Academic journal article Environmental Health Perspectives

Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

Academic journal article Environmental Health Perspectives

Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

Article excerpt

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 proinllammatory 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]

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Hexachlorobenzene (HCB) was used as a fungicide until the 1970s, when such use was prohibited. Considerable amounts are still generated as waste by-products of industrial processes and emitted into the environment. Because of its chemical stability, persistence, and long-range transport, HCB can be found throughout the environment and is detectable in human milk, blood, and adipose tissue.

In the 1950s, an accidental poisoning in Turkey revealed several toxic effects of HCB in humans. Approximately 3,000-5,000 people ingested HCB-treated seed grain and developed a disease called porphyria turcica (Gocmen et al. 1986), characterized by hepatic porphyria and cutaneous skin lesions caused by a disturbed porphyrin metabolism (Bickers 1987). Other clinical symptoms include enlarged liver, spleen, lymph nodes (LNs), and thyroid, neurological symptoms, and arthritis. Infants born to mothers exposed to HCB developed a different syndrome called pembe yarn, characterized by high mortality, diarrhea, fever, hepatomegaly, and skin lesions in the absence of porphyria, but with infiltrations of macrophages and lymphocytes and infiltrates in the lung (Cam 1960). Immunotoxic effects were reported in the Turkish poisoning victims, but also in occupationally exposed workers in Brazil. Increased levels of IgM and IgG were observed, as well as impaired function of neutrophil granulocytes (Queiroz et al. 1998a, 1998b).

In rats HCB induced hepatic porphyria and neurotoxic effects (Courtney 1979), and toxic effects on the reproductive system (Jarrell et al. 1998), thyroid function (Kleiman de Pisarev et al. 1990), and immune system (Michielsen et al. 1999; Vos 1986). Because HCB is a lipophilic xenobiotic, exposure leads to accumulation in adipose tissue, whereas only a small part of ingested HCB is metabolized. HCB can be converted in a cytochrome P450 (CYP)-dependent manner (Van Ommen and Van Bladeren 1989) and also via the mercapturic acid pathway (Renner 1981). …

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