Arsenic Cardiac Effects

BrooklynDodger(s) comment: Another exploration of the neglected organ system. Hazard ID in a specialized strain of mice. Need to think about potency (exposure response) assessment.



Toxicology and Applied Pharmacology
Volume 241, Issue 1, 15 November 2009, Pages 90-100

Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice

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Sanjay Srivastava^{a, d, ,} , Elena N. Vladykovskaya^a, Petra Haberzettl^a, Srinivas D. Sithu^b, Stanley E. D'Souza^b and J. Christopher States^{c, d}

^aDiabetes and Obesity Center and Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA

^bDepartment of Physiology and Biophysics, University of Louisville, Louisville, KY 40202, USA

^cDepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA

^dCenter for Environmental Genomics and Integrative Biology, University of Louisville, Louisville, KY 40202, USA

Received 23 February 2009;

revised 3 August 2009;

accepted 4 August 2009.

Available online 12 August 2009.

Abstract

Exposure to arsenic-contaminated water has been shown to be associated with cardiovascular disease, especially atherosclerosis. We examined the effect of arsenic exposure on atherosclerotic lesion formation, lesion composition and nature in ApoE-/- mice. Early post-natal exposure (3-week-old mice exposed to increased the atherosclerotic lesion formation by 3- to 5-fold in the aortic valve and the aortic arch, wit49 ppm arsenic as NaAsO₂ in drinking water for 7 weeks) without affecting plasma cholesterol. Exposure to arsenic for 13 weeks (3-week-old mice exposed to 1, 4.9 and 49 ppm arsenic as NaAsO₂ in drinking water) increased the lesion formation and macrophage accumulation in a dose-dependent manner. Temporal studies showed that continuous arsenic exposure significantly exacerbated the lesion formation throughout the aortic tree at 16 and 36 weeks of age. Withdrawal of arsenic for 12 weeks after an initial exposure for 21 weeks (to 3-week-old mice) significantly decreased lesion formation as compared with mice continuously exposed to arsenic. Similarly, adult exposure to 49 ppm arsenic for 24 weeks, starting at 12 weeks of age increased lesion formation by 2- to 3.6-fold in the aortic valve, the aortic arch and the abdominal aorta. Lesions of arsenic-exposed mice displayed a 1.8-fold increase in macrophage accumulation whereas smooth muscle cell and T-lymphocyte contents were not changed. Expression of pro-inflammatory chemokine MCP-1 and cytokine IL-6 and markers of oxidative stress, protein-HNE and protein-MDA adducts were markedly increased in lesions of arsenic-exposed mice. 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.