Developmental Neurotoxicity Health Effects Innovation Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

Given the vast number of chemicals that require evaluation for their potential developmental neurotoxicity (DNT) hazard, the international regulatory and scientific communities have embarked on a decades-long effort to develop a more effective method for DNT testing. Experts in the field have created an integrated framework that consolidates all existing data, including in silico, in vitro, and in vivo studies, to be used in chemical regulatory assessments. This framework aims to shed light on the mechanisms that lead to adverse neurodevelopmental outcomes following chemical exposure. The current focus of the DNT Hazard Evaluation Initiative (DNT HEI) is on implementing and refining this newly developed framework to better assess the DNT potential of environmental chemicals. Objective 1. The DNT HEI implemented a screening battery that models key neurodevelopmental processes. Selected assays include proliferation and apoptosis of human neural progenitor cells (hNPC), migration of human neural crest cells (NCC), neurite outgrowth in human induced pluripotent stem cells (iPSCs), synaptogenesis and network formation/maturation in multi electrode array (MEA) using rat primary cortical neurons, zebrafish behavior during early development (total distanced and larval movement pattern), and 3D neurosphere assay using hNPCs (proliferation, apoptosis, migration and differentiation) to allow for interaction of multiple brain cell types. A first phase (Phase 1) and a second phase (Phase 2) library of stakeholder nominated chemicals was procured and distributed to contract laboratories and collaborators to run in the screening battery. Phase 1 testing has been finalized and a manuscript is in review. Phase 2 testing is completed and a manuscript is in preparation. The chemical libraries are composed of a diverse set of chemicals representing the following classes: botanicals, chemical mixtures, cannabinoids, fungicides, herbicides, industrial chemicals, therapeutic drugs, flame retardants, insecticides, positive DNT controls and negative DNT controls. Data from the screening of the Phase 1 and Phase 2 libraries will provide weight of evidence evaluation of DNT potential and will serve to prioritize compounds for further study (e.g., using short-term in vivo behavioral, in vivo neuroimaging, and mechanistic studies). Objective 2. The DNT HEI continued to refine high throughput assessment of rodent behavior using automated home cage monitoring. Automated home cage monitoring was used in conjunction with open field assessment and metabolomics to characterize the long term neurobehavioral and metabolic consequences arising from prolonged in utero exposure to a low dose of chlorpyrifos. These findings highlight the ability of automated home cage monitoring to detect subtle behavioral perturbations following chemical exposure. The goal of these studies is to link behavioral changes from neurotoxicants to mechanisms modeled in the screening battery. Additional behavior assays using Drosophila and Planarian are being evaluated for inclusion in the DNT screening battery using the Phase 1 chemical library. Furthermore, high-throughput in vitro assays for neurite outgrowth (1536-wells format) are being explored for inclusion in the battery using the Phase 1 chemical library. IVIVE and in silico approaches are being used to contextualize in vitro and in vivo findings with human exposure to provide relevant and translatable information to protect human health. The DNT HEI is also currently developing assays to assess microglia and astrocyte functional changes contributing to chemical-induced DNT. Objective 3. The DNT HEI continued to update and refine the Developmental NeuroToxicity Data Integration and Visualization Enabling Resource (DNT DIVER). DNT-DIVER is a web-based application that allows public access and visualization of all data from compounds screened by the DNT HEI. The updated version of DNT-DIVER allows users to visualize experimental design summary, quality control, chemical-specific concentration response curves, ranking of chemical toxicity per lab/assay, and comparison of results across assays.