title: Microarray analysis of gene expression in peripheral blood mononuclear cells from dioxin-exposed human subjects.
abstract: Tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen and exerts toxic effects on the skin (chloracne). Effects on reproductive, immunological, and endocrine systems have also been observed in animal models. TCDD acts through the aryl hydrocarbon receptor (AhR) pathway influencing largely unknown gene networks. An industrial accident in Seveso, Italy in 1976 exposed thousands of people to substantial quantities of TCDD. Twenty years after the exposure, this study examines global gene expression in the mononuclear cells of 26 Seveso female never smokers, with similar age, alcohol consumption, use of medications, and background plasma levels of 22 dioxin congeners unrelated to the Seveso accident. Plasma dioxin levels were still elevated in the exposed subjects. We performed analyses in two different comparison groups. The first included high-exposed study subjects compared with individuals with background TCDD levels (average plasma levels 99.4 and 6.7ppt, respectively); the second compared subjects who developed chloracne after the accident, and those who did not develop this disease. Overall, we observed a modest alteration of gene expression based on dioxin levels or on chloracne status. In the comparison between high levels and background levels of TCDD, four histone genes were up-regulated and modified expression of HIST1H3H was confirmed by real-time PCR. In the comparison between chloracne case-control subjects, five hemoglobin genes were up-regulated. Pathway analysis revealed two major networks for each comparison, involving cell proliferation, apoptosis, immunological and hematological disease, and other pathways. Further examination of the role of these genes in dioxin induced-toxicity is warranted.
authors.affiliation: School of Public Health, University of California, Berkeley, CA 94720-7360, USA. cmchale@berkeley.edu
authors.forename: Cliona M
authors.initials: CM
authors.lastname: McHale
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Alan E
authors.initials: AE
authors.lastname: Hubbard
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
authors.forename: Angela C
authors.initials: AC
authors.lastname: Pesatori
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
mesh_terms: D017486:Acneiform Eruptions / Q000139:chemically induced / Q000235:genetics; D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D004781:Environmental Exposure / Q000032:analysis; D004785:Environmental Pollutants / Q000097:blood / Q000506:poisoning; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005982:Glutathione Transferase / Q000235:genetics; D006454:Hemoglobins / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D007558:Italy; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D000072317:Polychlorinated Dibenzodioxins / Q000097:blood / Q000506:poisoning*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004785:Environmental Pollutants; D006454:Hemoglobins; D006657:Histones; D000072317:Polychlorinated Dibenzodioxins; C483009:GSTM3 protein, human; D005982:Glutathione Transferase