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
Drobná, Zuzana; Martin, Elizabeth; Kim, Kyung Su et al. (2016) Analysis of maternal polymorphisms in arsenic (+3 oxidation state)-methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis. Reprod Toxicol 61:28-38
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:
Brooks, Samira A; Martin, Elizabeth; Smeester, Lisa et al. (2016) miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia. Food Chem Toxicol 98:50-57
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
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
Laine, Jessica E; Fry, Rebecca C (2016) A Systems Toxicology-based Approach Reveals Biological Pathways Dysregulated by Prenatal Arsenic Exposure. Ann Glob Health 82:189-96
Martin, Elizabeth; Ray, Paul D; Smeester, Lisa et al. (2015) Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-β Pathway. PLoS One 10:e0141294
Laine, Jessica E; Bailey, Kathryn A; Rubio-Andrade, Marisela et al. (2015) Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. Environ Health Perspect 123:186-92
Rager, Julia E; Tilley, Sloane K; Tulenko, Samantha E et al. (2015) Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol 28:1144-55
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

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