A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling

Area of Science:

• Toxicology
• Genomics
• Chemical Risk Assessment

Background:

• Current cancer risk assessment methods are resource-intensive.
• Thousands of chemicals remain untested for carcinogenic potential.
• Earlier studies developed a new approach methodology (NAM) for identifying liver tumorigens using gene expression biomarkers.

Purpose of the Study:

• To confirm NAM's ability to identify liver tumorigens at a single time point/dose.
• To assess NAM's applicability to targeted RNA-Seq analyses.
• To predict the six most common rodent liver cancer molecular initiating events.

Main Methods:

• Male rats were exposed to 15 chemicals for 4 days via gavage.
• Liver transcript profiles were generated using Affymetrix arrays and TG-GATES or DrugMatrix data.
• NAM was coupled with targeted RNA-Seq (TempO-Seq) on liver samples from rats exposed to 16 chemicals for 5 days.

Main Results:

• The NAM achieved 75% and 85% predictive accuracy using TG-GATES and DrugMatrix TALs, respectively.
• NAM combined with targeted RNA-Seq demonstrated up to 91% predictive accuracy in identifying tumorigenic chemicals.
• The study confirmed NAM's effectiveness with both microarray and targeted RNA-Seq data.

Conclusions:

• The NAM effectively identifies liver tumorigenic chemicals, their doses, and modes of action.
• This approach is applicable to both microarray and targeted RNA-Seq data from short-term rat exposures.
• NAM offers a more feasible and efficient method for chemical risk assessment compared to traditional approaches.