Establishing an AOP for the Role of the Vitamin D Receptor in Developmental NeurotoxicityEPA Grant Number: R835541
Title: Establishing an AOP for the Role of the Vitamin D Receptor in Developmental Neurotoxicity
Investigators: Kullman, Seth W. , Levin, Edward D , Slotkin, Theodore
Institution: Duke University Medical Center , North Carolina State University
EPA Project Officer: Lasat, Mitch
Project Period: July 1, 2013 through June 30, 2016 (Extended to January 31, 2018)
Project Amount: $799,496
RFA: Development and Use of Adverse Outcome Pathways that Predict Adverse Developmental Neurotoxicity (2012) RFA Text | Recipients Lists
Research Category: Health , Human Health , Safer Chemicals
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.
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 Phase I, II and E1K 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 though 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.
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.