Bisphenol A Inhibits Cl− Secretion by Inhibition of Basolateral K+ Conductance in Human Airway Epithelial Cells
- Division II (Respiratory Division), Internal Medicine II, University of Nagoya School of Medicine, Nagoya, Japan
- Dr. Yasushi Ito, Division II (Respiratory Division), Internal Medicine II, University of Nagoya School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail: itoyasu{at}med.nagoya-u.ac.jp
Abstract
There has been growing concern about the potential threat of hormone-disrupting chemicals like bisphenol A to various aspects of animal and human health. We studied the effects of bisphenol A on the Cl− secretion in human airway epithelial Calu-3 cells. Pretreatment with bisphenol A (IC50 = 60 μM, for 30 min) prevented isoproterenol (10 nM)-generated short-circuit current (Isc) more potently than 17β-estradiol or tamoxifen (IC50 = 1 mM). 5′-Nitro-2-(3-phenylpropylamino) benzoate-sensitive apical conductance potentiated by isoproterenol was not affected by the pretreatment with either of these estrogenic compounds. The effects of bisphenol A were simulated in Isc responses to forskolin (10 μM) and 8-bromo-cAMP (1 mM). Nystatin permeabilization of Calu-3 monolayers revealed that bisphenol A attenuated 8-bromo-cAMP-induced basolateral K+ current, which is sensitive to clotrimazole (30 μM) and insensitive to charybdotoxin (100 nM), without affecting the apical Cl−current. Bisphenol A, but neither 17β-estradiol nor tamoxifen, interrupted the charybdotoxin-sensitive component ofIsc stimulated by 1-ethyl-2-benzimidazolinone (1-EBIO; 500 μM). The inhibitory effects of bisphenol A on these Cl− secretory stimuli were remarkable when applied to the apical rather than the basolateral membrane. Alternatively, long-term incubation of bisphenol A (1 μM; 12–72 h) had no discernible effect on isoproterenol- and 1-EBIO-induced Cl− secretion. These findings indicate that short-term exposure to bisphenol A attenuates transepithelial Cl− secretion through inhibition of both cAMP- and Ca2+-activated K+ channels on the basolateral membrane, interacting from the cytosolic surface in Calu-3 cells.
Footnotes
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This work was supported by Research Grant Funds (11770305) from the Japan Society for the Promotion of Science to Y.I.
- Abbreviations:
- CFTR
- cystic fibrosis transmembrane conductance regulator
- NPPB
- 5′-nitro-2-(3-phenylpropylamino) benzoate
- 1-EBIO
- 1-ethyl-2-benzimidazolinone
- KCa channel
- Ca2+-activated K+ channel
- GAp
- apical membrane conductance
- Gt
- transepithelial conductance
- Isc
- short-circuit currents
- ICl
- apical membrane Cl−current
- IK
- basolateral membrane K+ current
- BAPTA-AM
- 1,2-bis-(o-amino-phenoxy)-ethane-N,N,N′,N′-tetraacetic acid tetra-(acetoxymethyl)-ester
- DMSO
- dimethyl sulfoxide
- KcAMP channel
- cAMP-activated K+ channel
- hIK1 channel
- inward-rectifying intermediate-conductance Ca2+-activated K+ channel
- 17β-ES
- 17β-estradiol
- TAM
- tamoxifen
- ISO
- isoproterenol
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- Received December 6, 2001.
- Accepted March 14, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
