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Title: The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic

Abstract

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. Inmore » fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. Highlights: ► We used transplacental CD1 mice model for inorganic arsenic (iAs) carcinogenesis. ► We examined the effects of gestational iAs and high folate exposure on DNA methylation. ► iAs–folate interaction resulted in low fetal weights and changes in DNA methylation. ► Epigenetically altered genes were associated with cancer and neurodevelopment. ► We showed that in utero iAs–folate interaction negatively affects fetal development.« less

Authors:
 [1];  [2];  [3];  [2]; ;  [1];  [1];  [4];  [5];  [1];  [1]
  1. Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)
  2. Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)
  3. UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)
  4. (United States)
  5. NIEHS, Research Triangle Park, NC 27709 (United States)
Publication Date:
OSTI Identifier:
22215965
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 264; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARSENIC; BIOLOGICAL PATHWAYS; CARCINOGENESIS; CARCINOGENS; CELL CYCLE; CONCENTRATION RATIO; DNA; FETUSES; INTAKE; LIVER; METABOLITES; METHYLATION; MICE; NEOPLASMS

Citation Formats

Tsang, Verne, Fry, Rebecca C., Niculescu, Mihai D., Rager, Julia E., Saunders, Jesse, Paul, David S., Zeisel, Steven H., UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, Waalkes, Michael P., Stýblo, Miroslav, and Drobná, Zuzana, E-mail: drobnazu@med.unc.edu. The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.08.022.
Tsang, Verne, Fry, Rebecca C., Niculescu, Mihai D., Rager, Julia E., Saunders, Jesse, Paul, David S., Zeisel, Steven H., UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, Waalkes, Michael P., Stýblo, Miroslav, & Drobná, Zuzana, E-mail: drobnazu@med.unc.edu. The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic. United States. doi:10.1016/J.TAAP.2012.08.022.
Tsang, Verne, Fry, Rebecca C., Niculescu, Mihai D., Rager, Julia E., Saunders, Jesse, Paul, David S., Zeisel, Steven H., UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, Waalkes, Michael P., Stýblo, Miroslav, and Drobná, Zuzana, E-mail: drobnazu@med.unc.edu. Thu . "The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic". United States. doi:10.1016/J.TAAP.2012.08.022.
@article{osti_22215965,
title = {The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic},
author = {Tsang, Verne and Fry, Rebecca C. and Niculescu, Mihai D. and Rager, Julia E. and Saunders, Jesse and Paul, David S. and Zeisel, Steven H. and UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 and Waalkes, Michael P. and Stýblo, Miroslav and Drobná, Zuzana, E-mail: drobnazu@med.unc.edu},
abstractNote = {Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. Highlights: ► We used transplacental CD1 mice model for inorganic arsenic (iAs) carcinogenesis. ► We examined the effects of gestational iAs and high folate exposure on DNA methylation. ► iAs–folate interaction resulted in low fetal weights and changes in DNA methylation. ► Epigenetically altered genes were associated with cancer and neurodevelopment. ► We showed that in utero iAs–folate interaction negatively affects fetal development.},
doi = {10.1016/J.TAAP.2012.08.022},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 264,
place = {United States},
year = {2012},
month = {11}
}