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Partha Basu,¹ Richik N. Ghosh,² Linnette E. Grove,³ Linda Klei,⁴ and Aaron Barchowsky⁴

¹Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania, USA; ²Thermo Fisher Scientific, Rockford, Illinois, USA; ³Thermo Fisher Scientific, Pittsburgh, Pennsylvania, USA; ⁴Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Abstract
Background: Roxarsone (3-nitro-4-hydroxy benzene arsonic acid) is an arsenic compound widely used in the poultry industry as a feed additive to prevent coccidiosis, stimulate growth, and to improve tissue pigmentation. Little is known about the potential human health effects from roxarsone released into the environment from chicken waste or from residual compound in chicken products.

Objective: The growth potentiation and enhanced tissue pigmentation suggest that low levels of roxarsone exposure may have an angiogenic potential similar to that of inorganic arsenite (As^III) . The goal of this investigation was to test the hypothesis described above using cultured human aortic and lung microvascular endothelial cells in high-content imaging tube-forming assays and begin developing a molecular level understanding of the process.

Methods: We used a three-dimensional Matrigel assay for probing angiogenesis in cultured human endothelial cells, and a polymerase chain reaction (PCR) array to probe the gene changes as a function of roxarsone or As^III treatment. In addition, we used Western blot analysis for changes in protein concentration and activation.

Results: Roxarsone was found to exhibit a higher angiogenic index than As^III at lower concentrations. Increased endothelial nitric oxide synthase (eNOS) activity was observed for roxarsone but not for As^III-induced angiogenesis. However, As^III caused more rapid and pronounced phosphorylation of eNOS. Quantitative PCR array on select genes revealed that the two compounds have different and often opposite effects on angiogenic gene expression.

Conclusions: The results demonstrate that roxarsone and As^III promote angiogenic phenotype in human endothelial cells through distinctly different signaling mechanisms.

Key words: angiogenesis, animal feed, arsenic, gene expression, nitric oxide, roxarsone, tube formation. Environ Health Perspect 116:520–523 (2008) . doi:10.1289/ehp.10885 available via http://dx.doi.org/ [Online 17 January 2008]

Address correspondence to P. Basu, Department of Chemistry and Biochemistry, 600 Forbes Ave., Duquesne University, Pittsburgh, PA 15282 USA. Telephone: (412) 396-6345. Fax: (412) 396-5683. E-mail: basu@duq.edu

We thank J. Stolz and D. Stolz for numerous stimulating discussions.

P.B. was supported by National Research Service Award fellowship ES-1415201 from the National Institute of Environmental Health Sciences. Financial support from Duquesne University is also acknowledged.

L.E.G. and R.N.G. are employees of Thermo Fisher Scientific. P.B., L.K., and A.B. are employees of nonprofit educational organizations with no competing financial interests.

Received 13 September 2007 ; accepted 15 January 2008.