PMID- 22719926
OWN - NLM
STAT- MEDLINE
DCOM- 20121213
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 6
DP  - 2012
TI  - Prenatal arsenic exposure alters gene expression in the adult liver to a 
      proinflammatory state contributing to accelerated atherosclerosis.
PG  - e38713
LID - 10.1371/journal.pone.0038713 [doi]
LID - e38713
AB  - The mechanisms by which environmental toxicants alter developmental processes 
      predisposing individuals to adult onset chronic disease are not well-understood. 
      Transplacental arsenic exposure promotes atherogenesis in apolipoprotein 
      E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in 
      atherosclerosis, diabetes and metabolic syndrome, we hypothesized that 
      accelerated atherosclerosis may be linked to altered hepatic development. This 
      hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from 
      gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 microg/g in dams and 350 
      ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis 
      to assess mRNA and microRNA abundance in control and exposed pups at postnatal 
      day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental 
      trajectory of mRNA and microRNA profiles. We identified an arsenic exposure 
      related 51-gene signature at PND1 and PND70 with several hubs of interaction 
      (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that 
      pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at 
      PND1, and pathways for protein export, ribosome, antigen processing and 
      presentation, and complement and coagulation cascades were induced by PND70. 
      Promoter analysis of differentially-expressed transcripts identified enriched 
      transcription factor binding sites and clustering to common regulatory sites. 
      SREBP1 binding sites were identified in about 16% of PND70 
      differentially-expressed genes. Western blot analysis confirmed changes in the 
      liver at PND70 that included increases of heat shock protein 70 (Hspa8) and 
      active SREBP1. Plasma AST and ALT levels were increased at PND70. These results 
      suggest that transplacental arsenic exposure alters developmental programming in 
      fetal liver, leading to an enduring stress and proinflammatory response 
      postnatally that may contribute to early onset of atherosclerosis. Genes 
      containing SREBP1 binding sites also suggest pathways for diabetes mellitus and 
      rheumatoid arthritis, both diseases that contribute to increased cardiovascular 
      disease in humans.
FAU - States, J Christopher
AU  - States JC
AD  - Department of Pharmacology and Toxicology, University of Louisville, Louisville, 
      Kentucky, United States of America. jcstates@louisville.edu
FAU - Singh, Amar V
AU  - Singh AV
FAU - Knudsen, Thomas B
AU  - Knudsen TB
FAU - Rouchka, Eric C
AU  - Rouchka EC
FAU - Ngalame, Ntube O
AU  - Ngalame NO
FAU - Arteel, Gavin E
AU  - Arteel GE
FAU - Piao, Yulan
AU  - Piao Y
FAU - Ko, Minoru S H
AU  - Ko MS
LA  - eng
SI  - GEO/GSE30783
GR  - P20 RR016481/RR/NCRR NIH HHS/United States
GR  - P30 ES014443/ES/NIEHS NIH HHS/United States
GR  - P30ES014443/ES/NIEHS NIH HHS/United States
GR  - R21 ES015812/ES/NIEHS NIH HHS/United States
GR  - R01ES011314/ES/NIEHS NIH HHS/United States
GR  - R01 ES011314/ES/NIEHS NIH HHS/United States
GR  - P20RR016481/RR/NCRR NIH HHS/United States
GR  - R21ES015812/ES/NIEHS NIH HHS/United States
GR  - P20RR016481S1/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120615
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Messenger)
RN  - N712M78A8G (Arsenic)
SB  - IM
MH  - Animals
MH  - Arsenic/*toxicity
MH  - Atherosclerosis/*etiology
MH  - Blotting, Western
MH  - Female
MH  - Gene Expression Regulation/*drug effects
MH  - Liver/*drug effects/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - MicroRNAs/genetics
MH  - Models, Animal
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - RNA, Messenger/genetics
PMC - PMC3376138
COIS- Competing Interests: The authors declare the following interest: co-author J. 
      Christopher States is a PLoS ONE Editorial Board member. This does not alter the 
      authors' adherence to all the PLoS ONE policies on sharing data and materials. 
      The authors have declared that no other competing interests exist.
EDAT- 2012/06/22 06:00
MHDA- 2012/12/14 06:00
PMCR- 2012/06/15
CRDT- 2012/06/22 06:00
PHST- 2012/02/17 00:00 [received]
PHST- 2012/05/11 00:00 [accepted]
PHST- 2012/06/22 06:00 [entrez]
PHST- 2012/06/22 06:00 [pubmed]
PHST- 2012/12/14 06:00 [medline]
PHST- 2012/06/15 00:00 [pmc-release]
AID - PONE-D-12-04932 [pii]
AID - 10.1371/journal.pone.0038713 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(6):e38713. doi: 10.1371/journal.pone.0038713. Epub 2012 Jun 15.