Identification and Scientific Validation of AOPS Involving Genomic and Nongenomic Intracellular Thyroid Hormone Signaling in NeurodevelopmentEPA Grant Number: R835550
Title: 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: Lasat, Mitch
Project Period: October 1, 2013 through September 30, 2016
Project Amount: $800,000
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
(1) Identify neurodevelopmental processes regulated by thyroid hormone (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.
Primary rat (neurospheres and dissociated cortical cultures) and human (neurospheres and induced pluripotent stem cells, aka iPSCs) cultures will be used to determine which early [neural precursor cell (NPC) proliferation, migration and differentiation] and late [axonal and dendritic outgrowth, synaptogenesis, network formation) neurodevelopmental processes are most vulnerable to modulation by experimental manipulation of TH receptor (TR) ligands and antagonists. The genomic and non-genomic mechanisms by which TH regulates sensitive early and late neurodevelopmental processes will be interrogated using pharmacological inhibitors and gene targeting. These same approaches will be used to identify pathways of toxicity for chemicals identified using automated high content imaging to screen for chemicals that interfere with TH-mediated neurodevelopment. To confirm that TH disrupting chemicals identified using in vitro models exert similar molecular and cellular effect in vivo and that these are linked to adverse outcomes at the organismal level, neurodevelopmental processes, relevant TH signaling molecules and behavioral endpoints will be quantitatively analyzed in wildtype and transgenic zebrafish.
The outputs of the project will include: (1) presentations and peer-reviewed journal publications that describe advances in understanding the basic neurobiological mechanisms by which TH regulates normal neurodevelopment as well as the mechanism(s) by which chemicals interfere with TH-mediated normal neurodevelopment; and (2) model systems (hNPC cell lines and transgenic zebrafish) that can be readily adapted to high throughput screening for TH disrupting chemicals with DNT potential. The outcomes include: (1) better understanding of AOP for DNT consequent to TH disruption; (2) insight as to windows of susceptibility for chemically-induced disruption of TH-mediate neurodevelopment based on the identification of specific neurodevelopmental processes (or stages) most vulnerable to THdisrupting chemicals); and (3) improved risk assessment based on identification of and mechanistic understanding of species differences in TH-mediated neurodevelopment.