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Prioritization of Chemicals for Effects on Steroidogenesis Using an Integrated Statistical Approach to High-Throughput H295R Data
Citation:
Haggard, Derik E., Woodrow Setzer, R. Judson, AND K. Paul-Friedman. Prioritization of Chemicals for Effects on Steroidogenesis Using an Integrated Statistical Approach to High-Throughput H295R Data. Presented at FutureToxIV - Predictive Toxicology for Healthy Children, Arlington, VA, November 14 - 16, 2018. https://doi.org/10.23645/epacomptox.7488530
Impact/Purpose:
This work examines the utility of a novel prioritization metric that reduced these 11-dimensional data to 1-dimension via calculation of a mean Mahalanobis distance (mMd) at each chemical concentration screened. The most selective chemicals from the HT-H295R assay may be the best candidates for further in vitro or in silico screening efforts to better characterize potential disruption of steroid biosynthesis.
Description:
The synthesis of 11 steroid hormones in the human adrenocortical carcinoma cell line, H295R, was measured in a high-throughput steroidogenesis assay (HT-H295R) as part of the US Environmental Protection Agency’s ToxCast program for 656 unique chemicals in concentration-response. This work examines the utility of a novel prioritization metric that reduced these 11-dimensional data to 1-dimension via calculation of a mean Mahalanobis distance (mMd) at each chemical concentration screened. First, a data simulation was performed to investigate the robustness of estimated mMd values, i.e. the quantitative influence of the covariance matrix on the mMd, the type I error rate, and the relative power to identify different bioactivities of interest. Second, the patterns of steroid hormone responses of prototypical aromatase inhibitors in the HT-H295R assay were examined. Third, to demonstrate prioritization, the mMd was compared to ToxCast/Tox21 assay indicators of mitochondrial and cytotoxicity. The covariance structure among hormones was stable, and mMd values were reproducible and similar from simulation to experimental, with sufficient power to detect ≥1.5-fold changes in hormone responses. Aromatase inhibitors decreased estrogen synthesis, but demonstrated variable effects on other hormones. The most selective chemicals from the HT-H295R assay may be the best candidates for further in vitro or in silico screening efforts to better characterize potential disruption of steroid biosynthesis. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Prioritization of Chemicals for Effects on Steroidogenesis Using an Integrated Statistical Approach to High-Throughput H295R Data
HAGGARD_FUTURETOXIV_POSTER_V3_20181106.PDF (PDF, NA pp, 1300.509 KB, about PDF)