Bisphenol A (BPA) and octylphenol (OP) are abundant in the environment, bind to the estrogen receptor (ER) and act as partial estrogen agonists. In spite of accumulating evidence on their multiple effects on the reproductive tract, little is known about their spectrum of actions within the neuroendocrine axis, especially on the estrogen-sensitive pituitary lactotroph. We previously reported that these compounds induced lactotroph proliferation, increased prolactin (PRL) gene expression and release, altered pituitary ERalpha and ERbeta expression and affected the growth and morphology of the female reproductive tract. Whereas these effects take hours to days to occur and involve gene transcription and protein synthesis, we recently found that low nanomolar concentrations of estrogens/xenoestrogens induced very rapid (within 10 min) activation of the MAP kinase (MAPK) system and stimulated PRL release from cultured anterior pituitary cells. Our main objective is to compare genomic vs. non-genomic actions of estrogens/ xenoestrogens in the pituitary and determine interactions between intracellular calcium, nitric oxide (NO) release, MAPK activation and nuclear ER transactivation which result in increased hormone release, gene activation and lactotroph cell proliferation.
Specific aim 1 will test the hypothesis that estrogens rapidly stimulate PRL release via a membrane ER that is linked to calcium-dependent exocytosis and may also involve nitric oxide (NO) release. Free and conjugated estrogens/xenoestrogens will be used to determine: a) rapid stimulation of PRL release from dispersed anterior pituitary cells or GH3 lactotrophs in the absence and presence of ER antagonists, b) reversal of this effect by blockers of calcium, NO or MAPK, c) changes in intracellular calcium concentrations or NO release in response to estrogens, d) the ability of estrogens to increase PRL release in the presence of dopamine, and e) whether the PRL secretory response to estrogens is subjected to receptor desensitization.
Specific aim 2 will test the hypothesis that a short exposure to estrogens/xenoestrogens is sufficient to initiate sequential activation of the MAPK and ER signaling pathways, resulting in the induction of selected target genes and altered cell proliferation/apoptosis. Lactotrophs will be pulse-chased with free and conjugated estrogens in the presence or absence of MAPK and ER inhibitors. At various times thereafter we will determine: a) induction PRL and vascular endothelial growth factor (VEGF) gene expression, b) expression of ER isoforms that alter cellular sensitivity to estrogens, and c) increased lactotroph proliferation.
Specific aim 3 will use a gene array approach to test the hypothesis that the profile of pituitary genes that are upregulated/downregulated in response to estradiol and BPA differs between the estrogensensitive Fischer 344 (F344) and the estrogen-insensitive Sprague Dawley (SD) rat. The results of these studies should provide much needed experimental foundation for assessing the vulnerability of the pituitary gland to insults by endocrine disruptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012212-02
Application #
6745117
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
2003-05-02
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$287,378
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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