PMID- 22959928
OWN - NLM
STAT- MEDLINE
DCOM- 20121228
LR  - 20211021
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 264
IP  - 3
DP  - 2012 Nov 1
TI  - The epigenetic effects of a high prenatal folate intake in male mouse fetuses 
      exposed in utero to arsenic.
PG  - 439-50
LID - S0041-008X(12)00376-6 [pii]
LID - 10.1016/j.taap.2012.08.022 [doi]
AB  - 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.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Tsang, Verne
AU  - Tsang V
AD  - Department of Nutrition, University of North Carolina at Chapel Hill, Chapel 
      Hill, NC 27599, USA.
FAU - Fry, Rebecca C
AU  - Fry RC
FAU - Niculescu, Mihai D
AU  - Niculescu MD
FAU - Rager, Julia E
AU  - Rager JE
FAU - Saunders, Jesse
AU  - Saunders J
FAU - Paul, David S
AU  - Paul DS
FAU - Zeisel, Steven H
AU  - Zeisel SH
FAU - Waalkes, Michael P
AU  - Waalkes MP
FAU - Styblo, Miroslav
AU  - Styblo M
FAU - Drobna, Zuzana
AU  - Drobna Z
LA  - eng
GR  - P30 ES010126/ES/NIEHS NIH HHS/United States
GR  - R01 ES019315/ES/NIEHS NIH HHS/United States
GR  - P30 DK056350/DK/NIDDK NIH HHS/United States
GR  - DK056350/DK/NIDDK NIH HHS/United States
GR  - P30ES010126/ES/NIEHS NIH HHS/United States
GR  - P42 ES005948/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120831
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Arsenites)
RN  - 0 (Sodium Compounds)
RN  - 48OVY2OC72 (sodium arsenite)
RN  - 7LP2MPO46S (S-Adenosylmethionine)
RN  - 935E97BOY8 (Folic Acid)
RN  - 979-92-0 (S-Adenosylhomocysteine)
SB  - IM
MH  - Animals
MH  - Arsenites/administration & dosage/*toxicity
MH  - *Epigenomics
MH  - Female
MH  - Fetal Weight/drug effects
MH  - Fetus/drug effects
MH  - Folic Acid/administration & dosage/blood/*pharmacology
MH  - Gene Expression Regulation, Developmental/*drug effects
MH  - Liver/drug effects/embryology/metabolism
MH  - Male
MH  - Mice
MH  - Pregnancy
MH  - S-Adenosylhomocysteine/metabolism
MH  - S-Adenosylmethionine/metabolism
MH  - Sodium Compounds/administration & dosage/*toxicity
PMC - PMC3478409
MID - NIHMS404968
COIS- Conflict of interest The authors declare that there are no conflicts of interest.
EDAT- 2012/09/11 06:00
MHDA- 2012/12/29 06:00
PMCR- 2013/11/01
CRDT- 2012/09/11 06:00
PHST- 2012/05/22 00:00 [received]
PHST- 2012/08/20 00:00 [revised]
PHST- 2012/08/21 00:00 [accepted]
PHST- 2012/09/11 06:00 [entrez]
PHST- 2012/09/11 06:00 [pubmed]
PHST- 2012/12/29 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - S0041-008X(12)00376-6 [pii]
AID - 10.1016/j.taap.2012.08.022 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2012 Nov 1;264(3):439-50. doi: 
      10.1016/j.taap.2012.08.022. Epub 2012 Aug 31.