Researchers report that bisphenol A potentiated the effect of retinoic acid to disrupt neurodevelopmental gene signaling

Bisphenol A, a synthetic chemical used in plastic production, is known to interfere with various cell signaling pathways affecting development processes. However, its signaling mechanism, especially in brain development, remains elusive. Researchers from Japan have now investigated the effect of co-exposure of bisphenol A and retinoic acid on brain development. They observed disruption in HOX gene expression and developmental abnormalities, highlighting effects detrimental to fetal health.

Synthetic chemicals and plastics are useful and indispensable in our lives. On the other hand, the world is grappling with plastic pollution—clogging oceans, threatening wildlife, and leaching into ecosystems. While eco-friendly alternatives are on the way, researchers have been trying to identify the various effects of the synthetic plastics present within the ecosystem.

Bisphenol A (BPA) is a common chemical used in synthetic plastics and is known to act as an endocrine disruptor. Upon exposure to the human body, it interacts with multiple steroid hormone receptors, including estrogen, androgen, and thyroid receptors, causing various damage to the reproductive system, immune system, and neuroendocrine system. However, its mechanisms of action remain incompletely understood. While BPA is commonly leached into water bodies, retinoic acid (RA), a nutrient derivative which is essential for organ development, has also been reported to be found in low levels in water sources.

To investigate a mechanistic link between BPA and a wide range of disorders, a team of researchers led by Professor Tatsuyuki Takada from the College of Pharmaceutical Sciences, Ritsumeikan University, Japan, along with Dr. Akira Hirasawa from Kyoto University, Japan, focused on RA signaling, which plays fundamental roles in early development and explored how co-exposure to these two substances affects early neurodevelopment. Their findings were published online in Environmental Health Perspectives on May 13, 2025.

By exposing human induced pluripotent stem cells (iPSCs) and zebrafish embryos to exogenous RA and BPA (alone and in combination), they found that the combination of BPA and RA triggered abnormal brain and facial development by overstimulating RA-responsive genes, particularly a group known as HOX genes.

“When cells were exposed to BPA and RA together, it was observed that BPA potentiated the RA signaling pathway more than the normal condition (RA alone), leading to abnormalities in body patterning of critical organs during development,” explains Prof. Takada.

While BPA is already known to be an endocrine-disrupting chemical, its ability to interfere with development through the RA signaling pathway was previously unknown. Notably, BPA alone had no effect, but when combined with RA, it caused a dramatic shift in gene expression and brain structure. Moreover, upon treating the exposed iPSCs with RA receptor blockers, the effects were reduced, which confirms that BPA also acts through the RA receptors and not through estrogenic activity.

Upon exposure to the chemical pair, the zebrafish embryos exhibited various brain abnormalities, such as the rostral shift in brain region markers (e.g., hoxb1a gene), duplication of key neurons (Mauthner cells), and craniofacial malformations. These outcomes might be associated with neurodevelopmental disorders like autism spectrum disorder and attention deficit hyperactivity disorder.

This discovery, while rooted in laboratory models, has immediate relevance. Recently, RA-like activity has been detected in drinking water sources, and BPA continues to be found in food containers, receipts, and household products. With this research, the team hopes to inspire not only stricter environmental health policies but also deeper investigation into chemical-nutrient interactions.

“Our study reveals a causal link between chemical exposure and neurodevelopmental disorders, shedding light on the mechanisms of endocrine disruption. Because RA signaling plays many key roles during development and homeostasis, it may explain the pleiotropic effect of endocrine-disrupting chemicals. Moreover, it emphasizes the potential risk posed by simultaneous exposure to BPA and RA for the safety of fetus and pregnant women,” concludes Prof. Takada.

Title of original paper: Effects of Bisphenol A and Retinoic Acid Exposure on Neuron and Brain Formation: A Study in Human Induced Pluripotent Stem Cells and Zebrafish Embryos
Journal: Environmental Health Perspectives
DOI: 10.1289/EHP15574

About Professor Tatsuyuki Takada from Ritsumeikan University, Japan

Dr. Tatsuyuki Takada is a Professor at the College of Pharmaceutical Sciences, Ritsumeikan University, Japan. He earned a Ph.D. from Tohoku University and conducted postdoctoral research at the National Institutes of Health (USA). He has expertise in applied molecular and cellular biology. His research mainly focuses on the mechanism of how chemicals affect development and the conservation of endemic species by investigating cell differentiation signals and their regulation in different biological systems.

Funding information

This study was funded in part by a Grant-in-Aid for Challenging Exploratory Research (17K20049 to T.T.).