Arsenic is a known developmental toxicant and carcinogen that affects the health of tens of millions of people around the globe. Prenatal exposure to arsenic has been associated with poor birth outcomes as well as increased risk for cancer later in life. While detrimental health effects have been linked to in utero exposure to arsenic, the underlying biological mechanisms have yet to be identified. Using a Thai cohort, we recently showed that in utero exposure to arsenic results in profound genome-wide alterations in transcript levels, and these transcripts enrich for the nuclear factor-kappa beta (NF-:B) pathway. In preliminary data, we have utilized next-generation sequencing to establish that arsenicosis may be associated with altered DNA methylation patterns in CpG islands of genes of the NF-:B pathway. Taken together, these data suggest that arsenic exposure may influence both genomic and epigenomic deregulation of the NF-:B pathway. The results have piqued our interest in understanding whether in utero exposure to arsenic may result in potentially heritable epigenetic changes to DNA. Based on the preliminary findings and our interest in understanding mechanisms by which prenatal exposure to arsenic may affect health later in life, we propose this study. Here we will examine the modulation of this pathway in newborns in Gsmez Palacio, Mexico and will assess two potential contributors to this modulation, namely epigenetic alterations and genetic variation. The central hypothesis is that exposure to arsenic alters newborn expression of the NF-:B inflammatory response pathway, and that this modulation is influenced by newborn genetics and epigenetics. This research will, in a comprehensive manner, examine the effects of in utero exposure to arsenic on the signaling of the NF-:B pathway in newborns in Mexico. The proposed study leverages and promotes ongoing partnerships among researchers at the Gillings School of Global Public Health at the University of North Carolina and the University of Juarez in the State of Durango, Mexico. The investigative team includes toxicogenomicists, epidemiologists, biochemical toxicologists, clinicians and biostatisticians from both countries. The study benefits from oversight from the U.S.-Mexico Binational Center in Arizona. Data derived from this study will elucidate insights into mechanisms that associate in utero arsenic exposure with potentially long-lasting epigenetic effects that may underlie disease later in life.

Public Health Relevance

Arsenic is a known developmental toxicant and carcinogen that affects the health of tens of millions of people around the globe. This study seeks to elucidate the underlying biological mechanisms for arsenic-induced disease. Leveraging a study site in Gsmez Palacio, Mexico, we will investigate the hypothesis that exposure to arsenic alters newborn expression of the NF-:B inflammatory response pathway, and that this modulation is influenced by newborn genetics and epigenetics. Results from this research will identify biological pathways and pathogenic mechanisms that may associate prenatal arsenic exposure with long-term health effects in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019315-05
Application #
8698635
Study Section
Special Emphasis Panel (ZES1-TN-J (R))
Program Officer
Shaughnessy, Daniel
Project Start
2010-09-20
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$363,075
Indirect Cost
$105,069
Name
University of North Carolina Chapel Hill
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Edwards, Sharon E; Maxson, Pamela; Miranda, Marie Lynn et al. (2015) Cadmium levels in a North Carolina cohort: Identifying risk factors for elevated levels during pregnancy. J Expo Sci Environ Epidemiol 25:427-32
Nye, Monica D; Fry, Rebecca C; Hoyo, Cathrine et al. (2014) Investigating Epigenetic Effects of Prenatal Exposure to Toxic Metals in Newborns: Challenges and Benefits. Med Epigenet 2:53-59
Sanders, Alison P; Smeester, Lisa; Rojas, Daniel et al. (2014) Cadmium exposure and the epigenome: Exposure-associated patterns of DNA methylation in leukocytes from mother-baby pairs. Epigenetics 9:212-21
Sanders, Alison P; Desrosiers, Tania A; Warren, Joshua L et al. (2014) Association between arsenic, cadmium, manganese, and lead levels in private wells and birth defects prevalence in North Carolina: a semi-ecologic study. BMC Public Health 14:955
Rager, Julia E; Moeller, Benjamin C; Miller, Sloane K et al. (2014) Formaldehyde-associated changes in microRNAs: tissue and temporal specificity in the rat nose, white blood cells, and bone marrow. Toxicol Sci 138:36-46
Johnston, Jill E; Valentiner, Ellis; Maxson, Pamela et al. (2014) Maternal cadmium levels during pregnancy associated with lower birth weight in infants in a North Carolina cohort. PLoS One 9:e109661
Bailey, Kathryn; Fry, Rebecca C (2014) Long-term health consequences of prenatal arsenic exposure: links to the genome and the epigenome. Rev Environ Health 29:9-12
Fry, Rebecca C; Rager, Julia E; Bauer, Rebecca et al. (2014) Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects. Am J Physiol Lung Cell Mol Physiol 306:L1129-37
Rager, Julia E; Bailey, Kathryn A; Smeester, Lisa et al. (2014) Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood. Environ Mol Mutagen 55:196-208
Sanders, Alison P; Miller, Sloane K; Nguyen, Viet et al. (2014) Toxic metal levels in children residing in a smelting craft village in Vietnam: a pilot biomonitoring study. BMC Public Health 14:114

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