Duke University
Project 1
Title: Developmental Neurotoxicity of Superfund Pesticides: Biomarkers & Mechanisms
PI: Theodore Slotkin, Ph.D.
Chlorpyrifos, an organophosphate (OP) insecticide, is a documented contaminant at Superfund sites. It is used in the home and in agriculture, largely becasuse of its persistence relative to other organophosphates (OPs) and its percieved lesser environmental impact compared to DDT, aldrin, dieldrin or related pesticides. Exposure of pregnant women, infants and children, especially around Superfund sites, may lead to infant exposures substantially above the projected NOAEL, and indeed, routine home application produces short-term exposures oders of magnitude above acceptable levels.
The determination of mechanisms and consequences of chlorpyrifos exposure represent the necessary initial step in this process, since available biomarkers for chlorpyrifos-induced developmental toxicity are inadequate. The thrust of this project is:
1. to identify the the cellular mechanisms underlying the developmental neurotoxicity of chlorpyrifos so as to provide appropriate biomarkers with which to estimate the NOAEL and to identify the window of vulnerability; and
2. to determine the functional behavioral consequences of these cellular changes in the developing brain.
The proposed project will examine two models, one for mammalian neurotoxicity (rat) and one for piscine neurotoxicity (zebrafish). The mammalian model will provide a closer model for human health effects and the piscine model will provide a potential biomaker for environmental monitoring. The zebrafish model is also valuable becuase the processes of neurodevelopment are readily observable through its clear chorion. In both cases we will concentrate on the specific targeting of brain development at exposure levels below the thresold for dysmorphogenesis or standard teratogen testing.
Control (b) and chlorpyrifos-exposed (d) rat embryo forebrain neuropithelium.
There are three Specific Aims:
1. To determine the cellular mechanisms by which chlorpyrifos disrupts mammalian neural cell replication and differentiation
2. To determine the functional/behavioral consequences of chlorpyrifos' effects on cell development
3. To develop a non-mammalian model (zebrafish) of developmental neurotoxicity of chlorpyrifos for estimation of NOAEL in ecotoxicologic settings