Bisphenol\nC Induces Cardiac Developmental Defects\nby Disrupting m<sup>6</sup>A Homeostasis

Bisphenol A (BPA)\nis a commonly used plastic additive. Since BPA\nhas been banned in maternal and infant food containers in many countries,\nBPA substitutes have been widely introduced to replace it. By systematically\nassessing the potential developmental toxicity of BPA substitutes,\nwe observed that the 41–150 nM <i>in vivo</i> BPC\nexposure (around the reported concentration detected in infant urine:\n6–186 nM) induced cardiac defects in zebrafish. Mechanistically,\nBPC disrupted m<sup>6</sup>A homeostasis by downregulation of the\nkey m<sup>6</sup>A methyltransferase, Mettl3, thereby causing the\nm<sup>6</sup>A reader, Igf2bp2b, to fail in recognizing and stabilizing\nthe inefficiently m<sup>6</sup>A-modified <i>acox1</i> and <i>tnnt2d</i> mRNA. Then, downregulation of Acox1 (a regulator\nin cardiac fatty acid metabolism) and Tnnt2d (a component of cardiac\ntroponin for muscle contraction) led to cardiac defects. Indeed, the\ndual cardiac functional axes regulated by the same m<sup>6</sup>A\nreader in response to BPC provided new insight into the regulatory\nmechanisms of epitranscriptomics and cardiac development. Collectively,\nour study not only presented evidence showing that the internal exposure\nlevels of BPC in humans could lead to cardiac developmental defects\nbut also demonstrated the underlying mechanism of BPC-mediated defects\nby disrupting the Mettl3-m<sup>6</sup>A-Igf2bp2b-Acox1/Tnnt2d pathways,\nwhich provided potential molecular markers associated with BPC exposure.