Systems Approach to Assessing Cumulative Exposure to Endocrine Disrupting ChemicalsEPA Grant Number: R832739
Title: Systems Approach to Assessing Cumulative Exposure to Endocrine Disrupting Chemicals
Investigators: LeBlanc, Gerald A.
Institution: North Carolina State University
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2005 through September 30, 2008 (Extended to September 30, 2009)
Project Amount: $585,206
RFA: Exposure Measurement Tools for Endocrine Disrupting Chemicals in Mixtures (2005) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Health , Safer Chemicals , Endocrine Disruptors
US EPA must be equipped with tools that allow for the comprehensive assessment of exposure to and effects of endocrine-disrupting chemicals (EDCs) in order to adequately evaluate risks associated with such chemicals. EDC exposure issues are particularly tenacious since EDC mixtures can elicit toxicity through a variety of mechanisms that cannot be discerned by analytical chemistry or reporter-gene approaches. The overall objective of this proposed research program is to develop a gene-expression based, whole-organism approach to evaluating cumulative exposure to EDCs. This will be accomplished using the water flea (Daphnia magna) as a sentinel of exposure and a systematic array of gene-expression based signals that will serve as a dosimeter of exposure to EDCs individually or in mixture.
The first aim of the program will be to identify a suite of biological markers that specifically respond to chemical modulators of hormone-signaling pathways. Differential-display and targeted RT-PCR approaches will be used to identify changes in gene expression that are specific indicators of exposure to EDCs. Having identified a suite of biomarkers of exposure (the goal is to identify 12-50 functional signals), the sensitivity, dosimetry value, and strength in identifying EDC types of each signal will be established (Aim 2). These results will be used to refine the development of a sensor (sentinel/signal unit) that can be used to evaluate exposure to EDCs. The final aim (3) of the program will be to evaluate the ability of the sensor to detect and assess exposure associated with EDC mixtures. Predicted response of the sensor to at least 20 formulated mixtures in aqueous solution will be modeled using our Integrated Addition and Interactions model for chemical mixtures. The sensor then will be used to measure exposure to these mixtures and outcome will be compared to model results. Comparison results will be used to establish the functionality of the sensor as well as additional refinement needs.
Unlike other exposure assessment approaches that utilize single reporter gene assays, this sensor will exploit hormone signaling circuitry in an intact organism that encompasses processes of hormone synthesis, hormone-receptor interactions, hormone elimination, and hormone-receptor cross-communication. In addition, the sensor will provide for EDC-biotic interactions involving biotransformation processes and EDC-EDC interactions that may result in synergy or antagonism. Finally, results from this proposed research will provide the basic research necessary for validation of the sensor of EDC exposure under field conditions and in various sample matrices (i.e., using extracts from sediments, plasma from human blood samples, plasma from lab animals following EDC exposure experiments). This research will provide scientists with novel tools and approaches for the assessment of cumulative exposure to endocrine disrupting chemicals in the environment.