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. 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.
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Verne
authors.initials: V
authors.lastname: Tsang
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
authors.forename: Mihai D
authors.initials: MD
authors.lastname: Niculescu
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rager
authors.forename: Jesse
authors.initials: J
authors.lastname: Saunders
authors.forename: David S
authors.initials: DS
authors.lastname: Paul
authors.forename: Steven H
authors.initials: SH
authors.lastname: Zeisel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stýblo
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Drobná
mesh_terms: D000818:Animals; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D057890:Epigenomics; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D011247:Pregnancy; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine