There is very little known about the neurobehavioral and neurodevelopmental impact of low levels of organophosphate pesticides during early embryonic development. Until more is known about the detrimental effects of early exposure to organophosphates, adherence to risk prevention guidelines are unlikely. The long- term goal of the proposed research is to determine the impact of small doses of Chlorpyrifos and Malathion on brain development and anxiety-related behavior using zebrafish embryos. The objective of the proposed research is to determine the extent to which various concentrations of organophosphates during early development cause changes in anxiety-related behaviors such as a preference to be on an edge and avoidance of a visual stimulus and to identify neural patterning defects in brain regions controlling anxiety- related behavior. Zebrafish make an excellent model for the proposed research because large numbers can be collected daily, they can be directly exposed to the organophosphates, and they are transparent, allowing for easy identification of brain abnormalities during development. The main hypothesis, supported by preliminary data, is that even very low levels of organophosphate pesticides during early embryonic development will decrease anxiety-related behavior and cause changes to occur in neural numbers, growth, and patterning, particularly in brain regions linked to these behaviors, such as the ventral habenula. The rationale for the proposed research is that a better understanding of the behavioral and neurodevelopmental impacts of early and embryonic exposure to certain organophosphates has the potential to drive molecular and genetic studies and to change dietary guidelines and risk prevention strategies for pregnant women and children. The hypothesis will be guided by two specific aims: 1) To assess changes in the development of anxiety-related behaviors after exposure to organophosphates;and 2) To identify developmental neural patterning defects in the brain after exposure to organophosphates.
The first aim will be performed using an already established high-throughput imaging system that is a novel system in the applicant's laboratory and is useful for the study anxiety-related behavior.
The second aim will be performed using confocal microscopy coupled with in situ hybridization to create 3-D images of larval brain regions using a transgenic line of Zebrafish that express GFP in early developing neurons. The proposed research is significant because it is expected to advance understanding of the potential risks of exposure to organophosphates early in development. The results gathered from the proposed research have the capability to promote the development of alternative treatments for pest control and to augment dietary guidelines for the human population.

Public Health Relevance

The proposed research project encompassing examination of the effects of early organophosphate exposure on brain development and behavior is relevant to public health because it will facilitate an increase in knowledge about organophosphate pathogenesis and may lead to novel risk prevention strategies such as revised dietary guidelines. Therefore, the proposed research fits well within the scope of the NIH's mission to increase the knowledge of the impact of environmental influences in order to reduce the risk and progression of human disease and disorder.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F03B-S (20))
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Humble, Michael C
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Brown University
Schools of Medicine
United States
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Clift, Danielle; Richendrfer, Holly; Thorn, Robert J et al. (2014) High-throughput analysis of behavior in zebrafish larvae: effects of feeding. Zebrafish 11:455-61
Richendrfer, Holly; Creton, Robbert (2013) Automated high-throughput behavioral analyses in zebrafish larvae. J Vis Exp :e50622