Science Inventory

Comprehensive analyses and prioritization of Tox21 10K chemicals affecting mitochondrial function by in-depth mechanistic studies

Citation:

Xia, M., R. Huang, Q. Shi, W. Boyd, J. Zhao, N. Sun, J. Rice, P. Dunlap, A. Hackstadt, M. Bridge, M. Smith, S. Dai, W. Zheng, P. Chu, D. Gerhold, K. Witt, M. DeVito, J. Freeman, C. Austin, K. Houck, R. Thomas, R. Paules, R. Tice, AND A. Simeonov. Comprehensive analyses and prioritization of Tox21 10K chemicals affecting mitochondrial function by in-depth mechanistic studies. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 126(7):1-16, (2018). https://doi.org/10.1289/EHP2589

Impact/Purpose:

Using a tiered testing approach to prioritize for more extensive testing 622 compounds identified from a primary, quantitative high-throughput screen of 8300 unique small molecules, we identified four not well-characterized potential mitochondrial toxicants (lasalocid, picoxystrobin, pinacyanol, triclocarban) that merit additional in vivo characterization, based on by their ability to significantly decrease the mitochondrial membrane potential (MMP) in secondary MMP assays in HepG2 cells and rat hepatocytes.

Description:

The Tox21 program is re-focusing toxicity testing from animal studies to less expensive and higher throughput in vitro methods using target/pathway-specific, mechanism-driven assays. Consistent with this effort, we used a tiered testing approach to prioritize for more extensive testing 622 compounds identified from a quantitative high throughput screen of 8300 unique small molecules, including drugs and industrial chemicals, as potential mitochondrial toxicants by their ability to significantly decrease the mitochondrial membrane potential (MMP). Based on results from MMP assays in HepG2 cells and rat hepatocytes, 34 compounds were selected for testing in a group of tertiary assays that included formation of reactive oxygen species (ROS), upregulation of p53 and Nrf2/ARE (antioxidant response element), mitochondrial oxygen consumption, cellular Parkin translocation, and larval development and ATP status in the nematode Caenorhabditis elegans. Known mitochondrial complex inhibitors (e.g., rotenone) and un-couplers (e.g., chlorfenapyr), as well as potential novel complex inhibitors and un-couplers, were detected. Overall, we identified four not well-characterized mitochondrial toxicants (lasalocid, picoxystrobin, pinacyanol, triclocarban) that merit additional in vivo characterization.

URLs/Downloads:

https://doi.org/10.1289/EHP2589   Exit

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Product Published Date: 07/26/2018
Record Last Revised: 12/13/2018
OMB Category: Other
Record ID: 343396

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY