The broad long-term overall goal of the proposed research is to understand the physiological role of estrogen (E2) and estrogen receptors (ERs) during neuronal development and to determine to what extent environmental estrogens (EEs) can mimic or inhibit the effects of E2 in these developing neurons. Mechanisms of rapid E2-mediated signal transduction are not well understood. These actions vary greatly from cell type to cell type, and may even vary in the same cell. In addition to reproductive tissues &breast cancers, cells of the nervous system are a clinically very important E2 targets. Environmental estrogens, also known as endocrine disrupting chemicals, are a diverse group of compounds that can mimic or antagonize the normal actions of E2. The extent to which EEs impact the developing nervous system is unclear. Proposed experiments using primary cultures of estrogen-sensitive neonatal rat cerebellar neurons and the developing cerebellum as non-sexually related neuronal models, will address the following Specific Aims - Specific Aim 1 is to determine whether or not structurally diverse EEs modulate ERK1/2 signaling in developing cerebellar neurons. It is hypothesized that in E2-responsive neurons, EEs rapidly modulate ERK1/2 signaling and neuronal physiology in an E2-like fashion, and that differences in the chemical structure of individual EEs determine their ability to activate ERK-signaling &/or antagonize the rapid actions of E2.
Specific Aim 2 is to determine the nature of the signaling mechanism underlying E2-mediated rapid activation of ERK-signaling. It is hypothesized that a plasma membrane, localized version of ERp is acting as the mediator of rapid E2/EE-induced ERKsignaling. Membrane E2-binding proteins from primary granule cell and hippocampal neuronal cultures will be affinity purified and identified through LC-tandem mass spectrometry. Immunocytochemical and loss-of-function experiments are proposed to demonstrate the function of identified candidate membrane ERs. The ability of ERa, ERp, and the orphan G-protein coupled receptor GPR30 to act as the membrane ER will be directly addressed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015145-08
Application #
7822966
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2001-12-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
8
Fiscal Year
2010
Total Cost
$309,097
Indirect Cost
Name
University of Cincinnati
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Cookman, Clifford J; Belcher, Scott M (2015) Estrogen Receptor-? Up-Regulates IGF1R Expression and Activity to Inhibit Apoptosis and Increase Growth of Medulloblastoma. Endocrinology 156:2395-408
Kendziorski, Jessica A; Belcher, Scott M (2015) Strain-specific induction of endometrial periglandular fibrosis in mice exposed during adulthood to the endocrine disrupting chemical bisphenol A. Reprod Toxicol 58:119-30
Kendziorski, Jessica A; Belcher, Scott M (2015) Effects of whole life exposure to Bisphenol A or 17?-ethinyl estradiol in uterus of nulligravida CD1 mice. Data Brief 5:948-53
Patisaul, Heather B; Roberts, Simon C; Mabrey, Natalie et al. (2013) Accumulation and endocrine disrupting effects of the flame retardant mixture Firemaster® 550 in rats: an exploratory assessment. J Biochem Mol Toxicol 27:124-36
Kendig, Eric L; Buesing, Dana R; Christie, Susie M et al. (2012) Estrogen-like disruptive effects of dietary exposure to bisphenol A or 17?-ethinyl estradiol in CD1 mice. Int J Toxicol 31:537-50
Belcher, Scott M; Chen, Yamei; Yan, Sujuan et al. (2012) Rapid estrogen receptor-mediated mechanisms determine the sexually dimorphic sensitivity of ventricular myocytes to 17?-estradiol and the environmental endocrine disruptor bisphenol A. Endocrinology 153:712-20
Kendziorski, Jessica A; Kendig, Eric L; Gear, Robin B et al. (2012) Strain specific induction of pyometra and differences in immune responsiveness in mice exposed to 17?-ethinyl estradiol or the endocrine disrupting chemical bisphenol A. Reprod Toxicol 34:22-30
Cooper, James E; Kendig, Eric L; Belcher, Scott M (2011) Assessment of bisphenol A released from reusable plastic, aluminium and stainless steel water bottles. Chemosphere 85:943-7
Kendig, Eric L; Le, Hoa H; Belcher, Scott M (2010) Defining hormesis: evaluation of a complex concentration response phenomenon. Int J Toxicol 29:235-46
Le, Hoa H; Belcher, Scott M (2010) Rapid signaling actions of environmental estrogens in developing granule cell neurons are mediated by estrogen receptor ├č. Endocrinology 151:5689-99

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