Toxicity profiling of metal compounds using the Tox21 screening data

Authors

• PA Adesina
• M Ooka
• R Huang
• S Ferguson
• D Reif
• A Simeonov
• M Xia

Abstract

Metals are often found in various consumer and industrial products including electronics and pigments due to their unique physical and chemical properties. Their widespread use has raised significant global health concerns because of their toxicities leading to many adverse effects such as cancer. Although some heavy metals are known carcinogens, their mechanism of action is not completely understood. Understanding the toxicity and molecular mechanisms of heavy metal-induced toxicity will allow us to: 1) predict potential adverse health outcomes; 2) develop effective strategies to mitigate their risks; and 3) promote safer industrial practices. Leveraging on the Tox21 high-throughput screening data repository covering nuclear receptor-, cellular stress-, genotoxicity-, developmental-, and G protein coupled receptors-related signaling, we carried out an enrichment analysis to reveal pathways potentially affected by heavy metals. Several known heavy metal targets (e.g., estrogen receptor and γH2AX) were identified as targets, which supported the effectiveness of the datasets. We identified several potential novel pathways, including thyroid stimulating hormone receptor, transforming growth factor beta (TGF-beta)/ SMAD, and heat shock response. We also found a group of compounds containing gold, cadmium, lead, mercury, and tin, which had markedly higher activities than did the other heavy metal compounds in the Tox21 compound library. To confirm the interactions between heavy metal compounds and the potential novel pathways, several follow-up studies were conducted. This research unveiled potential novel targets/pathways of heavy metals and provides a comprehensive view of the heavy metal-related toxicological profiles.

Scientific Focus Area: Molecular Pharmacology

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