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Grantee Research Project Results

NCER Grantee Research Project Results

Developmental Neurobehavioral Toxicity of Bisphenol A: Defining the Role of ERRgamma

EPA Grant Number: FP917123
Title: Developmental Neurobehavioral Toxicity of Bisphenol A: Defining the Role of ERRgamma
Investigators: Saili, Katerine Schletz
Institution: Oregon State University
EPA Project Officer: Boddie, Georgette
Project Period: September 1, 2010 through August 31, 2013
Project Amount: $111,000
RFA: STAR Graduate Fellowships (2010)
Research Category: Academic Fellowships , Fellowship - Human Health: Risk Assessment and Decision Making

Description:

Objective:

BPA is a contaminant that leaches into food or drinks stored in polycarbonate plastic or resin-lined cans. Exposure to BPA either directly through the placenta or via ingestion of contaminated breast milk, food, or water during critical periods of brain development has been proposed to result in childhood behavioral disorders. Although BPA is a suspected endocrine disruptor, the extent to which this contaminant impacts classic estrogen signaling remains unclear. This project will investigate the role of estrogen-related receptor gamma (ERR3), a receptor that binds BPA with high affinity, in mediating the neurobehavioral effects of low-dose BPA exposure.

Synopsis:

Bisphenol A (BPA) leaches from polycarbonate plastic and resin linings of food cans. Ingestion of contaminated food or water is a major source of human exposure. Prenatal and infant BPA exposure may impact brain development and contribute to childhood behavioral disorders. Although BPA is a suspected endocrine disruptor, the underlying cause of BPA’s effects on the developing brain remains unclear. This project investigates how relevant BPA exposure levels impact brain development and behavior.

Approach:

Zebrafish express a form of ERR3 in the brain that is 95 percent identical to the human ortholog. Thus, the molecular events measured in embryonic zebrafish following developmental BPA exposure are expected to be relevant to humans. To determine the behavioral effects of low-dose BPA exposure, embryonic zebrafish will be exposed to BPA during neurogenesis, a 2-day period of central nervous system (CNS) development that is analogous to the first trimester. Following exposure, performance on behavior tests, including a test of locomotor activity in response to a startle stimulus, will be measured in both larval (5 days post fertilization; dpf) and adult (60 dpf) zebrafish. To determine the extent to which ERR3 mediates the neurobehavioral effects of BPA exposure, antisense oligonucleotide morpholinos will be used to repress ERR3 expression during the BPA exposure period, followed by the same behavior assessments. In addition to investigating the role of ERR3, biomarkers of BPA exposure will be identified by isolating neuron-specific RNA from 1 dpf transgenic zebrafish embryos, followed by global microarray analyses. By capitalizing on the strengths of the embryonic zebrafish model, this project will, for the first time, examine the role of ERR3 at both the molecular and behavioral levels and generate data that will help explain how BPA interacts with and perturbs vertebrate CNS development.

Expected Results:

Preliminary experiments identified a hyperactive behavioral phenotype in 6-day-old and mature zebrafish that were transiently exposed to environmentally relevant BPA concentrations during CNS development. These behavioral effects are expected to be directly dependent upon ERR3 signaling. BPA binds to ERR3 with 100 – 10,000 times greater affinity than it binds classical estrogen receptors. ERR3 is also highly expressed in the brain and placenta, supporting the likelihood that it has a significant role in mediating the behavioral effects of low-concentration BPA exposure during early brain development. Accordingly, it is expected that repression of ERR3 expression during BPA exposure will remove the principal BPA target, and therefore will rescue the behavioral phenotypes (e.g., hyperactivity) associated with BPA exposure. Furthermore, it is expected that a set of genes expressed downstream of ERR3 activation will be identified as biomarkers of BPA exposure by the microarray analyses. These studies will identify, for the first time, a set of neuron-specific ERR3 responsive genes that are misexpressed following exposure to environmentally relevant BPA concentrations.

Potential to Further Environmental/Human Health Protection:

A decision to redefine BPA regulatory standards to protect our youngest demographic would have significant economic and public health implications and therefore requires identification of a plausible mechanism of action acting at environmentally relevant concentrations. This study will generate critical information regarding BPA-mediated neurotoxicity, in addition to identifying low-dose BPA exposure biomarkers that can be used as risk management tools.

Supplemental Keywords:

bisphenol A, BPA, endocrine disruption, estrogen, estrogen related receptor gamma, ERR3, behavior, behavior disorder, hyperactivity, fetus, infant, children, polycarbonate, plastic, resin linings, zebrafish, microarray, genes, gene environment interactions, neurobehavioral development, development, brain, central nervous system, CNS, placenta, breast milk,

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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