Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors.
Workers occupationally exposed to cadmium, cobalt and lead have been reported to have increased levels of DNA damage. To analyze whether in vivo relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene array study using primary normal human bronchial epithelial cells. Cells were incubated with 15 microg/l Cd(II), 25 microg/l Co(II) and 550 microg/l Pb(II) either with individual substances or in combination. Differentially expressed genes were filtered out and used to identify enriched GO categories as well as KEGG pathways and to identify transcription factors whose binding sites are enriched in a given set of promoters. Interestingly, combined exposure to Cd(II), Co(II) and Pb(II) caused a coordinated response of at least seven stress response-related transcription factors, namely Oct-1, HIC1, TGIF, CREB, ATF4, SRF and YY1. A stress response was further corroborated by up regulation of genes involved in glutathione metabolism. A second major response to heavy metal exposure was deregulation of the cell cycle as evidenced by down regulation of the transcription factors ELK-1 and the Ets transcription factor GABP, as well as deregulation of genes involved in purine and pyrimidine metabolism. A third and surprising response was up regulation of genes involved in steroid metabolism, whereby promoter analysis identified up regulation of SRY that is known to play a role in sex determination. A forth response was up regulation of xenobiotic metabolising enzymes, particularly of dihydrodiol dehydrogenases 1 and 2 (AKR1C1, AKR1C2). Incubations with individual heavy metals showed that the response of AKR1C1 and AKR1C2 was predominantly caused by lead. In conclusion, we have shown that in vivo relevant concentrations of Cd(II), Co(II) and Pb(II) cause a complex and coordinated response in normal human bronchial epithelial cells. This study gives an overview of the most responsive genes.
Glahn
Felix
F
Institute of Environmental Toxicology, Martin-Luther-University, Halle-Wittenberg, Halle/Saale, Germany. felix.glahn@medizin.uni-halle.de
Schmidt-Heck
Wolfgang
W
Zellmer
Sebastian
S
Guthke
Reinhard
R
Wiese
Jan
J
Golka
Klaus
K
Hergenröder
Roland
R
Degen
Gisela H
GH
Lehmann
Thomas
T
Hermes
Matthias
M
Schormann
Wiebke
W
Brulport
Marc
M
Bauer
Alexander
A
Bedawy
Essam
E
Gebhardt
Rolf
R
Hengstler
Jan G
JG
Foth
Heidi
H
D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000368:Aged; D019187:Cadmium Compounds / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D003035:Cobalt / Q000633:toxicity*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013256:Steroids / Q000378:metabolism*; D013431:Sulfates / Q000633:toxicity*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D015089:20-Hydroxysteroid Dehydrogenases; D019187:Cadmium Compounds; D003035:Cobalt; D006913:Hydroxysteroid Dehydrogenases; D007854:Lead; D013256:Steroids; D013431:Sulfates; D014157:Transcription Factors; C029891:lead chloride; C037123:cadmium sulfate; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C018021:cobaltous chloride