Comprehensive profiling of metal compound toxicity: potential novel targets and mechanistic insights using Tox21...

Metals and metalloids are widely used in industrial applications, and increasing experimental and epidemiological evidence has linked metal exposure to adverse health outcomes. However, the underlying mechanisms for these effects have not been fully understood. As a part of the Toxicology in 21^st century (Tox21) program, we have screened more than 150 metal-containing compounds and their salt forms across over 90 biological endpoints. In this study, we analyzed the comprehensive toxicity of metal compounds using Tox21 screening data to enhance the understanding of their mechanism and molecular pathways involved in molecular initiating events. Integrated data analysis and in vitro confirmation experiments identified three potential novel targets of metal compounds (i.e., sonic hedgehog pathway, thyroid-stimulating hormone receptor, and thyrotropin-releasing hormone receptor). We also found that mercury- and tin-containing substances were highly bioactive. Furthermore, cell painting analysis uncovered metal-induced bioactivity could be classified into two patterns depending on their respective associations to mitochondrial-related morphology changes. Our results provide a comprehensive analysis of metals-association bioactivity data within Tox21 assays, which can be applied to estimate the potency ranges for metal-induced bioactivity that support risk assessment efforts for metal and metalloid exposures. These findings identify previously undercharacterized molecular targets of metal compounds, offering new insights into mechanisms of metal toxicity and informing improved risk assessment methodologies.