Grantee Research Project Results

2012 Progress Report: 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: Robbins, David J
Institution: University of Miami
EPA Project Officer: Callan, Richard
Project Period: February 15, 2010 through February 14, 2013 (Extended to February 14, 2014)
Project Period Covered by this Report: February 15, 2012 through February 14,2013
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:

A number of limited studies have shown a statistically significant increase in birth defects of children exposed to arsenic (As) in utero. This number is probably an underestimate of the prevalence of As induced birth defects, as the majority of early developmental abnormalities result in spontaneous abortion. Based on our unpublished results, we hypothesize that As exerts some of its teratogenic effects through modulation of Sonic Hedgehog (Shh) signaling. This hypothesis is consistent with the pivotal role Shh plays in the development of numerous structures, including those that are consistently malformed in children exposed to As in utero. Our identification of As as a modulator of Shh signaling may be particularly relevant to human development, as humans are much more sensitive to modulation of Shh activity than various animal models. Interestingly, although As exhibits teratogenic activity in mice, the concentrations of As required to elicit these effects are higher than those that are relevant to human exposure. Thus, similar to the increased sensitivity of humans to Shh levels, it has also been argued that humans are more sensitive to the teratogenic effects of As. Here we propose to: (1) determine the mechanism by which As modulates Shh signaling and (2) begin to develop the reagents and protocols necessary to analyze human maternal and embryonic derived tissues for biomarkers of Shh activity. In future work, such reagents will be used to correlate in utero As exposure to modulation of Shh signaling, and ultimately to correlate this modulation of Shh signaling with various human developmental defects. This latter analysis of human samples will be particularly important because of the relative insensitivity of animal models to the in utero perturbation of Shh signaling. Our experience in the dissection of the HH signaling pathway will provide us a unique position from which to elucidate how As is able to modulate this pathway and to determine whether such modulation is important from a human health perspective, and will help to inform GIS/epidemiologic Project 3 on birth defects. The knowledge gained as a result of this work could be used to design preventative strategies for the various human developmental disorders that result from a deregulated HH pathway.

Progress Summary:

We have now analyzed approximately 150 different placentas with about 50 nanostring probes—targeted to a series of arsenic target genes—that were activated in cell lines in vitro. These data allow us to derive a dependence model linking in utero arsenic exposure to birth outcomes (e.g., lower birth weight) of the exposed children. We have also begun to analyze the modulation of key developmental signaling pathways in these placenta samples, including target genes of the Shh, Wnt and Notch signaling pathways.

We have also begun to evaluate a chick embryo explant system for its ability to test the various hypotheses generated by our work on human placental exposure to low-levels of arsenic.

Future Activities:

Publish our manuscript on arsenic-related genes in the placenta in relation to birth outcomes.
Submit a manuscript on the modulation of key developmental signaling target genes by arsenic.
Continue to develop the chick embryo explant system as a relevant developmental model system.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 5 publications	2 publications in selected types	All 2 journal articles
Other center views:	All 76 publications	29 publications in selected types	All 29 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	Fei DL, Sanchez-Mejias A, Wang Z, Flaveny C, Long J, Singh S, Rodriguez-Blanco J, Tokhunts R, Giambelli C, Briegel KJ, Schulz WA, Gandolfi AJ, Karagas M, Zimmers TA, Jorda M, Bejarano P, Capobianco AJ, Robbins DJ. Hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Research 2012;72(17):4449-4458.	R834599 (2012) R834599 (Final) R834599C004 (2012) R834599C004 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: AACR-Full Text HTML Exit Abstract: AACR-Abstract Exit Other: AACR-Full Text PDF Exit

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, epidemiology, immunology, analytical, surveys, measurement methods, Northeast, EPA Region 1, food processing, water safety, Health, RFA, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, Environmental Policy, Biology, Environmental Chemistry, Exposure, Children's Health, Risk Assessment, dietary exposure, biological markers, drinking water, growth & development, prenatal exposure, children's vulnerablity, arsenic exposure, birth defects, developmental disorders

Relevant Websites:

http://www.dartmouth.edu/~childrenshealth/index.html Exit

Progress and Final Reports:

Original Abstract

2010 Progress Report

2011

Final Report

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

Top of Page

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.