Grantee Research Project Results

Final Report: Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity

EPA Grant Number: R840027
Title: Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity
Investigators:
Institution:
EPA Project Officer:
Project Period: August 1, 2020 through May 8, 2025
Project Amount: $790,441
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

The overall objective is to develop an in vitro Blood-Brain Barrier direct contact screening model to assess the exposure.

Summary/Accomplishments (Outputs/Outcomes):

We have investigated the bidirectional permeability of marker compounds to determine the permeation of over 70 compounds including known or purported environmental neurotoxicants across a human cell-based triculture model of the Blood-Brain Barrier. Permeability data has been integrated to rank order neurotoxicant exposure in reference to established BBB marker compounds at steady state plasma concentrations. Collaborative efforts have led to developing physiological-based High Throughput Toxicokinetic brain model (HTTK-R). We are now focused on validation and testing the HTTK-R brain model utilizing the neurotoxicant permeation rates across the BBB cell-based assays to improve accuracy in predicting doses of concern of chemicals that have been implicated in causing perturbations in brain function.

Future Activities:

We are currently in the process of expanding the BBB direct contact triculture model to include neurons in the basal chamber of the Transwell^® to mimic the in vivo neurovascular unit (NVU). Our goal will be to optimize the NVU culture conditions based on changes in permeability rates and then characterize changes in proteins involved in the tight junctions, efflux transporters, and cytoskeleton as indices of the barrier properties. Upon completion, we will perform permeability studies with selected neurotoxicants to further validate the HTTK-brain model.

Journal Articles:

No journal articles submitted with this report: View all 10 publications for this project

Relevant Websites:

Progress and Final Reports:

Original Abstract

The 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.