Grantee Research Project Results
Final Report: Arsenic and Maternal and Infant Immune Function
EPA Grant Number: R834599Center: Children's Environmental Health and Disease Prevention Center - Dartmouth College
Center Director: Karagas, Margaret Rita
Title: Arsenic and Maternal and Infant Immune Function
Investigators: Karagas, Margaret Rita , Purvis, Lisa A. , Korrick, Susan A. , Moeschler, John B. , Enelow, Richard I. , Robbins, David J , Folt, Carol L. , Cottingham, Kathryn L. , Onega, Tracy L. , Gui, Jiang , Rees, Judy , Madan, Juliette , Miller, Stephanie , Punshon, Tracy , Shi, Xun
Institution: University of Miami , Dartmouth Medical School , Dartmouth College
Current Institution: Dartmouth College , Dartmouth Medical School , University of Miami
EPA Project Officer: Callan, Richard
Project Period: February 15, 2010 through February 14, 2013 (Extended to February 14, 2014)
Project Amount: $1,079,663
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:
Our mission was to support and establish a formative Center for Children’s Environmental Health and Disease Prevention Research in rural New England. Overall goals of the Center were to fill critical gaps in our understanding of the impact of drinking water and food borne sources of environmental contaminants on children’s health, and to strengthen our ties with communities, parents/caregivers and other stakeholders to reduce the risk of environmental threats to children’s health.
Our formative Center successfully completed its aims to begin: (1) uniting multidisciplinary research teams equipped to identify and address new and emerging children’s health issues; (2) engage and mentor promising new investigators (as well as recognized scientists interested in expanding their research) in the investigation of problems related to children’s environmental health and disease prevention; and (3) identify and engage potential community collaborators to translate novel and important research findings to key stakeholders, clinicians and the community.
Capitalizing upon research and expertise presently underway at Dartmouth, the formative Center comprised an administrative core and four tightly interlinked, and interdisciplinary projects. We designed this formative phase of our Center to maximize our potential for garnering important results, developing a strong team of scientists, clinicians, and public health experts, and supporting an environment that prepared the groundwork for establishing a highly effective, full Center. Our integrated Center was comprised of a talented and diverse team designed to address emerging areas of concern, including the potential for significant exposure to arsenic in infant's food as well as water. Based on available evidence, these exposures could impact susceptibility to infection and vaccine response and disrupt major pathways involved in human development resulting in birth defects. We have made great strides and unearthed novel insights into the origin of human disease and shed light on places for potential policy change.
Project 1: Arsenic and Maternal and Infant Immune Function:
The aims of project 1 were to: (1) test the hypothesis that prenatal and early life exposure to arsenic (i.e., via drinking water and food) is associated with an increased risk of infant infections during the first year of life; and (2), to test the hypothesis that arsenic (As) exposure is related to an increased risk of maternal infection during pregnancy. This project extended the work of the New Hampshire Birth Cohort Study (NHBCS), an ongoing longitudinal study of women and infants who are residents of New Hampshire/Vermont and who obtain household water from wells, which are potential sources of arsenic exposure. Mother/infant dyads have been recruited into the study and were prospectively followed by interval telephone interviews, and by reviewing prenatal medical records for information on post-partum information on infections, allergies, breast feeding/formula/solid food and other information.
Project 2: Food Borne Exposure to Arsenic During the First Year of Life
This pilot project has contributed to the broader mission of the Dartmouth Center for Children’s Environmental Health and Disease Prevention Research to understand the health effects of low-dose exposure to environmental contaminants, including arsenic, by quantifying sources of arsenic exposure during the first year of life. The public health effects of arsenic in food, especially rice, are only beginning to be evaluated, but are a particularly pressing issue in regions such as New Hampshire where arsenic contamination of private well water is already a concern. We began the pilot project with one primary aim and two secondary aims:
Project 3: An Integrated Geospatial and Epidemiological Study of Associations Between Birth Defects and Arsenic Exposure in New England
The aims of this project were to: (1) quantitatively characterize the spatial distribution of birth outcomes in New Hampshire (NH) and Maine (ME) using geographic information systems (GIS) mapping methods; (2) evaluate associations between birth defects and low birth weight occurrence with arsenic concentrations; and (3) conduct a pilot epidemiological study to investigate associations between birth defects and arsenic exposure. The integrated methodology established in this project offers a new approach to investigating child environmental health issues, and will provide the preliminary data necessary to launch a larger scale investigation.
Project 4: Determining How Arsenic Modulates Hedgehog Signalin During Development
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, RD-83544201), 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):
Some of our major accomplishments include:
Project 1: Arsenic and Maternal and Infant Immune Function
- We obtained data on infant infections through interval phone interviews (e.g., at 4, 8 and 12 months) with response rates of about 80%.
- We conducted pilot analyses on infant microbiome as a marker of infant immunity and infection status.
- Our project yielded several novel manuscripts (listed in project progress report publications).
Project 2: Food Borne Exposure to Arsenic During the First Year of Life
- Findings from the organic brown rice syrup market basket work attracted considerable attention from the press, and brought the project into the public eye. (listed in project progress report publications).
- We created a novel food diary with emphasis on the source and amount of water added to foods (i.e., formula), so that we can accurately quantify intake from the multiple pathways of food and water.
- Market basket analyses for total arsenic concentration and speciation showed a strong relationship to rice content: solid foods containing rice (e.g., rice cereal, lentils & rice, chicken & rice) had higher total arsenic than solid foods without rice.
Project 3: An Integrated Geospatial and Epidemiological Study of Associations Between Birth Defects and Arsenic Exposure in New England
- We established and tested a methodology to characterize the spatial association between infants born with birth defects or with low birth weight, and their relation to arsenic exposures from drinking water in New Hampshire (NH) and Maine (ME).
- We began the Prenatal Environmental Exposures and Child Health (PEECH) Study Pilot sought to evaluate whether or not a larger scale epidemiological study evaluating the relationship between birth defects and arsenic exposure in groundwater can be successfully conducted in NH and ME. We obtained water samples, fingernail samples and DNA samples from participating mothers and children, and completed analysis on participant water and fingernail samples.
Project 4: Determining How Arsenic Modulates Hedgehog Signaling During Development
- We have discovered that arsenic acts to activate Hedgehog (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 (listed in project progress report publications).
- 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 over 100 placenta samples, using custom designed probes that cover various HH signaling components, as well as other reported Arsenic response genes (listed in project progress report publications).
- 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.
Research Integration, Support and Completion of Goals/Aims:
- We developed and fostered fruitful collaborations both within our Center, and within other EPA/NIEHS funded Children’s Centers, which will be maintained and grown during the P01 phase.
- We coalesced several multidisciplinary research teams and equipped them with the support and tools to identify and address new and emerging issues, leading to multiple high-tiered publications, some which received national and/or international press.
- We further developed the invaluable long-term data resource of the New Hampshire Birth Cohort Study (NHBCS), which serves as the main source of maternal/infant data for all of the formative, and P01 funded research projects.
- With obtained expert guidance from our External Advisory Committee through on site meetings and conference calls. Monthly group administrative and laboratory coordination meetings were held, encouraging Center collaborations, and ensuring projects were achieving a high level of productivity, with attention to quality assurance.
- Quality Assurance measures were developed and implemented including standard operating procedures for data collection, laboratory operation, quality assurance procedures, and key aspects of the project research, all which we will utilize and expand upon within our full Center.
Career Development
- Our Center supported the enhancement of early career core competencies by assisting in the design, and overseeing the conduct of their inter-disciplinary and translational research, and providing mentored research opportunities, including goal setting to achieve high level of productivity.
- Center early career investigators presented research findings at national and international conferences, attended annual meetings, and were mentored to effectively translate research findings to both scientific and non-scientific audiences alike.
- Seminars, meetings, and learning opportunities (i.e., workshops, webinars, etc.) were provided to Center members, and others within the Dartmouth community, fostering potential new collaborations with early career investigators.
- During the formative phase, we engaged talented early career investigators, such as Dr. Diane Gilbert-Diamond, who is now the faculty development investigator (Project 2) of our P01 Center. Additionally, all Center projects fostered collaborations with several talented postdoctoral fellows, as well as clinician-scientists.
Community Engagement / Children’s Health Specialist
- The community engagement portion of our Center conducted preliminary planning and outreach activities to engage key stakeholders and community members, and has established several valuable partnerships with pediatric and prenatal programs, in addition to state-level collaborations, all of which will be expanded and built upon in the P01 phase.
- The Children’s Health Specialist achieved the initial goals by providing support and consultation to Center investigators to ensure that the research was translated to clinical practice the public health sectors in a positive, productive, and appropriate manner.
- The Children’s Health Specialist and Community Engagement staff formulated collaborative, productive working relationships and momentum, which will be carried into the full Center.
Conclusions:
We are very excited to have a funded, P01 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 and other exposures on children’s health, and the potential impacts of these exposures later in life.
Journal Articles: 29 Displayed | Download in RIS Format
Other center views: | All 76 publications | 29 publications in selected types | All 29 journal articles |
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Carey AM, Norton GJ, Deacon C, Scheckel KG, Lombi E, Punshon T, Guerinot ML, Lanzirotti A, Newville M, Choi Y, Price AH, Meharg AA. Phloem transport of arsenic species from flag leaf to grain during grain filling. New Phytologist 2011;192(1):87-98. |
R834599 (2012) R834599C002 (2012) |
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Carey A-M, Lombi E, Donner E, de Jonge MD, Punshon T, Jackson BP, Guerinot ML, Price AH, Meharg AA. A review of recent developments in the speciation and location of arsenic and selenium in rice grain. Analytical and Bioanalytical Chemistry 2012;402(10):3275-3286. |
R834599 (2012) R834599 (Final) R834599C002 (2012) R834599C002 (Final) |
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Cottingham KL, Karimi R, Gruber JF, Zens MS, Sayarath V, Folt CL, Punshon T, Morris JS, Karagas MR. Diet and toenail arsenic concentrations in a New Hampshire population with arsenic-containing water. Nutrition Journal 2013;12:149. |
R834599 (2011) R834599 (Final) R834599C001 (Final) R834599C002 (Final) R835442 (2014) R835442 (2015) R835442 (2016) |
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Davis MA, Mackenzie TA, Cottingham KL, Gilbert-Diamond D, Punshon T, Karagas MR. Rice consumption and urinary arsenic concentrations in U.S. children. Environmental Health Perspectives 2012;120(10):1418-1424. |
R834599 (2012) R834599 (Final) R834599C001 (2012) R834599C001 (Final) R834599C002 (2012) R834599C002 (Final) |
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Farzan SF, Karagas MR, Chen Y. In utero and early life arsenic exposure in relation to long-term health and disease. Toxicology and Applied Pharmacology 2013;272(2):384-390. |
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Farzan SF, Korrick S, Li Z, Enelow R, Gandolfi AJ, Madan J, Nadeau K, Karagas MR. In utero arsenic exposure and infant infection in a United States cohort: a prospective study. Environmental Research 2013;126:24-30. |
R834599 (Final) R834599C001 (Final) |
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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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Gilbert-Diamond D, Cottingham KL, Gruber JF, Punshon T, Sayarath V, Gandolfi AJ, Baker ER, Jackson BP, Folt CL, Karagas MR. Rice consumption contributes to arsenic exposure in US women. Proceedings of the National Academy of Sciences of the United States of America 2011;108(51):20656-20660. |
R834599 (2011) R834599 (2012) R834599 (Final) R834599C001 (Final) R834599C002 (2012) R834599C002 (Final) |
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Gruber JF, Karagas MR, Gilbert-Diamond D, Bagley PJ, Zens MS, Sayarath V, Punshon T, Morris JS, Cottingham KL. Associations between toenail arsenic concentration and dietary factors in a New Hampshire population. Nutrition Journal 2012;11:45 (10 pp.). |
R834599 (2011) R834599 (2012) R834599 (Final) R834599C001 (2012) R834599C001 (Final) R834599C002 (2012) R834599C002 (Final) |
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Jackson BP, Taylor VF, Punshon T, Cottingham KL. Arsenic concentration and speciation in infant formulas and first foods. Pure and Applied Chemistry 2012;84(2):215-223. |
R834599 (2012) R834599 (Final) R834599C002 (2012) R834599C002 (Final) |
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Jackson BP, Taylor VF, Karagas MR, Punshon T, Cottingham KL. Arsenic, organic foods, and brown rice syrup. Environmental Health Perspectives 2012;120(5):623-626. |
R834599 (2011) R834599 (2012) R834599 (Final) R834599C001 (Final) R834599C002 (2012) R834599C002 (Final) |
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Karagas MR. Arsenic-related mortality in Bangladesh. The Lancet 2010;376(9737):213-214. |
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Karagas MR, Wasson JH. A World Wide Web-based survey of non-medical tattooing in the United States. Journal of the American Academy of Dermatology 2012;66(1):e13-e14. |
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Karagas MR, Choi AL, Oken E, Horvat M, Schoney R, Kamai E, Cowell W, Grandjean P, Korrick S. Evidence on the human health effects of low-level methylmercury exposure. Environmental Health Perspectives 2012;120(6):799-806. |
R834599 (2011) R834599 (2012) R834599 (Final) R834599C001 (2012) R834599C001 (Final) |
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Karagas MR, Andrew AS, Nelson HH, Li Z, Punshon T, Schned A, Marsit CJ, Morris JS, Moore JH, Tyler AL, Gilbert-Diamond D, Guerinot ML, Kelsey KT. SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer. Human Genetics 2012;131(3):453-461. |
R834599 (2011) R834599 (Final) R834599C001 (Final) R834599C002 (Final) |
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Koestler DC, Christensen B, Karagas MR, Marsit CJ, Langevin SM, Kelsey KT, Wiencke JK, Houseman EA. Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis. Epigenetics 2013;8(8):816-826. |
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Koestler DC, Avissar-Whiting M, Houseman EA, Karagas MR, Marsit CJ. Differential DNA methylation in umbilical cord blood of infants exposed to low levels of arsenic in utero. Environmental Health Perspectives 2013;121(8):971-977. |
R834599 (2011) R834599 (Final) R834599C001 (Final) R835442 (2014) R835442 (2015) R835442 (2016) |
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Lesseur C, Gilbert-Diamond D, Andrew AS, Ekstrom RM, Li Z, Kelsey KT, Marsit CJ, Karagas MR. A case-control study of polymorphisms in xenobiotic and arsenic metabolism genes and arsenic-related bladder cancer in New Hampshire. Toxicology Letters 2012;210(1):100-106. |
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Madan JC, Farzan SF, Hibberd PL, Karagas MR. Normal neonatal microbiome variation in relation to environmental factors, infection and allergy. Current Opinion in Pediatrics 2012;24(6):753-759. |
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Madan JC, Koestler DC, Stanton BA, Davidson L, Moulton LA, Housman ML, Moore JH, Guill MF, Morrison HG, Sogin ML, Hampton TH, Karagas MR, Palumbo PE, Foster JA, Hibberd PL, O'Toole GA. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. mBio 2012;3(4):e00251-12 (10 pp.). |
R834599 (2012) R834599 (Final) R834599C001 (2012) R834599C001 (Final) |
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Nadeau KC, Li Z, Farzan S, Koestler D, Robbins D, Fei DL, Malipatlolla M, Maecker H, Enelow R, Korrick S, Karagas MR. In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort. Clinical Immunology 2014;155(2):188-197. |
R834599 (2011) R835442 (2015) R835442 (2016) |
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Oken E, Choi AL, Karagas MR, Marien K, Rheinberger CM, Schoeny R, Sunderland E, Korrick S. Which fish should I eat? Perspectives influencing fish consumption choices. Environmental Health Perspectives 2012;120(6):790-798. |
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Punshon T, Tappero R, Ricachenevsky FK, Hirschi K, Nakata PA. Contrasting calcium localization and speciation in leaves of the Medicago truncatula mutant cod5 analyzed via synchrotron X-ray techniques. The Plant Journal 2013;76(4):627-633. |
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Punshon T, Ricachenevsky FK, Hindt MN, Socha AL, Zuber H. Methodological approaches for using synchrotron X-ray fluorescence (SXRF) imaging as a tool in ionomics: examples from Arabidopsis thaliana. Metallomics 2013;5(9):1133-1145. |
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Shi X, Miller S, Mwenda K, Onda A, Rees J, Onega T, Gui J, Karagas M, Demidenko E, Moeschler J. Mapping disease at an approximated individual level using aggregate data: a case study of mapping New Hampshire birth defects. International Journal of Environmental Research and Public Health 2013;10(9):4161-4174. |
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Sunderland EM, Amirbahman A, Burgess NM, Dalziel J, Harding G, Jones SH, Kamai E, Karagas MR, Shi X, Chen CY. Mercury sources and fate in the Gulf of Maine. Environmental Research 2012;119:27-41. |
R834599 (2011) R834599 (2012) R834599C001 (2012) |
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Wilhelm-Benartzi CS, Koestler DC, Karagas MR, Flanagan JM, Christensen BC, Kelsey KT, Marsit CJ, Houseman EA, Brown R. Review of processing and analysis methods for DNA methylation array data. British Journal of Cancer 2013;109(6):1394-1402. |
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Yang J, Punshon T, Guerinot ML, Hirschi KD. Plant calcium content: ready to remodel. Nutrients 2012;4(8):1120-1136. |
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Supplemental Keywords:
Arsenic, water, drinking water, ground water, exposure, risk, health effects, human health, vulnerability, sensitive populations, population, birth defects, 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, Biochemistry, Environmental Monitoring, Children's Health, Environmental Policy, Biology, Risk Assessment, birth defects, prenatal exposure, drinking water, perinatal exposure, children's vulnerablity, biological markers, arsenic exposure, dietary exposure, growth & development, developmental disordersRelevant Websites:
Children's Environmental Health and Disease Prevention Research Center at Dartmouth
Progress and Final Reports:
Original Abstract 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.