Delineating liver events in trichloroethylene-induced autoimmune hepatitis.
Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell activation in autoimmune-prone MRL+/+ mice. MRL+/+ mice are usually thought of as a model of systemic lupus rather than an organ-specific disease such as autoimmune hepatitis. Consequently, the present study examined gene expression and metabolites to delineate the liver events that skewed the autoimmune response toward that organ in TCE-treated mice. Female MRL+/+ mice were treated with 0.5 mg/mL TCE in their drinking water. The results showed that TCE-induced autoimmune hepatitis could be detected in as little as 26 weeks. TCE exposure also generated a time-dependent increase in the number of antibodies specific for liver proteins. The gene expression correlated with the metabolite analysis to show that TCE upregulated the methionine/homocysteine pathway in the liver after 26 weeks of exposure. The results also showed that TCE exposure altered the expression of selective hepatic genes associated with immunity and inflammation. On the basis of these results, future mechanistic studies will focus on how alterations in genes associated with immunity and inflammation, in conjunction with protein alterations in the liver, promote liver immunogenicity in TCE-treated MRL+/+ mice.
Gilbert
Kathleen M
KM
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202, USA. gilbertkathleenm@uams.edu
Przybyla
Beata
B
Pumford
Neil R
NR
Han
Tao
T
Fuscoe
James
J
Schnackenberg
Laura K
LK
Holland
Ricky D
RD
Doss
Jason C
JC
Macmillan-Crow
Lee Ann
LA
Blossom
Sarah J
SJ
D000284:Administration, Oral; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D025341:Principal Component Analysis; D014241:Trichloroethylene / Q000008:administration & dosage / Q000633:toxicity*
D004785:Environmental Pollutants; D014241:Trichloroethylene