Actions of Bisphenol A and Bisphenol S on the Reproductive Neuroendocrine System During Early Development in Zebrafish

Endocrinology. 2016 Feb;157(2):636-47. doi: 10.1210/en.2015-1785. Epub 2015 Dec 10.


Bisphenol A (BPA) is a well-known environmental, endocrine-disrupting chemical, and bisphenol S (BPS) has been considered a safer alternative for BPA-free products. The present study aims to evaluate the impact of BPA and BPS on the reproductive neuroendocrine system during zebrafish embryonic and larval development and to explore potential mechanisms of action associated with estrogen receptor (ER), thyroid hormone receptor (THR), and enzyme aromatase (AROM) pathways. Environmentally relevant, low levels of BPA exposure during development led to advanced hatching time, increased numbers of GnRH3 neurons in both terminal nerve and hypothalamus, increased expression of reproduction-related genes (kiss1, kiss1r, gnrh3, lhβ, fshβ, and erα), and a marker for synaptic transmission (sv2). Low levels of BPS exposure led to similar effects: increased numbers of hypothalamic GnRH3 neurons and increased expression of kiss1, gnrh3, and erα. Antagonists of ER, THRs, and AROM blocked many of the effects of BPA and BPS on reproduction-related gene expression, providing evidence that those three pathways mediate the actions of BPA and BPS on the reproductive neuroendocrine system. This study demonstrates that alternatives to BPA used in the manufacture of BPA-free products are not necessarily safer. Furthermore, this is the first study to describe the impact of low-level BPA and BPS exposure on the Kiss/Kiss receptor system during development. It is also the first report of multiple cellular pathways (ERα, THRs, and AROM) mediating the effects of BPA and BPS during embryonic development in any species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Benzhydryl Compounds / pharmacology*
  • Embryo, Nonmammalian
  • Embryonic Development / drug effects
  • Gonadotropin-Releasing Hormone / genetics
  • Gonads / drug effects*
  • Gonads / embryology*
  • Green Fluorescent Proteins / genetics
  • Neurosecretory Systems / drug effects*
  • Neurosecretory Systems / embryology*
  • Phenols / pharmacology*
  • Promoter Regions, Genetic
  • Pyrrolidonecarboxylic Acid / analogs & derivatives
  • Sulfones / pharmacology*
  • Zebrafish / embryology*
  • Zebrafish / genetics


  • Benzhydryl Compounds
  • Phenols
  • Sulfones
  • gonadotropin-releasing hormone-III
  • Green Fluorescent Proteins
  • Gonadotropin-Releasing Hormone
  • bis(4-hydroxyphenyl)sulfone
  • bisphenol A
  • Pyrrolidonecarboxylic Acid