Effects of 17beta-estradiol and xenoestrogens on the neuronal survival in an organotypic hippocampal culture

Neuroendocrinology. 2002 Oct;76(4):223-34. doi: 10.1159/000065948.


Xenoestrogens are man-made compounds that mimic the actions of estrogens through interactions with estrogen receptors (ERs). Although xenoestrogens have received a great deal of attention as possible causes of brain disfunctions, little information concerning the effects of xenoestrogens on the central nervous system is available. In this study, we investigated the effects of 17beta-estradiol (E(2)) and four xenoestrogens (17alpha-ethynylestradiol, diethylstilbestrol, p-nonylphenol and bisphenol A (BPA)) on the neuronal survival using organotypic hippocampal slice cultures. When the cultured hippocampal slices were exposed to glutamate (1 mM, 15 min), the CA1-selective neuronal damage was induced. Pretreatment with E(2) and the xenoestrogens (24 h) selectively exacerbated the CA3 neuronal damage caused by glutamate. In spite of the marked difference of binding affinities to ERs, all compounds revealed maximal effects at 1 nM. ER antagonists, tamoxifen and ICI 182,780, did not affect responses to E(2) and the xenoestrogens, indicating that these effects are mediated through mechanisms other than ERs. In spite of the fact that BPA has little interaction with ERs at 1 nM, E(2) and BPA equally increased the expression of N-methyl-D-aspartate receptor in CA3 and upregulated the spine density of the apical portion of CA3 dendrites at 1 nM. These compounds also enhanced the sprouting of mossy fibers to CA3 neurons. These results suggest that exposure to E(2) and xenoestrogens during the developmental stage results in a marked influence on synaptogenesis and neuronal vulnerability through mechanisms other than ERs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds
  • Cell Survival / drug effects
  • Diethylstilbestrol / pharmacology
  • Estradiol / pharmacology*
  • Estradiol Congeners / pharmacology*
  • Estrogens, Non-Steroidal / pharmacology
  • Ethinyl Estradiol / pharmacology
  • Glutamic Acid / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Hippocampus / physiology*
  • Neurons / drug effects*
  • Neurons / pathology
  • Neurons / physiology*
  • Organ Culture Techniques
  • Phenols / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Benzhydryl Compounds
  • Estradiol Congeners
  • Estrogens, Non-Steroidal
  • Phenols
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Ethinyl Estradiol
  • Estradiol
  • Diethylstilbestrol
  • 4-nonylphenol
  • bisphenol A