Systems Biology and Birth Defects Prevention: Blockade of the Glucocorticoid Receptor Prevents Arsenic-Induced Birth Defects

Bhavesh K. Ahir, Alison P. Sanders, Julia E. Rager, and Rebecca C. Fry

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract

Background: The biological mechanisms by which environmental metals are associated with birth defects are largely unknown. Systems biology–based approaches may help to identify key pathways that mediate metal-induced birth defects as well as potential targets for prevention.

Objectives: First, we applied a novel computational approach to identify a prioritized biological pathway that associates metals with birth defects. Second, in a laboratory setting, we sought to determine whether inhibition of the identified pathway prevents developmental defects.

Methods: Seven environmental metals were selected for inclusion in the computational analysis: arsenic, cadmium, chromium, lead, mercury, nickel, and selenium. We used an in silico strategy to predict genes and pathways associated with both metal exposure and developmental defects. The most significant pathway was identified and tested using an in ovo whole chick embryo culture assay. We further evaluated the role of the pathway as a mediator of metal-induced toxicity using the in vitro midbrain micromass culture assay.

Results: The glucocorticoid receptor pathway was computationally predicted to be a key mediator of multiple metal-induced birth defects. In the chick embryo model, structural malformations induced by inorganic arsenic (iAs) were prevented when signaling of the glucocorticoid receptor pathway was inhibited. Further, glucocorticoid receptor inhibition demonstrated partial to complete protection from both iAs- and cadmium-induced neurodevelopmental toxicity in vitro.

Conclusions: Our findings highlight a novel approach to computationally identify a targeted biological pathway for examining birth defects prevention.

Key words: birth defects, comparative toxicogenomic database, glucocorticoid receptor pathway, metals, systems biology.

Environ Health Perspect 121:332–338 (2013). http://dx.doi.org/10.1289/ehp.1205659 [Online 3 January 2013]

Address correspondence to R.C. Fry, Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Dr., CB 7431, University of North Carolina, Chapel Hill, NC 27599 USA. Telephone: (919) 843-6864. E-mail: rfry@unc.edu

Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205659).

We thank A.F. Olshan for helpful discussions and review of the manuscript.

This research was supported in part by grants from the National Institute of Environmental Health Sciences (T32-ES007018, P42-ES005948, ES019315, and P30-ES01026).

The authors declare they have no actual or potential competing financial interests.

Received 22 June 2012; Accepted 21 December 2012; Online 3 January 2013.