Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis

ABSTRACT: Developmental exposures play a role in adult onset chronic disease. The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to chronic disease are not understood. arsenic exposure via drinking water causes cancer and cardiovascular disease. Transplacental arsenic exposure accelerates and exacerbates atherosclerosis in ApoE-knockout mice. The liver plays a central role in the interlinked diseases diabetes, metabolic syndrome and atherosclerosis. The hypothesis that accelerated atherosclerosis is a consequence of altered hepatic development was investigated by microarray profiling of mRNA and microRNA abundance in livers isolated from 10 week old (PND70) and newborn (PND1) mice exposed or not exposed to arsenic from day 8 post-fertilization to birth. The results show that arsenic exposure alters the trajectory of both mRNA and microRNA expression as mice age. A 51-gene signature of arsenic exposure in both PND1 and PND70 mice was identified. Pathway Architect analysis of this signature identified nodes of interaction including Hspa8, IgM and Hnf4a. Gene ontology analysis of arsenic exposure-altered mRNAs indicated that pathways for gluconeogenesis and glycolysis were suppressed in PND1 mice and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced in PND70 mice. Analysis of promoters of differentially expressed genes identified enriched transcription factor binding sites and cluster analyses revealed groups of genes sharing sets of transcription factor binding sites suggesting common regulation. Srebp1 binding sites are present in ~1/6 of the genes differentially expressed in PND70 livers. Western blot analyses of PND70 liver proteins showed that the inducible form of heat shock protein 70 (Hspa1, Hsp70) and the active form of Srebp1 were induced in arsenic-exposed mice as were plasma AST and ALT levels. These results suggest that transplacental ar Samples from three frozen livers from each group (newborn exposed and unexposed, 10 week old exposed and unexposed), and from separate litters, were homogenized and total RNA purified using mirVANA RNA pufification kits (Ambion, Carlsbad, CA). RNA was quantitated and intergrity determined on a Nanochip using a Bioanalyzer (Agilent, Santa Clara, CA). Microarray analyses for miRNAs abundance in total liver RNAs was performed by Exiqon (Woburn, MA) using two-color design against mouse standard total RNA (Ambion, now part of Applied Biosystems) and Exiqon LNA 1500 microarrays. Microarray analyses for mRNA abundance was performed using 2 color design against mouse standard total RNA (Stratgene, LaJolla, CA) and 44k arrays produced at the NIA . The processed data on Exiqon LNA-1500 are attached as a Series supplementary file. The data are based on the same samples as described in Agilent data submitted here. The supplementary data includes only the murine miRNA data on the array because these are the only data supplied by Exiqon. The relationship between GEO's sample names here (Agilent data) and column heads of spreadsheets (Exiqon data) are described in the first sheet of supplemental file: Project_Summary_Report_Heather_Miller_01042009_MTE.xls

ORGANISM(S): Mus musculus

SUBMITTER: Christopher States 

PROVIDER: E-GEOD-30783 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress