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 #
5R01ES019315-02
Application #
8145332
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
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$523,110
Indirect Cost
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
Martin, Elizabeth M; St├Żblo, Miroslav; Fry, Rebecca C (2017) Genetic and epigenetic mechanisms underlying arsenic-associated diabetes mellitus: a perspective of the current evidence. Epigenomics 9:701-710
Smeester, Lisa; Bommarito, Paige A; Martin, Elizabeth M et al. (2017) Chronic early childhood exposure to arsenic is associated with a TNF-mediated proteomic signaling response. Environ Toxicol Pharmacol 52:183-187
Brooks, Samira A; Fry, Rebecca C (2017) Cadmium inhibits placental trophoblast cell migration via miRNA regulation of the transforming growth factor beta (TGF-?) pathway. Food Chem Toxicol 109:721-726
Tilley, Sloane K; Reif, David M; Fry, Rebecca C (2017) Incorporating ToxCast and Tox21 datasets to rank biological activity of chemicals at Superfund sites in North Carolina. Environ Int 101:19-26
Tilley, Sloane K; Joseph, Robert M; Kuban, Karl C K et al. (2017) Genomic biomarkers of prenatal intrauterine inflammation in umbilical cord tissue predict later life neurological outcomes. PLoS One 12:e0176953
Laine, Jessica E; Bailey, Kathryn A; Olshan, Andrew F et al. (2017) Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure. Environ Sci Technol 51:625-633
Bailey, Kathryn A; Smith, Allan H; Tokar, Erik J et al. (2016) Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. Environ Health Perspect 124:170-5
Harrington, James M; Young, Daniel J; Fry, Rebecca C et al. (2016) Validation of a Metallomics Analysis of Placenta Tissue by Inductively-Coupled Plasma Mass Spectrometry. Biol Trace Elem Res 169:164-73
Martin, Elizabeth M; Fry, Rebecca C (2016) A cross-study analysis of prenatal exposures to environmental contaminants and the epigenome: support for stress-responsive transcription factor occupancy as a mediator of gene-specific CpG methylation patterning. Environ Epigenet 2:
Bommarito, P A; Fry, R C (2016) Developmental Windows of Susceptibility to Inorganic Arsenic: A Survey of Current Toxicologic and Epidemiologic Data. Toxicol Res (Camb) 5:1503-1511

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