Differential gene expression in the olfactory bulb following exposure to the olfactory toxicant 2,6-dichlorophenyl methylsulphone and its 2,5-dichlorinated isomer in mice.
2,6-Dichlorophenyl methylsulphone and a number of structurally related chemicals are CYP-activated toxicants in the olfactory mucosa in mice and rats. This toxicity involves both the olfactory neuroepithelium and its subepithelial nerves. In addition, 2,6-dichlorophenyl methylsulphone induces glial acidic fibrillary protein expression (Gfap, a biomarker for gliosis) in the olfactory bulb, as well as long-lasting learning deficits and changes in spontaneous behavior in mice and rats. So far the 2,5-dichlorinated isomer has not been reported to cause toxicity in the olfactory system, although it gives rise to transient changes in spontaneous behavior. In the present study we used 15k cDNA gene arrays and real-time RT-PCR to determine 2,6-dichlorophenyl methylsulphone-induced effects on gene expression in the olfactory bulb in mice. Seven days following a single ip dose of 2,6-dichlorophenyl methylsulphone, 56 genes were found to be differentially expressed in the olfactory bulb. Forty-one of these genes clustered into specific processes regulating, for instance, cell differentiation, cell migration and apoptosis. The genes selected for real-time RT-PCR were chosen to cover the range of B-values in the cDNA array analysis. Altered expression of Gfap, mt-Rnr2, Ncor1 and Olfml3 was confirmed. The expression of these genes was measured also in mice dosed with 2,5-dichlorophenyl methylsulphone, and mt-Rnr2 and Olfml3 were found to be altered also by this isomer. Combined with previous data, the results support the possibility that the persistent neurotoxicity induced by 2,6-dichlorophenyl methylsulphone in mice represents both an indirect and a direct effect on the brain. The 2,5-dichlorinated isomer, negative with regard to CYP-catalyzed toxicity in the olfactory mucosa, may prove useful to resolve this issue.
Bergström
U
U
Department of Environmental Toxicology, Uppsala University, Norbyv. 18A, 752 36 Uppsala, Sweden. ulrika.bergstrom@ebc.uu.se
Olsson
J A
JA
Hvidsten
T R
TR
Komorowski
J
J
Brandt
I
I
D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000633:toxicity*; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007536:Isomerism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D009830:Olfactory Bulb / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
C507859:2,6-dichlorophenyl methylsulfone; D001555:Benzene Derivatives; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; C539128:Ncor1 protein, mouse; C539129:Ncor1 protein, rat; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D012097:Repressor Proteins; D013450:Sulfones