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.
