Grantee Research Project Results
Final Report: Determining How Arsenic (As) Modulates Sonic Hedgehog (Shh) Signaling During Development
EPA Grant Number: R834599C004Subproject: 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)
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 Based on our unpublished results we hypothesized that As exerts some of its teratogenic effects through modulation of Sonic Hedgehog (HH) signaling. This hypothesis is consistent with the pivotal role HH 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 HH signaling may be particularly relevant to human development, as humans are more sensitive to modulation of HH 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 HH levels, it has also been argued that humans are more sensitive to the teratogenic effects of As. In our P20 project, we proposed to 1) determine the mechanism by which As modulates HH 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 our project in the full Center (P01 ES022832, RD83544201), such reagents are being used to correlate in utero As exposure to modulation of pivotal developmental signaling pathways, which will ultimately be used to associate the modulation of these developmental biomarkers with various human developmental defects. This latter analysis of human samples is particularly important because of the relative insensitivity of animal models to the in utero perturbation of Shh signaling.
Summary/Accomplishments (Outputs/Outcomes):
HH 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. Consistent with this important developmental role, mutations in various components of the HH signaling pathway have been implicated as the causative events in many distinct human developmental disorders. We, and others, have begun to identify environmental modifiers of HH signaling. We have shown that As is able to modulate HH signaling, and that this modulation occurs at doses relevant to human exposure. Consistent with its ability to modulate HH signaling, As has been shown to exhibit teratogenic activity in various animal models, and to increase the risk of birth defects in a small cohort of As exposed patients. During the time period supported by the P20, we obtained the following results:
- Arsenic acts to activate HH signaling downstream of the GPCR Smoothened and upstream of the transcription factor GLI3. The ability of As to activate HH signaling has also directly led to our discovery that HH signaling plays a pivotal role in bladder cancer. A manuscript outlining this discovery was published (Fei, et al., 2012).
- We optimized our ability to extract high quality RNA from human placenta samples. We then optimized for Q-PCR Taqman probes to various relevant target genes, and decided against this being a good way to obtain representative data over a larger period of time with many samples and many individual runs.
- We used the Nanostring technique to examine ~100 placenta samples, using custom designed probes that cover various HH signaling components, as well as other reported arsenic response genes (Fei, et al., 2013).
- We have data that suggests that arsenic can both activate or inhibit HH signaling. We have identified additional factors that might regulate this partial agonist like activity. A manuscript outlining this discovery was submitted for publication, and we are currently in the process of revising this manuscript.
- 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.
During the project period, we developed and implemented standard operating procedures for data collection, laboratory operation, quality assurance procedures, and key aspects of the project research.
Conclusions:
We are very excited to have received funding for a new (P01) Children's Center, and look forward to continuing our research to underscore the importance of evaluating the effects of in utero and early life exposure to arsenic on children’s health, and the potential impacts of this exposure later in life.Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other subproject views: | All 5 publications | 2 publications in selected types | All 2 journal articles |
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| Other center views: | All 76 publications | 29 publications in selected types | All 29 journal articles |
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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) |
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Fei DL, Koestler DC, Li Z, Giambelli C, Sanchez-Mejias A, Gosse JA, Marsit CJ, Karagas MR, Robbins DJ. Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study. Environmental Health 2013;12:58 (8 pp.). |
R834599 (Final) R834599C001 (Final) R834599C004 (Final) R835442 (2014) R835442 (2015) R835442 (2016) |
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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;, 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 disordersRelevant Websites:
Children's Environmental Health and Disease Prevention Research Center at Dartmouth ExitProgress and Final Reports:
Original AbstractMain 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
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.
Project Research Results
2 journal articles for this subproject
Main Center: R834599
76 publications for this center
29 journal articles for this center