New insight into the adverse effect and molecular mechanism of thyroid disrupting chemicals on retinal cone differentiation: A case study of bisphenol S.

Thyroid hormone (TH), coordinating with its receptor (TRβ), plays a conserved role in regulating retinal cone differentiation. Environmental thyroid disrupting chemicals (TDCs) exposure has been proved as an emerging cause of retinal photosensitive dysfunction; however, the molecular target and underlying mechanisms of action have not been well explored. Here, a TH- and TDCs-sensitive transgenic zebrafish, of which the TRE: TRβ promoter-driven mCherry expressed in red cones, was constructed. By using this model, it was revealed that bisphenol S (BPS), a widely-used plastic additive with similar structure to TH, exhibited an agonist effect on TRβ and specialized retinal progenitor cells (RPCs) into red cones in larval zebrafish retina. Then, the essential role of TRβ in both BPS- and TH- stimulated red cone differentiation was convinced by a loss-of-function study. Single cone cell transcriptomic data showed both BPS and TH diminished the phototransduction cascade in red cone cells by interfering with different aspects of the transduction process, finally causing color vision defects in larval fish. Overall, it was demonstrated that BPS exposure, mimicking TH, disturbed RPCs specifying into red (not UV) cones via activating TRβ signaling, which further induced photosensitive dysfunction in cone cells. Our work highlights a new way of TRβ-mediated modulation of cone differentiation fate upon TDCs exposure.