Arsenic at Very Low Concentrations Alters Glucocorticoid Receptor (GR)-Mediated Gene Activation but Not GR-Mediated Gene Repression:  Complex Dose−Response Effects Are Closely Correlated with Levels of Activated GR and Require a Functional GR DNA Binding Domain

Arsenic (As) contamination of drinking water is considered a principal environmental health threat throughout the world. Chronic intake is associated with an increased risk of cancer, diabetes, and cardiovascular disease, and recent studies suggest increased health risks at levels as low as 5−10 ppb...

Full description

Saved in:
Bibliographic Details
Published in:Chemical research in toxicology 2004-08, Vol.17 (8), p.1064-1076
Main Authors: Bodwell, Jack E, Kingsley, Lauren A, Hamilton, Joshua W
Format: Article
Language:English
Subjects:
Animals
Arsenic - chemistry
Arsenic - pharmacology
Base Sequence
Cell Line, Tumor
Cysteine - chemistry
Dexamethasone - pharmacology
DNA-Binding Proteins - chemistry
Dose-Response Relationship, Drug
Down-Regulation
Gene Expression Regulation
Humans
Molecular Sequence Data
Mutation
Promoter Regions, Genetic
Protein Conformation
Rats
Receptors, Glucocorticoid - chemistry
Receptors, Glucocorticoid - metabolism
Transcription, Genetic - drug effects
Transcriptional Activation
Tyrosine Transaminase - genetics
Water Pollutants, Chemical - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Arsenic (As) contamination of drinking water is considered a principal environmental health threat throughout the world. Chronic intake is associated with an increased risk of cancer, diabetes, and cardiovascular disease, and recent studies suggest increased health risks at levels as low as 5−10 ppb. We report here that 0.05−1 μM (6−120 ppb) As showed stimulatory effects on glucocorticoid receptor (GR)-mediated gene activation in rat EDR3 hepatoma cells of both the endogenous tyrosine aminotransferase (TAT) gene and the reporter genes containing TAT glucocorticoid response elements. At slightly higher concentrations (1−3 μM), the effects of As became inhibitory. Thus, over this narrow concentration range, the effects of As changed from a 2- to 4-fold stimulation to a greater than 2-fold suppression in activity. Interestingly, the inhibitory effect of GR on both AP1- and NF-κB-mediated gene activation was not affected by As. The magnitude of GR stimulation and inhibition by As was highly dependent on the cellular level of hormone-activated GR. Mutational deletion studies indicated that the central DNA binding domain (DBD) of GR is the minimal region required for the As effect and does not require free sulfhydryls. Point mutations located within the DBD that have known structural consequences significantly altered the GR response to As. In particular, point mutations in the DBD that confer a DNA-bound GR confirmation abolished the low dose As stimulatory effect but enhanced the inhibitory response, further indicating that the DBD is important for mediating these As effects.
ISSN:0893-228X
1520-5010
DOI:10.1021/tx0499113