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

Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States of America.
PLoS ONE (Impact Factor: 3.23). 06/2012; 7(6):e38713. DOI: 10.1371/journal.pone.0038713
Source: PubMed


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.

Download full-text


Available from: Amar V Singh, Oct 04, 2015
48 Reads
  • Source
    • "Acetaminophen, allyl alcohol, and ␣-naphthyl isothiocyanate Liver Rat miR-122 [124] 2,3,7,8-tetrachlorodibenzo-p-dioxin (environmental contaminant) Thymus Mouse miR-122 and miR-181a miR-23a, miR-18b, miR-31 miR-182 [125] 2,3,7,8-tetrachlorodibenzo-p-dioxin Embryo Zebrafish miR-27e [126] Doxorubicin Heart Mouse 208b, miR-216b, miR-215, miR-34c and miR-367 [127] Cyanobacterial hepatotoxin microcystin-LR Whitefish let-7c, miR-9b), (miR-16a, miR-21a, miR-34a) (miR-122) [128] Ethanol Liver Rat Mir-21 [129] Printex 90 carbon black nanoparticles Lung Mouse miR-135b [130] Arsenic Umbilical endothelial cell Human [128] Arsenic Liver Mouse [131] Acetaminophen Liver Mouse 74-5p, 135a*, 466g, 1196, 466f-3p, 877, 342-3p, 195, 375, 29c, 148a, 652 [132] Gentamicin Kidney Mouse Mir-21, 155 [133] 2-Amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (carcinogen from cooked meat) "
    [Show abstract] [Hide abstract]
    ABSTRACT: MiRNAs (microRNAs) are single-stranded non-coding RNAs of approximately 21-23 nucleotides in length whose main function is to inhibit gene expression by interfering with mRNA processes. MicroRNAs suppress gene expression by affecting mRNA (messenger RNAs) stability, targeting the mRNA for degradation, or both. In this review, we have examined how microRNA expression could be altered following exposure to chemicals and how they could represent appropriate tissue and more interestingly circulating biomarkers. Among the key questions before using the microRNA for evaluation of risk toxicity, it remains still to clarify how they could be causally involved in the adverse effects and how stable their changes are.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 01/2014; 764. DOI:10.1016/j.mrgentox.2014.01.010 · 3.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prenatal arsenic exposure accelerates atherosclerosis in ApoE(-/-) mice by unknown mechanism. Arsenic is an hepatotoxicant, and liver disease increases atherosclerosis risk. Prenatal arsenic exposure may predispose to liver disease by priming for susceptibility to other environmental insults. Earlier microarray analyses showed prenatal arsenic exposure increased Hsc70 (HspA8) and Hsp70 (HspA1a) mRNAs in livers of 10 week old mice. We determined effects of prenatal arsenic exposure on hepatic Hsp70 and Hsc70 expression by western blot and on DNA methylation by methyl acceptance assay during prenatal and postnatal development. Pregnant ApoE(-/-) mice were given drinking water containing 85 mg/L NaAsO(2) (49 ppm arsenic) from gestation day (GD) 8 - 18. Hsp70 and Hsc70 expression and DNA methylation were determined in GD18 fetuses, and 3, 10 and 24 week old mice. Hsc70 expression was unchanged at all ages. Hsp70 induction was observed at 3 and 10 weeks, but was unchanged in GD18 and 24 week livers. Global DNA methylation increased with age; arsenic had no effects. Bisulfite sequencing of DNA from livers of 10 week old mice showed Hsp70 promoter region methylation was unchanged, but methylation was increased within the transcribed region. Hsf1 and Nrf2 nuclear translocation were investigated as potential mechanisms of Hsp70 induction, and found unaltered. Putative binding sites were identified in HSP70 for in utero arsenic exposure suppressed microRNAs suggesting a possible mechanism. Thus, prenatal arsenic exposure causes delayed temporal hepatic Hsp70 induction, suggesting a transient state of stress in livers which can predispose the mice to developing liver disease.
    Toxicological Sciences 09/2012; 131(1). DOI:10.1093/toxsci/kfs264 · 3.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a growing body of evidence that prenatal and early childhood exposure to arsenic from drinking water can have serious long-term health implications. Our goal was to understand the potential long-term health and disease risks associated with in utero and early life exposure to arsenic, as well as to examine parallels between findings from epidemiological studies with those from experimental animal models. We examined the current literature and identified relevant studies through PubMed by using combinations of the search terms "arsenic", "in utero", "transplacental", "prenatal" and "fetal". Ecological studies have indicated associations between in utero and/or early life exposure to arsenic at high levels and increases in mortality from cancer, cardiovascular disease and respiratory disease. Additional data from epidemiologic studies suggest intermediate effects in early life that are related to risk of these and other outcomes in adulthood. Experimental animal studies largely support studies in humans, with strong evidence of transplacental carcinogenesis, atherosclerosis and respiratory disease, as well as insight into potential underlying mechanisms of arsenic's health effects. As millions worldwide are exposed to arsenic and evidence continues to support a role for in utero arsenic exposure in the development of a range of later life diseases, there is a need for more prospective studies examining arsenic's relation to early indicators of disease and at lower exposure levels.
    Toxicology and Applied Pharmacology 07/2013; 272(2). DOI:10.1016/j.taap.2013.06.030 · 3.71 Impact Factor
Show more