Grantee Research Project Results
2014 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, 2013 through July 30,2014
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:
Recent evidence suggests a linkage between exposure to environmental neurotoxic chemicals and the marked increase in neurodevelopmental disorders including learning disabilities, attention deficit and hyperactivity disorder, autism spectrum disorders, and Parkinson’s disease. Neurotoxic chemical exposure during development can have adverse functional effects expressed either during the process of neurobehavioral development or later in life. Vitamin D receptors are critical regulators for neurodevelopment and interruption of vitamin signaling during ontogeny can have important consequences on neural differentiation and the development of neural circuitry, particularly with regard to dopaminergic innervation.
Experimental approach: Here we provide an adverse outcome pathway to test the hypothesis that modulation of the vitamin D neuroendocrine axis is associated with developmental neurotoxicity and may play a pathophysiological role in adult neurobehavioral disorders. Our AOP is based upon four specific aims. Aim 1: Identify and validate VDR as a nuclear receptor target for chemical agents identified in the EPA’s ToxCast and Tox21 chemical libraries; Aim 2: Establish integrative neuronal cell response to select VDR agonists/antagonists; Aim 3: Utilize the zebrafish vivo model to assess xenobiotic induced modulation of dopaminergic neurons through alterations in tyrosine hydroxylase expression and activity; and Aim 4: Establish a linkage between developmental exposures, modulation of VDR signaling and adult neural behavioral consequence in zebrafish.
Anticipated results: Our AOP is designed to facilitate prediction of a chemical’s potential for developmental neurotoxicity in a manner that is both informative of mechanisms and relevant to human health risk assessment. These studies are directed at establishing the adverse outcome pathway for toxicant actions on vitamin D receptors causing neurobehavioral impairment. The intent is to define a screening system to enable testing large chemical libraries for receptor activities in relation to developmental neurotoxicity and implement predictive strategies for human risk based upon evaluation of mechanistic and apical data derived from a linked series of in vitro and in vivo responses.
Progress Summary:
Progress on the project is proceeding on schedule and as intended based on the original grant submission and research plans. Preliminary data for individual aims are as described below. To date, we have made significant accomplishments on aims 1, 3 and 4. Activity on aim 2 will begin as significant data are acquired for aims 1 and 2 and prioritization of compounds can be accomplished.
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. 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.
Aim 3: We have localized VDR expression in zebrafish and medaka brain, and have begun experiments examining how compounds may induce/inhibit VDR and dopaminergic signaling in vivo.
Aim 4: We employed selective VDR antagonists as pharmacological probes to demonstrate behavioral outcomes of disruption in VDR signaling.
Aims of the project have not changed from the original application and are proceeding as planned with exception of acquisition of reaming chemical agents for screening. Overall, data derived in year one is consistent with the proposed timeline in the proposal.
Future Activities:
Activities for Aims 1 – 4 will continue, with specific focus on identifying VDR agonists/antagonists and their biological function in vivo.
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.