Bisphenol A enhances retinoic acid-HOX genes signaling disrupting brain development: zebrafish

Plastic pollution and exposure to endocrine- disrupting chemicals (EDCs) like Bisphenol A (BPA) are emerging environmental concerns with potential impacts on human health and development. Despite evidence from epidemiological studies linking chemical exposure1,2 to neurodevelopmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder, the underlying causal mechanisms remain unclear3. Here, we show quantitative evidence that chemical exposure and detrimental outcomes are mechanistically linked to interference with retinoic acid (RA) signaling, a critical pathway in brain and neuronal development. Utilizing human induced pluripotent stem cells and zebrafish embryos, we found that BPA potentiated exogenous RA effects on 3' HOX gene expression and brain patterning, resulting in abnormalities such as duplication of Mauthner cell and abnormal craniofacial cartilage defects. Crucially, this potentiation effect was abolished by retinoic acid receptor antagonists but not estrogen receptor antagonists, suggesting a direct interaction with RA signaling pathways. Notably, the phenomenon was also observed with other chemicals, indicating a potential generalizable mechanism for a broader range of EDCs. Our findings provide a causal link between chemical exposure and neurodevelopmental impairments, contributing to the potential adverse effects of plastic pollution on development processes.