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.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.

Maternal arsenic exposure and nonsyndromic orofacial clefts

“…Although we observed mostly null associations between arsenic exposures and OFCs, some animal studies reported OFCs (Burk & Beaudoin, 1977;Ferm et al, 1971;Hood et al, 1982;Rogers et al, 1981) and other craniofacial defects (Aggarwal et al, 2007;Ahir et al, 2013) following maternal inorganic arsenic administration during pregnancy. It should be noted that the arsenic doses expected to produce birth defects in animals are likely higher than those typically experienced in human populations, which may account for differences between our results, particularly for drinking water and dietary arsenic exposure, and results from animal studies.…”

“…Few studies reported OFCs among offspring (Burk & Beaudoin, 1977;Ferm et al, 1971;Hood et al, 1982;Rogers et al, 1981). More recently, two studies examined oral exposures to inorganic arsenic, with one study reporting mid-facial clefts in rats exposed to a combination of an organophosphate pesticide and sodium arsenate (Aggarwal et al, 2007), and the second study reporting craniofacial and neural tube abnormalities in chick embryos exposed to inorganic arsenic at levels under the current Safe Drinking Water Act (SDWA) maximum contaminant level (MCL) for arsenic (Ahir, Sanders, Rager, & Fry, 2013).…”

Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

“…Several researchers have identified the GR as a key target for arsenic effects (Ahir et al, 2013; Barr et al, 2009; Bodwell et al, 2004; Gosse et al, 2014; Simons et al, 1990; Stancato et al, 1993). The GR pathway sits at a critical interaction and integration point to play a role in all of the key arsenic associated effects from: inflammation to cognition, and from immunity to neoplasia.…”

“…The GR pathway sits at a critical interaction and integration point to play a role in all of the key arsenic associated effects from: inflammation to cognition, and from immunity to neoplasia. Using a comparative toxicogemonics data base, Ahir and colleagues (Ahir et al, 2013) identified the GR pathway as the top affected pathway for arsenic, along with several other thiol reactive metals. The GR pathways were affected by as little as 7.5 ppb arsenic.…”

“…The GR signaling system, has been linked with cognitive deficits (Rodriguez et al, 2011), cardiovascular (Santos and Joles, 2012), metabolic (Sarr et al, 2012; Spencer, 2012), immune (Bellavance and Rivest, 2014) and metastatic diseases (Kitchin and Wallace, 2008; Schmitz et al, 2009). Several studies have demonstrated that arsenic produces specific disruptions in glucocorticoid transcriptional activity and steroid receptor function (Ahir et al, 2013; Barr et al, 2009; Bodwell et al, 2004; Davey et al, 2007; Gosse et al, 2014; Hamilton et al, 1998; Kaltreider et al, 2001; Shaw et al, 2007). Many of these studies have utilized cell lines or cultured cells, which provide a great deal of mechanistic information regarding the impact of toxins on specific cellular regulators but precludes the ability to assess the impact of arsenic on developmental programming including the interaction between maternal and fetal physiology.…”