Grantee Research Project Results
2014 Progress Report: Identification and Scientific Validation of AOPS Involving Genomic and Nongenomic Intracellular Thyroid Hormone Signaling in Neurodevelopment
EPA Grant Number: R835550Title: Identification and Scientific Validation of AOPS Involving Genomic and Nongenomic Intracellular Thyroid Hormone Signaling in Neurodevelopment
Investigators: Lein, Pamela J , Fritsche, Ellen
Institution: University of California - Davis
Current Institution: University of California - Davis , Leibniz Research Institute for Environmental Medicine
EPA Project Officer: Aja, Hayley
Project Period: October 1, 2013 through September 30, 2016
Project Period Covered by this Report: December 9, 2013 through October 31,2014
Project Amount: $800,000
RFA: Development and Use of Adverse Outcome Pathways that Predict Adverse Developmental Neurotoxicity (2012) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability , Human Health
Objective:
The goal of this project is to identify adverse outcome pathways (AOPs) for chemicals that cause developmental neurotoxicity (DNT) by interfering with thyroid hormone (TH) signaling. Disrupted thyroid hormone (TH) signaling is widely postulated as a mechanism of DNT, but understanding how chemicals that disrupt TH signaling cause adverse neurodevelopmental outcomes has been hindered by significant gaps in our knowledge of which neurodevelopmental processes are sensitive to modulation by TH and the intracellular signaling pathways that mediate TH effects on the developing brain. The objectives of this project are to: (1) identify specific neurodevelopmental processes regulated by TH and determine whether these differ significantly between species; (2) elucidate genomic and/or non-genomic intracellular signaling pathways that mediate TH effects on neurodevelopment; (3) identify 'pathways of toxicity' by which chemicals interfere with TH-mediated neurodevelopment; and (4) link pathways of toxicity with adverse neurodevelopmental outcomes in an in vivo model (zebrafish).
Progress Summary:
Future Activities:
In project year 2, we anticipate identifying the neurodevelopmental processes most sensitive to TH signaling and beginning to elucidate the genomic and non-genomic pathways that mediate TH effects on these endpoints. For assessing TH disruption on early neurodevelopment, we will establish a human neurosphere-based screening assay. We also will develop an assay for measuring TH levels in zebrafish, and complete in situ hybridization studies in zebrafish to localize TH signaling molecules, in particular the deiodinases and transport proteins. This will set us up for identifying pathways of toxicity in project year 3 and determining whether effects observed in vitro are replicated in vivo in the zebrafish.
Journal Articles:
No journal articles submitted with this report: View all 22 publications for this projectSupplemental Keywords:
developmental neurotoxicity, neurospheres, primary neuronal cell cultures, thyroid hormone, zebrafishProgress and Final Reports:
Original AbstractThe 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.