The objective of this proposal is to understand how a novel action of estrogen and man-made xenoestrogens affect the initial patterning and development of the nervous system. This will expand our knowledge of the signaling pathways that regulate a specific type of neuron. It also identifies a potential cellular target of endocrine disruptor molecules, which may be related to long-term effects on organismal development. These studies utilize Xenopus laevis, an NIH model organism. The first specific aim tests whether the amount and location of estrogen plays a role in the normal development of dopaminergic neurons and if exogenous estrogen and xenoestrogens are localized near the affected neuron population.
The second aim i dentifies the molecular signaling pathway utilized by estrogen to affect dopaminergic neurons through loss- and gain-of-function experiments with different estrogen receptors. These experiments use antisense morpholinos to knock down specific estrogen receptors and the RNA of individual receptors to achieve their overexpression. The effects will be measured on the dopaminergic neuron population during normal development and in response to additional estrogen.
The third aim tests the long- term consequences of brief embryonic exposure to estrogen and xenoestrogens. Prolonged exposure to estrogen during later periods of development affects sex determination and metamorphosis in Xenopus. Given the pronounced cellular effect on dopaminergic neurons after brief embryonic exposure, they could mediate these developmental changes. If estrogenic molecules including Bisphenol A and Octylphenol can alter sex determination and metamorphosis in developing Xenopus, it would indicate there are potential hazards associated with embryonic exposure to estrogenic compounds in a wide range of vertebrates, including humans. Relevance to public health. Endocrine disrupters are man-made molecules present in the environment that interfere with the normal hormonal signaling pathways in humans and animals alike. This proposal examines the molecular mechanisms used by estrogen and endocrine disrupters that mimic it (xenoestrogens) to affect the initial development of a specific population of neurons and its potential long term effects on the organism. ? ?
