Sonic Hedgehog (Shh) plays an important instructional role in mammalian development, localizing in and controlling the activity of the organizing centers that coordinate the specification and growth of numerous structures. Consistent with this important developmental role, mutations in various components of the Shh Signaling pathway have been implicated as the causative events in many distinct human developmental disorders. One such common disorder, Holoprocencephaly (HPE), affects the development of many midline structures including the forebrain and various facial defects, including cleft lip and cleft palate, and results from both inherited and sporadic loss of function mutations in Shh. The familial forms of HPE serve as another example of how genetic and environmental modifiers are able to regulate the outcome of any particular inherited mutation, as such family members exhibit a wide spectrum of developmental abnormalities while sharing the same exact Shh mutation. We, and others, have begun to identify such environmental modifiers of Shh signaling, which may also affect Shh driven developmental processes in the broader population. We have recently shown that the common environmental toxicant arsenic (As) is able to modulate Shh signaling, and that this modulation occurs at doses relevant to human exposure. Consistent with its ability to modulate Shh signaling. As has been shown to exhibit teratogenic activity in rodent models, and to increase the risk of birth defects in a small cohort of As exposed patients. Here we propose to 1) determine the mechanism by which As modulates Shh signaling, and 2) begin to develop the reagents 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 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.
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 Shh pathway. Furthermore, uncovering the mechanisms by which As acts as a teratogen addresses an important public health problem, which has the potetnial to affect millions of people world wide.
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