Typical persistent organic pollutant exposure induces body axial curvature through binding to Kdm1a transcriptionally activating expression of urp2 in zebrafish.

Body axial curvature is a common toxic effect of fish after exposure to environmental pollutants, but the molecular mechanism remains unclear. To investigate the underlying mechanisms, zebrafish were exposed to different persistent organic pollutants (POPs) including polychlorinated biphenyl (PCB) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47). PCB40 was chosen as the typical POP to discover the mechanism because of its remarkable body axial developmental toxicity. The PCB40 exposure reduced the density of spinal cord cilia. We observed the upregulation of neuropeptides urotensin II-related peptide (urp2), which is downstream of cilia signaling. Further analysis revealed an upregulation of lysine (K)-specific demethylase 1a (Kdm1a, also known as LSD1), and the microscale thermophoresis and chromatin immunoprecipitation assays indicated Kdm1a directly bound PCB40 and enriched in urp2 promoter regions to enhance urp2 expression. Both interventions of Kdm1a using a specific inhibitor and CRISPR/Cas9-mediated knockout partially rescued the body axial curvature induced by PCB40. Further molecular docking suggested that the previously reported pollutants which induced zebrafish body axial curvature could interact with Kdm1a. We found that PCB95 and BDE-47 also induced body axial curvature through Kdm1a and urp2. In conclusion, the study identified a previously unrecognized molecular pathway, specific POPs induced zebrafish body axial curvature by binding to Kdm1a, with urp2 emerging as a key candidate downstream mediator via Kdm1a-dependent upregulation. The study provides a new mechanism for fish body axial curvature caused by specific POPs and provides new insights for pollutant toxicity evaluation and prevention.