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A Curated Database of Rodent Uterotrophic Bioactivity
Nicole C Kleinstreuer1, Patricia C Ceger, David G Allen
1Integrated Laboratory Systems, in support of the National Toxicology Program Interagency Center for Evaluation of Alternative Toxicological Methods (NICEATM), Research Triangle Park, North Carolina, USA.
Background:
Novel in vitro methods are being developed to identify chemicals that may interfere with estrogen receptor (ER) signaling, but the results are difficult to put into biological context because of reliance on reference chemicals established using results from other in vitro assays and because of the lack of high-quality in vivo reference data. The Organisation for Economic Co-operation and Development (OECD)-validated rodent uterotrophic bioassay is considered the "gold standard" for identifying potential ER agonists.
Objectives:
We performed a comprehensive literature review to identify and evaluate data from uterotrophic studies and to analyze study variability.
Methods:
We reviewed 670 articles with results from 2,615 uterotrophic bioassays using 235 unique chemicals. Study descriptors, such as species/strain, route of administration, dosing regimen, lowest effect level, and test outcome, were captured in a database of uterotrophic results. Studies were assessed for adherence to six criteria that were based on uterotrophic regulatory test guidelines. Studies meeting all six criteria (458 bioassays on 118 unique chemicals) were considered guideline-like (GL) and were subsequently analyzed.
Results:
The immature rat model was used for 76% of the GL studies. Active outcomes were more prevalent across rat models (74% active) than across mouse models (36% active). Of the 70 chemicals with at least two GL studies, 18 (26%) had discordant outcomes and were classified as both active and inactive. Many discordant results were attributable to differences in study design (e.g., injection vs. oral dosing).
Conclusions:
This uterotrophic database provides a valuable resource for understanding in vivo outcome variability and for evaluating the performance of in vitro assays that measure estrogenic activity.
Citation:
Kleinstreuer NC, Ceger PC, Allen DG, Strickland J, Chang X, Hamm JT, Casey WM. 2016. A curated database of rodent uterotrophic bioactivity. Environ Health Perspect 124:556-562; http://dx.doi.org/10.1289/ehp.1510183.
Insights
This study created a database of rodent uterotrophic bioassays to assess estrogen receptor (ER) activity. The results highlight variability in in vivo data, crucial for evaluating new in vitro testing methods.
Area of Science:
- Toxicology
- Endocrinology
- Environmental Health
Background:
- Novel in vitro methods for detecting estrogen receptor (ER) signaling interference face challenges in biological context due to reliance on reference chemicals and lack of in vivo data.
- The Organisation for Economic Co-operation and Development (OECD)-validated rodent uterotrophic bioassay is the standard for identifying potential ER agonists.
Purpose of the Study:
- To conduct a comprehensive literature review of uterotrophic bioassays.
- To evaluate data quality and analyze study variability in identifying ER agonists.
- To create a curated database of rodent uterotrophic bioactivity.
Main Methods:
- Reviewed 670 articles, extracting data from 2,615 uterotrophic bioassays involving 235 unique chemicals.
- Captured study descriptors including species, administration route, dosing, effect levels, and outcomes.
- Assessed studies against six criteria based on regulatory guidelines; 458 bioassays meeting criteria were deemed guideline-like (GL).
Main Results:
- The immature rat model was used in 76% of GL studies.
- Active outcomes were more common in rats (74%) than mice (36%).
- Of 70 chemicals with multiple GL studies, 18 (26%) showed discordant results (active and inactive), often due to study design differences like route of administration.
Conclusions:
- The curated database provides a valuable resource for understanding in vivo outcome variability.
- This resource aids in evaluating the performance of in vitro assays for estrogenic activity.
- The findings underscore the importance of standardized methods and data quality in toxicological assessments.
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