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Evaluation of 5-Day In Vivo Rat Liver and Kidney with High-Throughput Transcriptomics for Estimating Benchmark Doses of Apical Outcomes

William M. Gwinn, Scott S. Auerbach, Fred Parham, Matthew D. Stout, Suramya Waidyanatha, Esra Mutlu, Brad Collins, Richard S Paules, B. Alex Merrick, Stephen Ferguson, Sreenivasa Ramaiahgari, John R. Bucher, Barney Sparrow, Heather Toy, Jenni Gorospe, Nick Machesky, Ruchir R. Shah, Michele R. Balik-Meisner, Deepak Mav, Dhiral P. Phadke, Georgia Roberts, Michael J. DeVito


CEBS DOI: https://doi.org/10.22427/NTP-DATA-002-00058-0002-0000-7
GEO No.: GSE147072: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE147072
BioProject No.: PRJNA612884: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA612884
SRA No.: SRP253005: https://www.ncbi.nlm.nih.gov/sra?term=SRP253005

Publication

Abstract

The Division of the National Toxicology Program (DNTP) is currently evaluating high-throughput transcriptomics (HTT) as an approach to provide estimates of chemical exposure that may pose minimal risk. HTT was evaluated in a 5-day in vivo rat model (with repeated dosing) with the objective to determine if benchmark doses (BMD) values for transcriptional pathway changes in the liver and kidney could estimate BMD values for traditional toxicological (apical) endpoints. Eighteen chemicals, most having been tested by the NTP in 2-year bioassays, were chosen for this study. Some of these chemicals are known to be potent hepatotoxicants (e.g. DE71, PFOA, furan, and methyl eugenol) in rodents, some exhibit toxicity but have minimal effects on the liver (e.g. acrylamide and α,β-thujone), and some exhibit little overt toxicity (e.g. ginseng and milk thistle extract) based on traditional toxicological evaluations. Male Sprague Dawley rats were exposed daily for 5 consecutive days by oral gavage to 8 to 10 dose levels of each chemical. Liver and kidney were collected 24 hours after the final exposure and assayed using HTT with the rat S1500+ platform. HTT dose-response data were analyzed using BMD Express 2.2 to determine transcriptional BMD values for liver and kidney. BMDS Wizard was used to determine apical BMD values for histopathological effects from historical chronic or sub-chronic toxicity studies. For many of the chemicals, the lowest transcriptional BMDs from the 5-day assays were within a factor of 5 of the lowest histopathological BMDs estimated from the traditional toxicity studies. These data suggest that using HTT in a 5-day in vivo model provides reasonable estimates of BMD values for traditional apical endpoints. This approach may be useful to prioritize chemicals for further testing while providing actionable data in a timely and cost-effective manner. Key words: 5-day assay, high-throughput transcriptomics, benchmark dose.

Tables

3,3',4,4'-Tetrachloroazobenzene

Acrylamide

Bromodichloroacetic Acid

Coumarin

Di(2-ethylhexyl)phthalate

Ethinyl Estradiol

Fenofibrate

Furan

Ginseng

Hexachlorobenzene

Methyleugenol

Milk thistle extract

Pentabromodiphenyl ether mixture (DE-71)

Perfluorooctanoic acid

Pulegone

Thujone

Tris(chloropropyl)phosphate

Tetrabromobisphenol A

BMD Analysis

BMD Values for GO BPs