 with
Jiawei Yang1, Qiong Zhang1, Haichen Zhang1
1Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China.
Abstract:
Bis(2-ethylhexyl) tetrabromophthalate (TBPH), an emerging brominated flame retardant, has raised environmental concern due to its endocrine-disrupting potential. While epidemiological evidence and our previous animal studies have linked TBPH to thyroid disruption, the molecular mechanisms remain unclear. This study aimed to identify potential molecular targets and downstream pathways involved in TBPH-induced effects on thyroid. We found that TBPH (100 nM) significantly upregulated the expression of key thyroid hormone synthesis markers PAX-8, TPO, and TG in human thyroid follicular cells (Nthy-ori 3-1). In silico docking identified S1PR3 as a potential interactor with moderate predicted affinity, and cellular thermal shift assay (CETSA) provided initial evidence of target engagement. S1pr3 knockdown partially attenuated TBPH-induced marker upregulation. Mechanistically, TBPH increased interleukin-10 (IL-10) in an S1PR3-dependent manner, coupled with activation of a non-canonical JAK-STAT pathway (JAK3, TYK2, STAT2, and STAT5). Further, overexpression of Il-10 enhanced downstream effector expression, whereas overexpression of Jak3 similarly promoted PAX-8 and TPO levels; conversely, Tyk2 knockdown reduced these markers, supporting a functional role for this alternative signaling cascade. Importantly, key elements of this pathway were recapitulated in thyroid tissues of TBPH-treated rats, providing in vivo corroboration for the cellular observations. Collectively, our results suggest a S1PR3/IL-10/non-canonical JAK-STAT axis as a candidate mechanism for TBPH-induced thyroid marker upregulation, providing a hypothesis-generating framework for future toxicological investigations of TBPH and related emerging brominated flame retardants.
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