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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-LKB-G)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
United States
Zip Code
Punshon, Tracy; Li, Zhigang; Marsit, Carmen J et al. (2016) Placental Metal Concentrations in Relation to Maternal and Infant Toenails in a U.S. Cohort. Environ Sci Technol 50:1587-94
Chernikova, Diana A; Koestler, Devin C; Hoen, Anne Gatewood et al. (2016) Fetal exposures and perinatal influences on the stool microbiota of premature infants. J Matern Fetal Neonatal Med 29:99-105
Carignan, Courtney C; Punshon, Tracy; Karagas, Margaret R et al. (2016) Potential Exposure to Arsenic from Infant Rice Cereal. Ann Glob Health 82:221-4
Carignan, Courtney C; Karagas, Margaret R; Punshon, Tracy et al. (2016) Contribution of breast milk and formula to arsenic exposure during the first year of life in a US prospective cohort. J Expo Sci Environ Epidemiol 26:452-7
Carignan, Courtney C; Cottingham, Kathryn L; Jackson, Brian P et al. (2015) Estimated exposure to arsenic in breastfed and formula-fed infants in a United States cohort. Environ Health Perspect 123:500-6
Shi, Xun; Ayotte, Joseph D; Onda, Akikazu et al. (2015) Geospatial association between adverse birth outcomes and arsenic in groundwater in New Hampshire, USA. Environ Geochem Health 37:333-51
Hoen, Anne G; Li, Jing; Moulton, Lisa A et al. (2015) Associations between Gut Microbial Colonization in Early Life and Respiratory Outcomes in Cystic Fibrosis. J Pediatr 167:138-47.e1-3
Davis, Matthew A; Higgins, John; Li, Zhigang et al. (2015) Preliminary analysis of in utero low-level arsenic exposure and fetal growth using biometric measurements extracted from fetal ultrasound reports. Environ Health 14:12
Hermand, Victor; Julio, Emilie; Dorlhac de Borne, François et al. (2014) Inactivation of two newly identified tobacco heavy metal ATPases leads to reduced Zn and Cd accumulation in shoots and reduced pollen germination. Metallomics 6:1427-40
Davis, Matthew A; Li, Zhigang; Gilbert-Diamond, Diane et al. (2014) Infant toenails as a biomarker of in utero arsenic exposure. J Expo Sci Environ Epidemiol 24:467-73

Showing the most recent 10 out of 36 publications