Grantee Research Project Results

A number of limited studies have shown a statistically significant increase in birth defects of children exposed to arsenic (As) in utero. This number is probably an underestimate of the prevalence of As induced birth defects, as the majority of early developmental abnormalities result in spontaneous abortion.  Based on our unpublished results, we hypothesize that As exerts some of its teratogenic effects through modulation of Sonic Hedgehog (Shh) signaling. This hypothesis is consistent with the pivotal role Shh plays in the development of numerous structures, including those that are consistently malformed in children exposed to As in utero. Our identification of As as a modulator of Shh signaling may be particularly relevant to human development, as humans are much more sensitive to modulation of Shh activity than various animal models.

Interestingly, although As exhibits teratogenic activity in mice, the concentrations of As required to elicit these effects are higher than those that are relevant to human exposure. Thus, similar to the increased sensitivity of humans to Shh levels, it also has been argued that humans are more sensitive to the teratogenic effects of As.  Here we propose to 1) determine the mechanism by which As modulates Shh signaling, and 2) begin to develop the reagents and protocols necessary to analyze human maternal and embryonic derived tissues for biomarkers of Shh activity.  In future work, such reagents will be used to correlate in utero As exposure to modulation of Shh signaling, and ultimately to correlate this modulation of Shh signaling with various human developmental defects. This latter analysis of human samples will be particularly important because of the relative insensitivity of animal models to the in utero perturbation of Shh signaling.

Our experience in the dissection of the HH signaling pathway will provide us a unique position from which to elucidate how As is able to modulate this pathway and to determine whether such modulation is important from a human health perspective, and will help to inform Project 3 (An Integrated Geospatial and Epidemiological Study of Associations Between Birth Defects and Arsenic Exposure in New England) on birth defects. The knowledge gained as a result of this work could be used to design preventative strategies for the various human developmental disorders that result from a deregulated HH pathway.