Bisphenol C Induces Cardiac Developmental Defects by Disrupting m6A Homeostasis

• Published in: Environmental science & technology Vol. 58; no. 39; pp. 17259 - 17269
• Main Authors: Su, Kunhui, Liu, Jinfeng, Chen, Jiafeng, Wu, Hengyu, Tang, Wenbin, Sun, Siqi, Lin, Jiebo, Zhan, Guankai, Hsu, Chih-Hung
• Format: Journal Article
• Language: English
• Published: Easton American Chemical Society 01.10.2024
• Subjects: Biocompatibility; Bisphenol A; Cardiac muscle; Defects; Disruption; Down-regulation; Ecotoxicology and Public Health; Exposure; Food additives; Homeostasis; Infants; Methyltransferase; mRNA; Muscle contraction; Muscular function; Regulatory mechanisms (biology); Substitutes; Toxicity; Troponin; Zebrafish; cardiac defects; RNA m6A modification; BPC; developmental toxicity; m6A reader
• ISSN: 0013-936X; 1520-5851; 1520-5851
• DOI: 10.1021/acs.est.4c04373

Bisphenol A (BPA) is a commonly used plastic additive. Since BPA has been banned in maternal and infant food containers in many countries, BPA substitutes have been widely introduced to replace it. By systematically assessing the potential developmental toxicity of BPA substitutes, we observed that the 41–150 nM in vivo BPC exposure (around the reported concentration detected in infant urine: 6–186 nM) induced cardiac defects in zebrafish. Mechanistically, BPC disrupted m6A homeostasis by downregulation of the key m6A methyltransferase, Mettl3, thereby causing the m6A reader, Igf2bp2b, to fail in recognizing and stabilizing the inefficiently m6A-modified acox1 and tnnt2d mRNA. Then, downregulation of Acox1 (a regulator in cardiac fatty acid metabolism) and Tnnt2d (a component of cardiac troponin for muscle contraction) led to cardiac defects. Indeed, the dual cardiac functional axes regulated by the same m6A reader in response to BPC provided new insight into the regulatory mechanisms of epitranscriptomics and cardiac development. Collectively, our study not only presented evidence showing that the internal exposure levels of BPC in humans could lead to cardiac developmental defects but also demonstrated the underlying mechanism of BPC-mediated defects by disrupting the Mettl3-m6A-Igf2bp2b-Acox1/Tnnt2d pathways, which provided potential molecular markers associated with BPC exposure.