Transplacental Arsenic Induced Hepatic Dysfunction and Vascular Disease
Principal Investigator: J Christopher States
Abstract: Cardiovascular disease is the major cause of death in the U.S. Chronic arsenic ingestion causes atherosclerosis and is associated with increased mortality from myocardial infarction and stroke. Early life arsenic exposure may play a significant role in development of atherosclerosis in adult life, as suggested by reports of infant deaths from myocardial infarction caused by advanced arteriosclerosis in regions where mothers consumed water with high levels of arsenic. Transplacental arsenic exposure can disrupt liver DNA methylation patterns and thus alter liver gene expression. Underlying liver disease is an independent risk factor for atherosclerosis. Hence, arsenic exposure induced liver disease may predispose to atherogenesis, and widespread exposure to arsenic in drinking water in the U.S. likely contributes to atherogenesis and death from cardiovascular disease. Our working hypothesis is that arsenic exposure disrupts epigenetic control of hepatic gene expression predisposing the liver to inflammation that is an atherogenic trigger resulting in accelerated atherosclerosis in susceptible animals. Preliminary data indicate that atherosclerosis-prone apolipoprotein E knockout (ApoE -/-) mice transplacentally exposed to arsenic in drinking water develop overt vascular disease by 10 weeks of age without high lipid diet and that liver gene expression suggests a pro-inflammatory state. The aims of this exploratory grant application are 1) to refine and to optimize this newly developed model of transplacental arsenic induced atherogenesis by determining arsenic exposure response of arsenic blood levels in pregnant females and fetuses, determining exposure/time dependence of atherosclerotic lesion formation (rate and extent of lesion formation), assessing arsenic exposure-response of changes in vascular reactivity and characterizing the nature of arterial lesions (lesion cellularity, fibrosis and inflammation) in arsenic exposed mice;2) explore transplacental arsenic-induced hepatic changes by characterizing liver pathology, determining circulating biomarkers of liver dysfunction and test the hypothesis that there is a temporal correlation between hepatic changes and vascular changes. Tissues will be examined at birth and at 10, 16 and 24 weeks of age to determine the course of disease and stability of molecular changes induced by in utero arsenic exposure. The goal of the proposed studies is to determine whether there is a threshold level of arsenic exposure necessary to accelerate atherogenesis using the ApoE model. The relevance of this model to human atherosclerosis is that people prenatally exposed to arsenic are likely more susceptible to dietary influences later in life. These studies will provide important information on the mechanisms of arsenic induced atherosclerosis and the role that fetal arsenic exposure plays in disease progression. This model also will be a rich resource for future research on the mechanism of arsenic induced atherosclerosis including determination of the critical stages of development for the arsenic effect, and molecular studies of arsenic exposure induced changes in DNA methylation, chromatin structure, gene expression and genetic imprinting. PUBLIC HEALTH RELEVANCE: Exposure to arsenic drinking water is a major concern in the United States. The effect of early life arsenic exposure on adult disease progression is unknown but potentially very important. This project uses a mouse model of fetal arsenic exposure induced vascular disease to investigate effects of fetal arsenic exposure on liver development that likely cause vascular disease by young adulthood.
Funding Period: ----------------2009 - ---------------2010-
more information: NIH RePORT
- Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosisJ Christopher States
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States of America
PLoS ONE 7:e38713. 2012..Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans...
- Delayed temporal increase of hepatic Hsp70 in ApoE knockout mice after prenatal arsenic exposureNtube N O Ngalame
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, USA
Toxicol Sci 131:225-33. 2013..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...
- Arsenic and cardiovascular diseaseJ Christopher States
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292, USA
Toxicol Sci 107:312-23. 2009..The recent findings provide future directions for research into the cardiovascular effects of arsenic exposure...
- Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- miceSanjay Srivastava
Diabetes and Obesity Center and Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA
Toxicol Appl Pharmacol 241:90-100. 2009..Plasma concentrations of MCP-1, IL-6 and MDA were also significantly elevated in arsenic-exposed mice. These data suggest that arsenic exposure increases oxidative stress, inflammation and atherosclerotic lesion formation...
- Arsenic toxicology: translating between experimental models and human pathologyJ Christopher States
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
Environ Health Perspect 119:1356-63. 2011..We propose phenotypic anchoring as a means to unify experimental observations and disease outcomes...
- Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in miceMin Tan
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
Toxicol Appl Pharmacol 257:356-64. 2011..These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations...