<p>Perfluorinated alkyl substances (PFASs) have been widely used for consumer products such as water and grease repellents, household products, electronics, and food contact materials. Some of PFASs have been and are supposed to be listed as persistent organic pollutants (POPs) due to their persistent and bioaccumulative properties, as well as toxicity. The present study aimed at evaluating developmental toxicity of representative PFASs and understanding the possible mechanisms using zebrafish embryos. Embryos continuously exposed to perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) elicited pericardial edema and reduction of blood flow in trunk vessels at 96 hours post fertilization in a concentration-dependent manner, with greater potency observed in PFOS than in PFHxS. PFOS also elicited spinal curvature. RNA sequencing revealed that genes involved in calcium-related signaling (e.g., pth1a, fbxo32, nos2a, tcap, and tnni4b.1) and in metabolic process (e.g., nos2a, mlycd, ppp1r3aa, pdk2b, lepa, and lepb) were significantly and commonly affected by PFOS (10 μM) and PFHxS (100 μM). Co-exposure to PFOS and NMDA receptor antagonists (memantine and MK-801) rescued circulatory failure and spinal curvature caused by PFOS. In contrast, PFOS-induced circulatory failure and spinal curvature were exacerbated by co-exposure to a PPARα antagonist (MK-886). These results suggest that circulatory failure and spinal curvature caused by PFOS and possibly by PFHxS might be through disruption of calcium signaling, and PPARα signaling may have a protective role against it.</p>