# Advancing chemical and drug safety testing using single-cell RNA-sequencing

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2020 · $195,625

## Abstract

Title
Advancing chemical and drug safety testing using single-cell RNA-sequencing
Project Summary
Drug and chemical safety evaluations represent a significant challenge for the protection of human health. For
example, adverse drug responses required millions of hospitalizations and caused ~100,000 deaths in the US
while chemical safety evaluations are onerous tasks taking years to complete. More recently, gene expression
profiling has been used, providing a more comprehensive understanding of the mode of action (MOA), as well
as reducing the time, cost, and number of animals required for testing. In addition, dose-response modeling of
transcriptomic changes has provided point of departure (POD) estimates that are predictive of long-term apical
responses such as hepatotoxicity and carcinogenesis. Despite these advances, gene expression profiling relies
on bulk RNA-sequencing of heterogeneous tissue, which is unable to distinguish cell-specific adverse effects
within whole tissue. The ability to decipher cell-specific effects associated with adverse responses within a tissue
would significantly improve (i) MOA elucidation, (ii) the identification of sensitive cell types and (ii) predictions of
human toxicity relevance, especially when determining initial doses in clinical trials. Single-cell RNA-sequencing
(scRNAseq) circumvents the limitations of bulk RNA-sequencing. However, tools for assessing dose-dependent
effects using scRNAseq data do not exist. This proposal will develop a pipeline for the analysis of scRNAseq
dose response chemical and drug safety data. This will include experimental criteria (throughput and read depth)
required to ensure reproducibility. We will use the well-characterized non-genotoxic hepatocarcinogen, 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) as our test chemical. Comprehensive phenotypic and bulk RNA-seq data is
widely available for TCDD enabling phenotypic anchoring and detailed comparisons. Specific Aim 1 will
demonstrate the identification of the dose-dependent emergence of new cell types and states using scRNAseq
data while Aim 2 will adapt existing computational dose-response modelling tools to determine cell- and gene-
specific PODs that will be anchored to apical endpoints. This will be the first application of scRNAseq to
investigate dose-dependent response to an exogenous agent, thus establishing the foundation of scRNAseq in
pharmacology, toxicology and drug development.

## Key facts

- **NIH application ID:** 9985986
- **Project number:** 5R21HG010789-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Timothy R. Zacharewski
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985986

## Citation

> US National Institutes of Health, RePORTER application 9985986, Advancing chemical and drug safety testing using single-cell RNA-sequencing (5R21HG010789-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985986. Licensed CC0.

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