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Do Nitrates Interfere with Endocrine Signaling Processes?

EPA Grant Number: F6D40255
Title: Do Nitrates Interfere with Endocrine Signaling Processes?
Investigators: Reeves, Bethany
Institution: North Carolina State University
EPA Project Officer: Willett, Stephanie H.
Project Period: September 1, 2006 through September 1, 2009
Project Amount: $100,765
RFA: STAR Graduate Fellowships (2006)
Research Category: Academic Fellowships , Health Effects , Fellowship - Toxicology , Endocrine Disruptors

Description:

Objective:

We propose to use the freshwater crustacean, Daphnia magna, as a representative of aquatic organisms and a general animal model to mechanistically investigate the effects of nitrates and nitrites (NOx) on reproduction and development. The hypothesis will be tested that excess NO, derived from NOx, can cause abnormal embryo development by interfering with ecdysteroid signaling. We further hypothesize that this effect could be elicited by NO inhibiting ecdysteroid synthesis or by binding to NR1D3 (also called E75), a putative NO sensitive regulator of ecdysteroid signaling.

Approach:

The hypotheses will be tested with three specific aims. The first aim will be to characterize the relationship between environmental exposure to nitrate or nitrite and nitric oxide generation in daphnids. To accomplish this aim, experiments will be conducted to evaluate the conditions under which daphnids might convert nitrite or nitrate to NO using real-time amperometric detection. The second aim will be to evaluate the effects of nitric oxide on embryo development by examining embryos through gross and fine analysis for the effects of sodium nitroprusside (SNP, an NO donor) and NOx on developmental parameters known to be under the regulatory control of ecdysteroids.

Finally, the third aim will be to characterize the mechanism by which NO elicits developmental toxicity. For this aim, two possible mechanisms will be considered. First, radioimmunoassay will be used to quantify ecdysteroid levels following treatment with SNP/ NOx to determine if NO interfers with ecdysteroid levels. Second, I plan to determine whether or not exogenous NO causes developmental toxicity in daphnid embryos by interfering with the normal role and functioning of NR1D3 in this pathway. NR1D3 will be cloned, expressed, and recombinant protein will be expressed and evaluated with respect to sensitivity to NO.

Expected Results:

Results from this study will advance our understanding of the potential threat posed by nitrate/nitrate pollution to reproductive success.

Supplemental Keywords:

Endocrine toxicity, developmental toxicity, nitrates, nitric oxide, ecdysteroids, Daphnia magna, , Scientific Discipline, Health, RFA, Endocrine Disruptors - Environmental Exposure & Risk, Health Risk Assessment, endocrine disruptors, Biochemistry, Endocrine Disruptors - Human Health, animal models, endocrine disrupting chemicals, EDCs, nitrates, reproductive processes, endocrine signaling

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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