Toxicogenomics of Subchronic Hexachlorobenzene Exposure in Brown Norway Rats

Abstract

) 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 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.

Collembase: a repository for springtail genomics and soil quality assessment

“…The prospects are that gene expression studies will enable a fast and sensitive detection and evaluation of environmental stressors and toxicants. This is strengthened by the fact that several recent studies have shown that transcription profiling can be applied as an early indicator of toxicity [ 10 , 11 ] in a dose-dependent manner [ 12 ].…”

The endocrine disruptor hexachlorobenzene can cause oxidative damage in the testis of mice

“…The enriched genes also included many genes related to the inflammatory response, including IL‐2 and IL‐6, thus suggesting that HCB may also induce inflammation. Ezendam et al observed that HCB could induce systemic inflammation (testicular inflammation was not specifically investigated in their study), which was accompanied by oxidative stress and acute‐phase reactions (Ezendam et al., 2004). Overall, our results suggest that oxidative stress is involved in HCG‐induced damage to the testis and that the inflammatory response may also play a role in this process.…”

“…The excessive accumulation of ROS can lead to cell apoptosis, lipid peroxidation and mitochondrial dysfunction (Badgley et al., 2020; Ozawa et al., 2020; Yang & Kim, 2018). Studies have shown that HCB can increase the content of ROS and induce oxidative stress (Addae et al., 2013; Ezendam et al., 2004). For example, after rats were administered with HCB, there was a significant increase in liver lipid peroxidation and glutathione (GSH) content, while the activities of antioxidant enzymes, such as SOD and CAT, were significantly reduced.…”

“…An extensive body of research has investigated the effects of HCB on the immune, nervous and endocrine systems (Ezendam et al., 2004; Kass et al., 2020; Yang et al., 2020). However, the potential effects of HCB on the male reproductive system, and the mechanisms that might be involved in such effects, have yet to be elucidated.…”

“…However, the mechanisms underlying the effects of HCB on the male reproductive system have not been studied in depth. Previous research has shown that HCB can cause an increase in the levels of reactive oxygen species (ROS), thus leading to oxidative damage (Addae et al., 2013; Ezendam et al., 2004). As a downstream intracellular messenger, ROS can activate mitogen‐activated protein kinases, nuclear factor E2‐related factor 2 and nuclear transcription factor sKB to regulate the expression of related genes (Addae et al., 2013).…”