Xenoestrogens are chemicals with diverse structure that mimic or interfere with the action of endogenous estrogens. Two compounds, bisphenol A (BPA) and octylphenol (OP), are the focus of this proposal. These compounds are abundant in the environment, bind to the estrogen receptor (ER) and act as partial estrogen agonists. Previous studies have revealed that both agents affect pituitary hormone secretion and reproductive tract growth and morphology and their in vivo bioactivity is higher than expected from their weak in vitro binding affinity. However, there is no information on their levels in tissues and body fluids and whether they undergo metabolic processing that enhances their bioactivity. It is also unknown whether BPA or OP promote developmental abnormalities in the neuroendocrine system that result in reduced fertility. It is proposed to use the neuroendocrine axis that regulates prolactin (PRL) as a model system for addressing the following questions: a) do xenoestrogens given to early neonatal rats before the final maturation of their regulatory apparatus, induce hyperprolactinemia, advance the onset of puberty and suppress estrous cyclicity, and b) do these alterations result from changes in specific estrogen target cells within the hypothalamus, pituitary or both? Specific Aim 1 will examine the in vivo distributions and metabolism of BPA and will develop an enzyme immunoassay for its detection.
Specific Aim 2 will investigate whether early neonatal exposure to BPA or OP increases PRL release and induces reproductive abnormalities during adulthood.
Specific Aim 3 will examine whether neonatal treatment with xenoestrogens alter ERa or ERb, tyrosine hydroxylase, dopamine type 2 receptors and PRL regulating factor (PRF) activity within the hypothalamo-pituitary complex. Fischer 344 female rats, which are especially sensitive to the effects of exogenous estrogens, will be used for all the proposed studies. The results should provide a much needed experimental foundation for assessing the vulnerability of the neuroendocrine system to insults by environmental factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009555-04
Application #
6635484
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Heindel, Jerrold
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2003-03-14
Budget End
2005-02-28
Support Year
4
Fiscal Year
2003
Total Cost
$236,039
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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