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

Rolf König, Ping Cai, Xin Guo, Ghulam Ansari

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)572-582
Number of pages11
JournalChemical Research in Toxicology
Volume21
Issue number3
DOIs
StatePublished - Mar 2008

Fingerprint

Liver
Toxicity
Chlorides
Trichloroethylene
Autoimmunity
Genes
Microarrays
Metabolites
Acute-Phase Reaction
Corn Oil
Metallothionein
Environmental Exposure
Microarray Analysis
Transcriptome
Pathology
Zinc
Liver Diseases
Hepatocellular Carcinoma
Carcinogenesis
Gene expression

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

@article{6956e2887c854afa9df1ea17a3c6386b,
title = "Transcriptomic analysis reveals early signs of liver toxicity in female MRL +/+ mice exposed to the acylating chemicals dichloroacetyl chloride and dichloroacetic anhydride",
abstract = "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.",
author = "Rolf K{\"o}nig and Ping Cai and Xin Guo and Ghulam Ansari",
year = "2008",
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T1 - Transcriptomic analysis reveals early signs of liver toxicity in female MRL +/+ mice exposed to the acylating chemicals dichloroacetyl chloride and dichloroacetic anhydride

AU - König, Rolf

AU - Cai, Ping

AU - Guo, Xin

AU - Ansari, Ghulam

PY - 2008/3

Y1 - 2008/3

N2 - 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.

AB - 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.

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