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Janine Ezendam,^1,2,3 Frank Staedtler,⁴ Jeroen Pennings,² Rob J. Vandebriel,² Raymond Pieters,¹
Johannes H. Harleman,⁵ and Joseph G. Vos^2,3

¹Institute for Risk Assessment Sciences (IRAS), Immunotoxicology, Utrecht University, Utrecht, the Netherlands; ²Laboratory for Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; ³Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, Utrecht, the Netherlands; ⁴Biomarker Development and ⁵Preclinical Safety, Novartis Pharma AG, Basel, Switzerland

Abstract
Hexachlorobenzene (HCB) is a persistent environmental pollutant with toxic effects in man and rat. Reported adverse effects are hepatic porphyria, neurotoxicity, and adverse effects on the reproductive and immune system. To obtain more insight into HCB-induced mechanisms of toxicity, we studied gene expression levels using DNA microarrays. For 4 weeks, Brown Norway rats were fed a diet supplemented with 0, 150, or 450 mg HCB/kg. Spleen, mesenteric lymph nodes (MLN) , thymus, blood, liver, and kidney were collected and analyzed using the Affymetrix rat RGU-34A GeneChip microarray. Most significant (p < 0.001) changes, compared to the control group, occurred in spleen, followed by liver, kidney, blood, and MLN, but only a few genes were affected in thymus. This was to be expected, as the thymus is not a target organ of HCB. Transcriptome profiles confirmed known effects of HCB such as stimulatory effects on the immune system and induction of enzymes involved in drug metabolism, porphyria, and the reproductive system. In line with previous histopathological findings were increased transcript levels of markers for granulocytes and macrophages. New findings include the upregulation of genes encoding proinflammatory cytokines, antioxidants, acute phase proteins, mast cell markers, complements, chemokines, and cell adhesion molecules. Generally, gene expression data provide evidence that HCB induces a systemic inflammatory response, accompanied by oxidative stress and an acute phase response. In conclusion, this study confirms previously observed (immuno) toxicological effects of HCB but also reveals several new and mechanistically relevant gene products. Thus, transcriptome profiles can be used as markers for several of the processes that occur after HCB exposure. Key words: Brown Norway rat, DNA microarray analysis, drug metabolism, estrogen metabolism, genomics, hexachlorobenzene, immunotoxicity, inflammation, oxidative stress, porphyria. Environ Health Perspect 112:782-791 (2004) . doi:10.1289/txg.6861 available via http://dx.doi.org/ [Online 7 April 2004]

Address correspondence to J. Ezendam, IRAS, Yalelaan 2, 3584 CM, Utrecht, the Netherlands. Telephone: 0031 302535328. Fax: 0031 302535077. E-mail: j.ezendam@iras.uu.nl

We thank S. Bongiovanni, M. Goetschy, S. Laurent, and N. Hartmann (Novartis, Basel, Switzerland) for performing the DNA microarray experiments. We thank M. de Baets (Department of Neurology, Academic Hospital of Maastricht, Maastricht, the Netherlands) for performing the radioimmunoassay to determine antiacetylcholine receptor antibodies, and we thank B. Baumann (RIVM, Bilthoven, the Netherlands) for measuring the dioxin-like contamination of HCB.

The authors declare they have no competing financial interests.

Received 13 November 2003 ; accepted 7 April 2004.