title: Systems biology and birth defects prevention: blockade of the glucocorticoid receptor prevents arsenic-induced birth defects.
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.
  
  
  OBJECTIVE
  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.
authors: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors: Bhavesh K
authors: BK
authors: Ahir
authors: Alison P
authors: AP
authors: Sanders
authors: Julia E
authors: JE
authors: Rager
authors: Rebecca C
authors: RC
authors: Fry
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002642:Chick Embryo; D000013:Congenital Abnormalities / Q000209:etiology / Q000517:prevention & control*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049490:Systems Biology; D013723:Teratogens / Q000633:toxicity*
chemical_list: D011965:Receptors, Glucocorticoid; D013723:Teratogens; D001151:Arsenic