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Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis.

States JC, Singh AV, Knudsen TB, Rouchka EC, Ngalame NO, Arteel GE, Piao Y, Ko MS - PLoS ONE (2012)

Bottom Line: 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.Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States of America. jcstates@louisville.edu

ABSTRACT
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 µg/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.

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Cluster maps of enriched transcription factor binding sites (TFBS) in promoters of genes that are differentially expressed at PND1 (101 genes) and PND70 (135 genes) and also are targets of differentially expressed microRNAs at PND1 (Table S6) and PND70 (Table S11) respectively.
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pone-0038713-g005: Cluster maps of enriched transcription factor binding sites (TFBS) in promoters of genes that are differentially expressed at PND1 (101 genes) and PND70 (135 genes) and also are targets of differentially expressed microRNAs at PND1 (Table S6) and PND70 (Table S11) respectively.

Mentions: Table 5 lists the differentially-expressed genes at each life stage that also were targets of differentially-expressed miRNAs at that age and that contained the enriched TFBS present in their promoters. Assuming genes with shared multiple TFBS are coordinately regulated, we noted (Figure 5) the upper left of the PND70 map showing 7 genes (Osgep, Armet, Cdca5, Cdkn2d, Kpnb1, Sec23b) sharing 4 TFBS (E2F1, ETF, Ap2, NFY). In addition, 113 genes with altered expression at PND70 had binding site(s) for SREBP1 (Table 4). SREBP1 target genes were not, however, represented among the differentially-expressed miRNAs. The large fraction of the genes with altered expression, all with a common TFBS, thus suggests that SREBP1 is activated and perhaps coordinately regulates this network of genes.


Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis.

States JC, Singh AV, Knudsen TB, Rouchka EC, Ngalame NO, Arteel GE, Piao Y, Ko MS - PLoS ONE (2012)

Cluster maps of enriched transcription factor binding sites (TFBS) in promoters of genes that are differentially expressed at PND1 (101 genes) and PND70 (135 genes) and also are targets of differentially expressed microRNAs at PND1 (Table S6) and PND70 (Table S11) respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376138&req=5

pone-0038713-g005: Cluster maps of enriched transcription factor binding sites (TFBS) in promoters of genes that are differentially expressed at PND1 (101 genes) and PND70 (135 genes) and also are targets of differentially expressed microRNAs at PND1 (Table S6) and PND70 (Table S11) respectively.
Mentions: Table 5 lists the differentially-expressed genes at each life stage that also were targets of differentially-expressed miRNAs at that age and that contained the enriched TFBS present in their promoters. Assuming genes with shared multiple TFBS are coordinately regulated, we noted (Figure 5) the upper left of the PND70 map showing 7 genes (Osgep, Armet, Cdca5, Cdkn2d, Kpnb1, Sec23b) sharing 4 TFBS (E2F1, ETF, Ap2, NFY). In addition, 113 genes with altered expression at PND70 had binding site(s) for SREBP1 (Table 4). SREBP1 target genes were not, however, represented among the differentially-expressed miRNAs. The large fraction of the genes with altered expression, all with a common TFBS, thus suggests that SREBP1 is activated and perhaps coordinately regulates this network of genes.

Bottom Line: 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.Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States of America. jcstates@louisville.edu

ABSTRACT
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 µg/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.

Show MeSH
Related in: MedlinePlus