Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish

TLDR

Bisphenol A is a widespread endocrine disruptor linked to obesity, cancer, and childhood neurobehavioral disorders, yet the mechanisms connecting exposure to these outcomes remain unclear. The study aimed to mechanistically link BPA exposure to neurodevelopmental disease using zebrafish. The authors exposed embryonic zebrafish to very low doses of BPA and BPS and quantified hypothalamic neurogenesis. Very low doses of BPA and BPS accelerated hypothalamic neurogenesis and, when exposure was limited to the neurogenic window, produced hyperactive behavior in larvae, effects mediated by androgen‑regulated aromatase rather than estrogen receptors, indicating that the neurogenic period is a vulnerability window and that BPA‑free products may not be safer.

Abstract

Bisphenol A (BPA), a ubiquitous endocrine disruptor that is present in many household products, has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity. However, how BPA exposure translates into these neurodevelopmental disorders remains poorly understood. Here, we used zebrafish to link BPA mechanistically to disease etiology. Strikingly, treatment of embryonic zebrafish with very low-dose BPA (0.0068 μM, 1,000-fold lower than the accepted human daily exposure) and bisphenol S (BPS), a common analog used in BPA-free products, resulted in 180% and 240% increases, respectively, in neuronal birth (neurogenesis) within the hypothalamus, a highly conserved brain region involved in hyperactivity. Furthermore, restricted BPA/BPS exposure specifically during the neurogenic window caused later hyperactive behaviors in zebrafish larvae. Unexpectedly, we show that BPA-mediated precocious neurogenesis and the concomitant behavioral phenotype were not dependent on predicted estrogen receptors but relied on androgen receptor-mediated up-regulation of aromatase. Although human epidemiological results are still emerging, an association between high maternal urinary BPA during gestation and hyperactivity and other behavioral disturbances in the child has been suggested. Our studies here provide mechanistic support that the neurogenic period indeed may be a window of vulnerability and uncovers previously unexplored avenues of research into how endocrine disruptors might perturb early brain development. Furthermore, our results show that BPA-free products are not necessarily safer and support the removal of all bisphenols from consumer merchandise.