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Endocrine Disruption and Adaptation: An Innovative Mechanism Utilizing Alternative Splicing in Estrogen SignalingEPA Grant Number: FP917445
Title: Endocrine Disruption and Adaptation: An Innovative Mechanism Utilizing Alternative Splicing in Estrogen Signaling
Investigators: Cotter, Kellie Anne
Institution: Boston University
EPA Project Officer: Cobbs-Green, Gladys M.
Project Period: September 1, 2012 through August 31, 2015
Project Amount: $126,000
RFA: STAR Graduate Fellowships (2012) RFA Text | Recipients Lists
Research Category: Academic Fellowships , Fellowship - Molecular and Cellular Biology
Endocrine disrupting chemicals present in many pollutants interfere with the normal hormonal signaling pathways regulating reproduction, development and other homeostatic processes. Their effects often occur at surprisingly low, non-toxic doses in human as well as wildlife populations. It remains poorly understood, however, how these low-dose exposures affect an organism across its entire lifetime, or how they affect populations across several lifetimes.
The study will utilize a population of killifish (Fundulus heteroclitus) from a highly polluted Superfund site that exhibits adaptive responses to pollutant exposure. Their resistance to the estrogenic nature of the polluted environment is of particular interest. The study first will identify and quantify alternatively spliced variants of the estrogen receptor in these fish in comparison to fish from a non-polluted environment. The study then will characterize these receptor variants to determine if they respond differently to estrogen. Lastly, the study will test these variants in the control fish to see if they are responsible for the estrogen resistance.
Previous studies in fish and other species have demonstrated a high level of variability in the splicing of estrogen receptors. Changes in the quantity of one or more variants within the available pool would allow a modulation in the response to estrogen. If a population upregulates the expression of a non-functional variant, the estrogen response pathway would be dampened, allowing the population to withstand higher-thannormal estrogen levels in the environment without significant effect. Replicating these splicing patterns in control fish will replicate this resistance seen in pollutant-exposed fish.
Potential to Further Environmental/Human Health Protection
This research would demonstrate a novel mechanism for action of endocrine disrupting chemicals, which likely will prove relevant to other hormone signaling pathways. Results from this study will aid in the development of new biomarkers for exposure, which will be helpful in the detection of new endocrine disrupting chemicals, and/or previously unidentified populations at risk.