Endocrine Disrupting Chemicals, Phthalic Acid and Nonylphenol, Activate Pregnane X Receptor-Mediated Transcription
Recently, Pregnane X receptor (PXR), a new member of the nuclear receptor superfamily, was shown to mediate the effects of several steroid hormones, such as progesterone, glucocorticoid, pregnenolone, and xenobiotics on cytochrome P450 3A genes (CYP3A) through the specific DNA sequence for CYP3A, su...
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Published in | Molecular endocrinology (Baltimore, Md.) Vol. 14; no. 3; pp. 421 - 428 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Endocrine Society
01.03.2000
Oxford University Press |
Subjects | |
Online Access | Get full text |
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Summary: | Recently, Pregnane X receptor (PXR), a new member
of the nuclear receptor superfamily, was shown to mediate the effects
of several steroid hormones, such as progesterone, glucocorticoid,
pregnenolone, and xenobiotics on cytochrome P450 3A genes (CYP3A)
through the specific DNA sequence for CYP3A, suggesting that
PXR may play a role in steroid hormone metabolism. In this
paper, we demonstrated that phthalic acid and nonylphenol,
endocrine-disrupting chemicals (EDCs), stimulated PXR-mediated
transcription at concentrations comparable to those at which they
activate estrogen receptor-mediated transcription using a transient
reporter gene expression assay in COS-7 cells. However, bisphenol A,
another EDC, had no effect on PXR-mediated transcription, although this
chemical significantly enhanced ER-mediated transcription. In the yeast
two-hybrid protein interaction assay, PXR interacted with two nuclear
receptor coactivator proteins, steroid hormone receptor coactivator-1
and receptor interacting protein 140, in the presence of
phthalic acid or nonylphenol. Thus, EDC-occupied PXR may regulate its
specific gene expression through the receptor-coactivator interaction.
In contrast, these EDCs had no effect on the interaction between PXR
and suppressor for gal 1, a component of proteasome. Finally, the
expression of CYP3A1 mRNA in the liver of rats exposed to phthalic acid
or nonylphenol markedly increased compared with that in rats treated
with estradiol, bisphenol A, or ethanol as assessed by competitive
RT-PCR. These data suggest that EDCs may affect endocrine functions by
altering steroid hormone metabolism through PXR. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0888-8809 1944-9917 |
DOI: | 10.1210/mend.14.3.0424 |