A Systems-Level Approach to Studying Birth Defects: Novel Method Identifies Potential Key Pathway
Kellyn S. Betts
Kellyn S. Betts writes about environmental contaminants, hazards, and technology for solving environmental problems for publications including EHP and Environmental Science & Technology.
Birth defects are a leading cause of infant mortality, and the majority of defects have unknown causes. Now researchers at the University of North Carolina–Chapel Hill have identified the glucocorticoid receptor pathway as a key mediator of birth defects caused by exposure to inorganic arsenic [EHP 121(3):332–338; Ahir et al.]. The researchers used a three-part strategy to test their hypothesis that a systems-level approach could uncover biological pathways involved in metal-induced birth defects.
The researchers were inspired to begin the project as a result of their ongoing studies to identify environmental causes of birth defects in North Carolina. They focused on seven metals commonly found in food, drinking water, air, and/or consumer products. All the metals are known or suspected to be developmental toxicants.
The first step was to search the publicly available Comparative Toxicogenomics Database for genes with any known relationship to at least one of the seven metals as well as to developmental defects. At the time of the study the database contained over 178,000 interactions between nearly 5,000 chemicals and more than 16,000 genes and proteins in 298 species. (The database has since grown significantly.)
Next, the researchers used systems-level computer analyses to overlay the identified genes onto known molecular networks to see which biological pathways were represented. They pinpointed the glucocorticoid receptor pathway as being significantly associated both with development and with exposure to arsenic, cadmium, mercury, and selenium.
The final step was to test the bioinformatically generated predictions in the laboratory setting. The team used in ovo chick embryos, an established model for assessing teratogenicity, to evaluate the effects of exposure to inorganic arsenic. They found that levels of arsenic as low as 7.5 ppb induced structural defects including microcephaly, neural tube defects, and gross craniofacial defects. When the glucocorticoid receptor pathway was blocked, chick embryos did not develop structural defects when exposed to arsenic.
Although the glucocorticoid receptor has been studied in relation to health effects of metal exposures, relatively little attention has been paid to its potential role in birth defects. One implication of this research—and a major strength of the study—is the ability to cost-effectively identify candidate biological pathways for further study in association with environmentally induced birth defects.
CEHN December 2014 Article of the Month
“The Navigation Guide—Evidence-Based Medicine Meets Environmental Health: Integration of Animal and Human Evidence for PFOA Effects on Fetal Growth” (Environ Health Perspect; DOI:10.1289/ehp.1307923) has been selected by the Children’s Environmental Health Network (CEHN) as its December 2014 Article of the Month. These CEHN summaries discuss the potential policy implications of current children’s environmental health research.
Introducing Children’s Health Collection 2014
EHP’s fifth annual Children’s Health Collection is now available. The collection comprises abstracts of all relevant articles published in EHP from October 2013 through September 2014: peer-reviewed research articles, news features, Science Selections, and editorials.
ISEE 2014 Abstracts Now Available
EHP is pleased to present the abstracts for the 26th annual conference of the International Society for Environmental Epidemiology (ISEE), From Local to Global: Advancing Science for Policy in Environmental Health, held 24–28 August 2014 in Seattle, Washington.
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Recent Advance Publications
Comparative Effects of Di(n-Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts
Interaction Effects of Temperature and Ozone on Lung Function and Markers of Systemic Inflammation, Coagulation, and Fibrinolysis: A Crossover Study of Healthy Young Volunteers
First Steps toward Harmonized Human Biomonitoring in Europe: Demonstration Project to Perform Human Biomonitoring on a European Scale
Children’s Health in Latin America: The Influence of Environmental Exposures
Global Analysis of Posttranscriptional Gene Expression in Response to Sodium Arsenite