Transcriptomic analysis reveals early signs of liver toxicity in female MRL +/+ mice exposed to the acylating chemicals dichloroacetyl chloride and dichloroacetic anhydride.

摘要

Dichloroacetyl chloride (DCAC) is a reactive metabolite of trichloroethene (TCE). TCE and its metabolites have been implicated in the induction of organ-specific and systemic autoimmunity, in the acceleration of autoimmune responses, and in the development of liver toxicity and hepatocellular carcinoma. In humans, effects of environmental toxicants are often multifactorial and detected only after long-term exposure. Therefore, we developed a mouse model to determine mechanisms by which DCAC and related acylating agents affect the liver. Autoimmune-prone female MRL +/+ mice were injected intraperitoneally with 0.2 mmol/kg of DCAC or dichloroacetic anhydride (DCAA) in corn oil twice weekly for six weeks. No overt liver pathology was detectable. Using microarray gene expression analysis, we detected changes in the liver transcriptome consistent with inflammatory processes. Both acylating toxicants up-regulated the expression of acute phase response and inflammatory genes. Furthermore, metallothionein genes were strongly up-regulated, indicating effects of the toxicants on zinc ion homeostasis and stress responses. In addition, DCAC and DCAA induced the up-regulation of several genes indicative of tumorigenesis. Our data provide novel insight into early mechanisms for the induction of liver disease by acylating agents. The data also demonstrate the power of microarray analysis in detecting early changes in liver function following exposure to environmental toxicants.