Molecular MechanismsEPA Grant Number: R834514C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834514
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: University of Washington Center for Child Environmental Health Risks Research (2010)
Center Director: Faustman, Elaine
Title: Molecular Mechanisms
Investigators: Faustman, Elaine
Institution: University of Washington
EPA Project Officer: Callan, Richard
Project Period: September 25, 2008 through September 24, 2016
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Health
Organophosphate (OP) pesticides are among the most widely applied pesticides worldwide and in Washington State. In adults, OPs are recognized to act as neurotoxicants through their ability to inhibit the enzyme acetylcholinesterase (AChE) which is necessary for proper functioning of the nervous system. In the developing organism it is still unknown whether OP-induced developmental neurotoxicity is a consequence of AChE inhibition. Increased reports from child cohort studies suggest gestational exposures to pesticides are of public health concern. Current risk assessment and management strategies may not be optimal with the use of AChE inhibition as an anchor reference point for regulations. This project will examine the relationship between AChE inhibition and neurotoxicity in depth, across pre- and postnatal developmental life stages. The overall hypothesis of our proposal is that pesticide exposure alters neurodevelopment and behavior in rodents by interfering with cellular pathways controlling proliferation, differentiation and apoptosis (cell death) in the central nervous system (CNS) during critical "windows of susceptibility" and that these mechanisms are independent of AChE inhibition. Using in vitro (lab-based) neurodevelopmental-stage specific models for both pre and postnatal developmental periods, we propose to assess the role of OP-induced oxidative stress and its consequential impact on these important cellular pathways, which underlie CNS development. The specific aims are: (1) To investigate the direct effects of OPs on neurite outgrowth, neuronal proliferation and viability in neurodevelopment-stage specific in vitro models (human stem cells, mouse neuronal precursor cells, and rodent hippocampal neurons); (2) To elucidate the impacts of OP-induced oxidative stress and effects on neurogenesis; (3) To examine developmental stage -pecific OP impacts on proliferation and differentiation gene expression pathways; and (4) to investigate OP effects on glial-neuronal communication.
These proposed experiments will provide significant new insight into the mechanisms of OP-induced neurotoxicity and the role of AChE inhibition during pre- and post-natal neurodevelopment. Working closely with the Biostatistics, Modeling and Risk Characterization Facility Core, results from these studies will be integrated and translated into developing biological and pathway based models relevant for risk assessment across developmental periods and across species.
Supplemental Keywords:environmental management, Scientific Discipline, Health, RFA, Risk Assessment, Biology, Children's Health, Biochemistry, Environmental Policy, Environmental Monitoring, exposure assessment, age-related differences, agricultural community, pesticide exposure, biological markers, pesticides, children's vulnerability, molecular research, RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Biochemistry, Environmental Monitoring, Children's Health, Environmental Policy, Biology, Risk Assessment, pesticide exposure, age-related differences, pesticides, children's vulnerablity, molecular research, biological markers, agricultural community
Progress and Final Reports:2011 Progress Report
2013 Progress Report
Main Center Abstract and Reports:R834514 University of Washington Center for Child Environmental Health Risks Research (2010)
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834514C001 Community-Based Participatory Research
R834514C002 Pesticide Exposure Pathways
R834514C003 Molecular Mechanisms
R834514C004 Genetic Susceptibility