Towards replacement of animal tests with in vitro assays: a gene expression biomarker predicts in vitro and in vivo estrogen receptor activity

Corton, J. Christopher; Liu, Jie; Kleinstreuer, Nicole; Gwinn, Maureen R.; Ryan, Natalia

doi:10.1016/j.cbi.2022.109995

Towards replacement of animal tests with in vitro assays: a gene expression biomarker predicts in vitro and in vivo estrogen receptor activity

Journal Article · Sat Jun 11 00:00:00 EDT 2022 · Chemico-Biological Interactions

DOI:https://doi.org/10.1016/j.cbi.2022.109995· OSTI ID:1981556

^[1]; Liu, Jie ^[1]; Kleinstreuer, Nicole ^[2]; Gwinn, Maureen R. ^[1]; Ryan, Natalia ^[3]

US Environmental Protection Agency (EPA), Research Triangle Park, NC (United States)
National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC (United States)
Oak Ridge Institute for Science and Education (ORISE), Research Triangle Park, NC (United States)

High-throughput transcriptomics (HTTr) has the potential to support efforts to reduce or replace some animal tests. In past studies, we described a computational approach utilizing a gene expression biomarker consisting of 46 genes to predict estrogen receptor (ER) activity after chemical exposure in ER-positive human breast cancer cells including the MCF-7 cell line. We hypothesized that the biomarker model could identify ER activities of chemicals examined by Endocrine Disruptor Screening Program (EDSP) Tier 1 screening assays in which transcript profiles of the same chemicals were examined in MCF-7 cells. For the 62 chemicals examined including 5 chemicals examined in this study using RNA-Seq, the ER biomarker model accuracy was 1) 97% for in vitro reference chemicals, 2) 76–85% for guideline uterotrophic assays, and 3) 87–88% for guideline and nonguideline uterotrophic assays. For the same chemicals, these accuracies were similar or slightly better than those of the ToxCast ER model based on 18 in vitro assays. The performance of the ER biomarker model indicates that HTTr interpreted using the ER biomarker correctly identifies active and inactive ER reference chemicals. Finally, as part of the HTTr screening program the approach could rapidly identify chemicals with potential ER bioactivities for additional screening and testing.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC); USEPA

Grant/Contract Number:: SC0014664

OSTI ID:: 1981556

Alternate ID(s):: OSTI ID: 2274996

Journal Information:: Chemico-Biological Interactions, Journal Name: Chemico-Biological Interactions Journal Issue: C Vol. 363; ISSN 0009-2797

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Biomarker
Estrogen receptor
Gene expression profiling
High-throughput transcriptomics
MCF-7 cell line
Uterotrophic assay

Towards replacement of animal tests with in vitro assays: a gene expression biomarker predicts in vitro and in vivo estrogen receptor activity

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