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.
ISEE 2015 Abstracts Now AvailableEHP is pleased to present the abstracts for the 2015 annual conference of the International Society for Environmental Epidemiology (ISEE), “Addressing Environmental Health Inequalities,” held 30 August–3 September 2015 in São Paulo, Brazil.
New Editor-in-ChiefWe are pleased to announce that Sally Perreault Darney has been selected as the new Editor-in-Chief of EHP. Sally comes to EHP from the U.S. Environmental Protection Agency, where she most recently co-led a large research project focused on assessing health disparities in vulnerable groups and providing healthy environments for children. Learn more about Sally and her vision for the journal in the September issue of EHP.
Sign Up to Receive E-mail Alerts
Recent Advance Publications
A Curated Database of Rodent Uterotrophic Bioactivity
Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts
E-Waste and Harm to Vulnerable Populations: A Growing Global Problem
Organophosphate Insecticide Metabolites in Prenatal and Childhood Urine Samples and Intelligence Scores at 6 Years of Age: Results from the Mother-Child PELAGIE Cohort (France)
Organophosphate Pesticide Exposures, Nitric Oxide Synthase Gene Variants, and Gene–Pesticide Interactions in a Case-Control Study of Parkinson’s Disease, California (USA)