Endocrine disrupting chemicals bind to a novel receptor, microtubule-associated protein 2, and positively and negatively regulate dendritic outgrowth in hippocampal neurons.
The present study demonstrates a novel high-affinity neuronal target for endocrine disrupting chemicals (EDCs), which potentially cause psychological disorders. EDCs competitively inhibited the binding of bovine serum albumin-conjugated progesterone to recombinant human microtubule-associated protein 2C (rhMAP2C) with an inhibition constant at picomolar levels. In the rhMAP2C-stimulated tubulin assembly assay, agonistic enhancement was observed with dibutyl phthalate and pentachlorphenol and pregnenolone, while an inverse agonistic effect was observed with 4-nonylphenol. In contrast, progesterone and many of the EDCs, including bisphenol A, antagonized the pregnenolone-induced enhancement of rhMAP2C-stimulated tubulin assembly. These agonistic and inverse agonistic actions were not observed in tubulin assembly stimulated with Delta1-71 rhMAP2C, which lacks the steroid-binding site. Using a dark-field microscopy, pregnenolone and pentachlorphenol were observed to generate characteristic filamentous microtubules in a progesterone- or bisphenol A-reversible manner. In cultured hippocampal neurons, similar agonist-antagonist relationships were reproduced in terms of dendritic outgrowth. Fluorescent recovery after photobleaching of hippocampal neurons showed that pregnenolone and agonistic EDCs enhanced, but that 4-nonylphenol inhibited the MAP2-mediated neurite outgrowth in a progesterone- or antagonistic EDC-reversible manner. Furthermore, none of the examined effects were affected by mifepristone or ICI-182,786 i.e. the classical progesterone and estrogen receptor antagonists. Taken together, these results suggest that EDCs cause a wide variety of significant disturbances to dendritic outgrowth in hippocampal neurons, which may lead to psychological disorders following chronic exposure during early neuronal development.
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Hayato
H
Matsunaga
Kaori
K
Mizota
Hitoshi
H
Uchida
Takafumi
T
Uchida
Hiroshi
H
Ueda
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D049108:Cell Enlargement / Q000187:drug effects; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D052244:Endocrine Disruptors / Q000378:metabolism*; D006131:Growth Inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
D052244:Endocrine Disruptors; D006131:Growth Inhibitors; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins