Endocrine disrupting potential of environmental chemicals characterized by high-throughput screening
Public Deposited- Last Modified
- March 22, 2019
- Creator
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Rotroff, Daniel
- Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
- Abstract
- Over the past 20 years, an increased focus on detecting environmental chemicals that pose a risk of endocrine disruption and congressional legislation have driven the creation of the U.S. EPA Endocrine Disruptor Screening Program (EDSP). Several thousand chemicals are subject to the EDSP, which will require millions of dollars and decades to process using current test batteries. In order to identify opportunities for increased chemical throughput, we initially investigated how well EPA ToxCast in vitro high-throughput screening (HTS) assays relevant for estrogen, androgen, steroidogenic, and thyroid disrupting mechanisms could identify compounds relative to in vitro and in vivo data collected from studies related to the EDSP Tier 1 screen. An iterative, balanced optimization model was implemented and indicated that ToxCast HTS assays measuring estrogen receptor (ER) and androgen receptor (AR) activation classify compounds with estrogenic and androgenic activity in guideline studies with a high degree of accuracy, respectively. The ER signaling pathway involves a wide array of molecular initiating events and cellular processes. This dissertation examined whether active chemicals in ToxCast ER transactivation assays could indicate chemical-induced upregulation of the ER pathway through ligand binding leading to induced changes in T47D growth kinetics. Considering the complex set of ER in vitro assays in toto increased the overall sensitivity of detection for ER reference chemicals. In addition, this research highlighted important aspects of the biological response such as non-ER specificity in the cell growth assay. These nuances are likely important considerations for the construction of a predictive model. In effort to accurately predict the estrogenic potential of environmental chemicals in a high-throughput format, multiple orthogonal in vitro ER assays were used to develop a predictive model for ~2000 chemicals. Model results indicate a high degree of predictivity for both the uterotrophic in vivo assay and ER reference chemicals. The information provided by the model will aid in understanding how environmental chemicals contribute to endocrine-related human health consequences and predict the estrogenic potential of chemicals through the use of in vitro assays, limiting the need to run more costly and animal-intensive in vivo bioassays.
- Date of publication
- May 2013
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Rusyn, Ivan
- Degree
- Doctor of Philosophy
- Graduation year
- 2013
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