Grantee Research Project Results

Determining How Arsenic (As) Modulates Sonic Hedgehog (Shh) Signaling During Development

EPA Grant Number: R834599C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R834599
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Children's Environmental Health and Disease Prevention Center - Dartmouth College
Center Director: Karagas, Margaret Rita
Title: Determining How Arsenic (As) Modulates Sonic Hedgehog (Shh) Signaling During Development
Investigators: Karagas, Margaret Rita
Current Investigators: Robbins, David J
Institution: University of Miami , Dartmouth Medical School , Dartmouth College
Current Institution: University of Miami
EPA Project Officer: Callan, Richard
Project Period: February 15, 2010 through February 14, 2013 (Extended to February 14, 2014)
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health

Objective:

To determine how Arsenic (As) modulates Sonic Hedgehold Homolog (Shh) signaling and develop methods to analyze human maternal and embryo tissues for biomarkers of Shh activity. Shh is one of three proteins in the signaling pathway in mammals called hedgehog. Shh plays an important instructional role in mammalian development, localizing in and controlling the activity of the organizing centers that coordinate the specification and growth of numerous structures (such as the growth of fingers and toes and the organization of the brain). Mutations in various components of the Shh signaling pathway are thought to cause developmental disorders in humans. We recently showed that arsenic modulates Shh signaling, and that this modulation occurs at doses relevant to human exposure. Arsenic has been shown to cause birth defects in various animal models, and to increase the risk of birth defects in a small cohort of As exposed patients. Project 4 aims to find out how arsenic changes Shh signaling, and how the extent of this modulation correlates with the incidence of a selection of arsenic-induced development effects.

Expected Results:

Project 4 will use a series of pharmacological inhibitors and molecular genetic tools, which activate or attenuate Shh signaling at discrete steps along its signal transduction pathway, to identify how arsenic is able to modulate Shh signaling. These experiments will be performed on As-treated mouse NIH3T3 cells and on immortalized human bronchial epithelial cells (BEAS-2B), both of which respond to arsenic treatment by activating Shh signaling. Results obtained with these various small-molecule modulators will be validated using specific lentiviral RNA constructs and mouse embryo fibroblasts derived from mice lacking various components of the Shh signaling pathway. These latter reagents will result in either increased or decreased Shh signaling, depending on whether the signaling component targeted is a positive or negative acting component of the Shh pathway. Noncanonical Shh signaling pathways will be explored if As modulation of Shh target genes is unaffected.

Publications and Presentations:

Publications have been submitted on this subproject: View all 5 publications for this subproject | View all 76 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 2 journal articles for this subproject | View all 29 journal articles for this center

Supplemental Keywords:

Water, drinking water, ground water, exposure, risk, health effects, human health, vulnerability, sensitive populations, population, infants, children, susceptibility, metals, heavy metals, public policy, decision making, community-based, public good, environmental chemistry, biology, geography, human health, environmental management, international cooperation, Scientific Discipline, Health, Risk Assessment, Biology, Children's Health, Biochemistry, Environmental Policy, Environmental Chemistry, Exposure, Environmental Monitoring, exposure assessment, arsenic exposure, birth defects, developmental disorders, perinatal exposure, prenatal exposure, drinking water, dietary exposure, biological markers, growth & development, children's vulnerability, RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, Exposure, Environmental Chemistry, Children's Health, Environmental Policy, Biology, Risk Assessment, birth defects, prenatal exposure, drinking water, children's vulnerablity, arsenic exposure, biological markers, dietary exposure, growth & development, developmental disorders

Progress and Final Reports:

Main Center Abstract and Reports:

R834599 Children's Environmental Health and Disease Prevention Center - Dartmouth College

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834599C001 Arsenic and Maternal and Infant Immune Function
R834599C002 Food Borne Exposure to Arsenic During the First Year of Life
R834599C003 An Integrated Geospatial and Epidemiological Study of Associations Between Birth Defects and Arsenic Exposure in New England
R834599C004 Determining How Arsenic (As) Modulates Sonic Hedgehog (Shh) Signaling During Development

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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.