Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective

Abstract

Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism-based, biological observations using in vitro assays and lower organism models. HTS uses biocomputational methods for probing thousands of chemicals in in vitro assays for gene-pathway response patterns predictive of adverse human health outcomes. In 1999, NIEHS began exploring the application of toxicogenomics to toxicology and recent advances in NextGen sequencing should greatly enhance the biological content obtained from HTS platforms. We foresee an intersection of new technologies in toxicogenomics and HTS as an innovative development in Tox21. Tox21 goals, priorities, progress, and challenges will be reviewed.

BCScreen: A gene panel to test for breast carcinogenesis in chemical safety screening

“…For example, some genes overlap between BCScreen and PAM50 [54], the estrogenicity panel [42], and the Tox21 S1500+ panel [31]. This overlap indicates that while the other panels cover some of the biological space in BCScreen, our approach produced a unique gene set.…”

Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126

“…We present here an in-depth investigation of the toxic effects of the PCB 126, a model chemical for the induction of TAFLD, on the transcriptome and metabolome of human liver HepaRG cells (Merrick et al 2015; Mueller et al 2014). We envisage that our investigation would be particularly useful for the establishment of high-throughput assays using the HepaRG cell line, which has been found to be a good model system to predict the results of acute and repeated dose toxicity (Mueller et al 2014) and to study human xenobiotic metabolism (Guillouzo et al 2007).…”

Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126

“…With the steadily increasing number of synthetic chemicals being released in our environment, the ability to use human cell lines to evaluate toxicity of pollutants and move away from more time-consuming and expensive risk assessment based on in vivo animal experiments, has become one of the challenges of the 21 st century (Hartung, 2009). We present here an in-depth investigation of the toxic effects of the PCB 126, a model chemical for the induction of TAFLD, on the transcriptome and metabolome of human liver HepaRG cells (Merrick et al, 2015;Mueller et al, 2014). We envisages that our investigation would be particularly useful for the establishment of high-throughput assays using the HepaRG cell line, which has been found to be a model system to predict the results of acute and repeated dose toxicity (Mueller et al, 2014) and to study human xenobiotic metabolism (Guillouzo et al, 2007).…”

“…All these processes are interrelated with a need for more studies providing mechanistic insight into the alteration of hepatic lipid metabolism, which in turn induces the development of NAFLD (Foulds et al, 2017). This is a priority for regulatory toxicology programs and includes a move away from a chemical risk assessment based on in vivo animal experiments (Merrick et al, 2015). This can be achieved by detailed molecular profiling studies describing the effects of known toxicants on validated tissue culture model systems, such as the human hepatocyte HepaRG cell line (Angrish et al, 2017).…”