Bisphenol A and its analogs perturb primitive myelopoiesis and inhibit innate immune cell formation during early developmental stages of zebrafish

Perinatal exposure to bisphenol A (BPA) promotes the development of inflammatory and immune diseases. Nevertheless, the potential mechanisms of this effect and the developmental immunotoxicity of BPA analogs are unclear. Here, embryonic zebrafish were exposed to a range of concentrations of BPA and its analogs. With the exception of bisphenol AF, all of the tested bisphenols reduced neutrophil or macrophage numbers, with the rank order of bisphenol P (BPP) ≈ bisphenol B (BPB) > bisphenol S > BPA ≈ bisphenol F (BPF) > bisphenol Z ≈ bisphenol AP > bisphenol E. We assessed BPA, BPB, BPF, and BPP and revealed that this effect was attributed to the inhibition of primitive myelopoiesis by restricting the differentiation of hemangioblasts to myeloid progenitor cells. Mechanistically, BPP partially overlapped with BPA, which restricted hemangioblast differentiation by acting on scl, gata2, and gata1, whereas BPA mainly acted on scl and gata1. In contrast, BPB targeted gata2, whereas BPF favored lmo2, causing abnormal hemangioblast differentiation. These results highlight the differential developmental immunotoxic targets and mechanisms of BPA and its analogs. Our findings reveal the modes of bisphenol-mediated developmental immunotoxicity, highlighting their link with hematopoiesis disorders.