Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells.
In humans, exposure to high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with chronic obstructive pulmonary disease and lung cancer. While several studies have shown that the lung is a target organ for TCDD toxicity, little is known on the specific biological pathways altered by TCDD. Studies have shown that the transcriptional response of TCDD (in vivo and in vitro) is complex, and exhibits cell type and tissue specificity. Thus, the purpose of this study was to look at global and concentration-dependent effects of TCDD on gene expression in human lung cells. Gene expression profiling of both a nontumorigenic (HPL1A) and a malignant, tumorigenic lung cell line (A549) was performed by microarray dual fluorescence hybridizations in cells treated with increasing concentrations of TCDD (0, 0.1, 1, 10 nM) for 24 h. Real time RT-PCR was used to verify alterations in specific genes. Results showed that 68 out of 2091 genes were changed in each cell line, and 15 of those genes were found altered in both cell lines. Common gene responses altered by TCDD were identified and included known xenobiotic metabolizing genes, genes known to alter cell cycle, as well as genes that are involved with cell signaling and that mediate cell motility or communication. Cell line specific differences in gene expression were found that indicate the nonmalignant HPL1A cells are retinoic acid responsive. In addition, TCDD altered specific immunomodulatory genes in the HPL1A cells. These data show that TCDD alters multiple integrated networks of signaling pathways associated with pulmonary disease, particularly that of lung cancer.
Martinez
Jeanelle M
JM
National Institute of Environmental Health Sciences, Rall Building 101, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
Afshari
Cynthia A
CA
Bushel
Pierre R
PR
Masuda
Akira
A
Takahashi
Takashi
T
Walker
Nigel J
NJ
D000465:Algorithms; D002273:Carcinogens / Q000633:toxicity*; D002277:Carcinoma / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects*; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007107:Immune System / Q000187:drug effects; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D009153:Mutagens / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D018076:DNA, Complementary; D005456:Fluorescent Dyes; D009153:Mutagens; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012313:RNA