Organophosphate flame retardants (OPFRs), as alternatives of polybrominated diphenyl ethers (PBDEs), have been frequently detected in the environment and biota, and could pose adverse effects on organisms. However, information on the potential endocrine disruption of OPFRs, especially their effects on steroid hormone receptors, such as glucocorticoid and mineralocorticoid receptors (GR/MR), is limited. In this study, the dual-luciferase reporter gene assay via GR/MR and a H295R steroidogenesis assay were employed to evaluate the endocrine disruption of nine OPFRs. We found TMPP, TPHP, and TDBPP exhibited both GR and MR antagonistic activities, while TNBP and TDCIPP only showed MR antagonistic property within a concentration range of 10 to 10 mol/L(M). In the H295R steroidogenesis assay, the fold changes of eight steroidogenic genes in response to OPFRs were further studied. We found CYP17,CYP21, and CYP11B1 expression were significantly down-regulated following TMPP, TPHP, or TDBPP exposure at a concentration of 2 × 10 M. Meanwhile TMPP decreased the production of cortisol and TDBPP down-regulated the secretion of aldosterone. Our results indicate that some OPFRs can interact with GR and MR, and have the potential to disturb steroidogenesis. Data provided here will be helpful to comprehensively understand the potential endocrine disruption of OPFRs.

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Migration of myoblasts derive from the occipital somites is critical for tongue morphogenesis. However, the molecular mechanisms of myoblast migration remain elusive. In this study, we report that deletion of Isl1 in the mandibular epithelium leads to aglossia due to myoblast migration defects. Isl1 regulates the expression pattern of chemokine ligand 12 (Cxcl12) in the first branchial arch through the Shh/Wnt5a cascade. Cxcl12+ mesenchymal cells in Isl1ShhCre embryos were unable to migrate to the distal region, but instead clustered in a relatively small proximal domain of the mandible. CXCL12 serves as a bidirectional cue for myoblasts expressing its receptor CXCR4 in a concentration-dependent manner, attracting Cxcr4+ myoblast invasion at low concentrations but repelling at high concentrations. The accumulation of Cxcl12+ mesenchymal cells resulted in high local concentrations of CXCL12, which prevented Cxcr4+ myoblast invasion. Furthermore, transgenic activation of Ihh alleviated defects in tongue development and rescued myoblast migration, confirming the functional involvement of Hedgehog signaling in tongue development. In summary, this study provides the first line of genetic evidence that the ISL1/SHH/CXCL12 axis regulates myoblast migration during tongue development.