Grantee Research Project Results
2015 Progress Report: Establishing an AOP for the Role of the Vitamin D Receptor in Developmental Neurotoxicity
EPA Grant Number: R835541Title: Establishing an AOP for the Role of the Vitamin D Receptor in Developmental Neurotoxicity
Investigators: Kullman, Seth W. , Levin, Edward D
Current Investigators: Kullman, Seth W. , Levin, Edward D , Slotkin, Theodore
Institution: Duke University Medical Center , North Carolina State University
EPA Project Officer: Aja, Hayley
Project Period: July 1, 2013 through June 30, 2016 (Extended to January 31, 2018)
Project Period Covered by this Report: August 1, 2014 through August 1,2015
Project Amount: $799,496
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:
Progress Summary:
Progress on project 835541 is proceeding on schedule and as intended based on the original grant submission and research plans. To date we have made significant accomplishments on aims 1, 3 and 4. Activity on Aim 2 was initiated Fall of 2015 as data is acquired for Aims 1 and 2 and prioritization of compounds is accomplished. In Aim 1, multiple Tox21/ToxCast compounds were selected based on bioinformatic validation criteria for orthogonal testing with in vitro receptor reported assays to identify VDR receptor agonists and antagonists. We have identified and validated VDR Tox21/ToxCast VDR agonists and antagonists in conjunction with members of EPA Computational Toxicology Program. Further assessments using assays for additional receptor functions including RXR heterodimerization and NR co-regulator recruitment suggest multiple ligand:receptor interactions that deviate from classical receptor functions. We also note inactivity of several compounds that were reported active within the Tox21/ToxCast datasets. This discrepancy may be a result of false positive calls in HTS screens or may reflect mechanistic differences between in vitro assays. In Aim 3, we have localized VDR expression in zebrafish and medaka brain, co-localized specific dopaminergic markers with VDR and have begun experiments examining how compounds may induce/inhibit VDR and dopaminergic signaling in vivo. Finally, in Aim 4 we employed selective VDR agonists and antagonists as pharmacological probes to demonstrate behavioral outcomes of disruption in VDR signaling. Aims of the project have not changes and are proceeding as planned. Overall, data derived in year two is consistent with proposed time line in stated proposal. Aims of the project have not changed from the original application.
Future Activities:
Activities for Aims 1-4 will continue.
Journal Articles:
No journal articles submitted with this report: View all 24 publications for this projectSupplemental Keywords:
vitamin D, developmental neurotoxicity, dopamine, 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.