Role of glucocorticoid receptor in acclimation of killifish (Fundulus heteroclitus) to seawater and effects of arsenic

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2007-02, Vol.292 (2), p.R1052-R1060
• Main Authors: Shaw, Joseph R, Gabor, Kristen, Hand, Emily, Lankowski, Alexander, Durant, Lydia, Thibodeau, Renee, Stanton, Caitlin R, Barnaby, Roxanna, Coutermarsh, Bonita, Karlson, Katherine H, Sato, J. Denry, Hamilton, Joshua W, Stanton, Bruce A
• Format: Article
• Language: English
• Subjects: Acclimatization - drug effects; Acclimatization - physiology; Anatomy & physiology; Animals; Arsenic - pharmacokinetics; Arsenic - toxicity; Blotting, Western; Chlorides - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - biosynthesis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Fish; Fundulidae - physiology; Fundulus heteroclitus; Gene expression; Gills - metabolism; Homeostasis - drug effects; Homeostasis - physiology; Hormone Antagonists - pharmacology; Hormones; Hydrocortisone - pharmacology; Hypothesis testing; Mass Spectrometry; Mifepristone - pharmacology; Mineralocorticoid Receptor Antagonists - pharmacology; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - physiology; Receptors, Mineralocorticoid - drug effects; Receptors, Mineralocorticoid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; Seawater; Sodium-Potassium-Chloride Symporters - biosynthesis; Sodium-Potassium-Chloride Symporters - genetics; Sodium-Potassium-Exchanging ATPase - biosynthesis; Sodium-Potassium-Exchanging ATPase - genetics; Solute Carrier Family 12, Member 2; Spironolactone - pharmacology; Teleostei; Tissue Distribution
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00328.2006

1 Department of Biological Sciences, Dartmouth College, and 2 Center for Environmental Health Sciences, Dartmouth Medical School, Hanover, New Hampshire; 3 Mount Desert Island Biological Laboratory, Salisbury Cove, Maine; and 4 Department of Physiology and 5 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire Submitted 15 May 2006 ; accepted in final form 2 October 2006 Killifish are euryhaline teleosts that adapt to rapid changes in the salinity of the seawater. It is generally accepted that acclimation to seawater is mediated by cortisol activation of the glucocorticoid receptor (GR), which stimulates CFTR mRNA expression and CFTR-mediated Cl – secretion by the gill. Because there is no direct evidence in killifish that the GR stimulates CFTR gene expression, quantitative PCR studies were conducted to test the hypothesis that cortisol activation of GR upregulates CFTR mRNA expression and that this response is required for acclimation to seawater. Inhibition of the GR by RU-486 prevented killifish from acclimating to increased salinity and blocked the increase in CFTR mRNA. In contrast, inhibition of the mineralocorticoid receptor by spironolactone had no effect on acclimation to seawater. Thus acclimation to increased salinity in killifish requires signaling via the GR and includes an increase in CFTR gene expression. Because arsenic, a toxic metalloid that naturally occurs in the aquatic environment, has been shown to disrupt GR transcriptional regulation in avian and mammalian systems, studies were also conducted to determine whether arsenic disrupts cortisol-mediated activation of CFTR gene expression in this in vivo fish model and thereby blocks the ability of killifish to acclimate to increased salinity. Arsenic prevented acclimation to seawater and decreased CFTR protein abundance. However, arsenic did not disrupt the GR-induced increase in CFTR mRNA. Thus arsenic blocks acclimation to seawater in killifish by a mechanism that does not disrupt GR-mediated induction of CFTR gene expression. cystic fibrosis transmembrane conductance regulator, chloride channel; ion transport; chloride secretion; environmental toxicant Address for reprint requests and other correspondence: B. A. Stanton, Dept. of Physiology, Dartmouth Medical School, N. College St., Hanover, NH 03755 (e-mail: bas{at}dartmouth.edu )