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.