Aroclor 1254 modulates gene expression of nuclear transcription factors: implications for albumin gene transcription and protein synthesis in rat hepatocyte cultures.
Human exposure to polychlorinated biphenyls (PCBs) may lead to increased albumin serum levels, but little is known about the underlying events. Certain PCBs are also ligands for the aryl hydrocarbon receptor (Ahr) and this receptor regulates transcriptional activation of many different genes, including CYP1A1. We tested our hypothesis that expression of certain nuclear transcription factors is altered upon treatment of rat hepatocyte cultures with Aroclor 1254 and we studied the gene expression of albumin and liver-enriched transcription factors simultaneously. We correlate albumin gene expression with protein synthesis and we used CYP1A1 gene expression and enzyme activity as a surrogate endpoint for aryl hydrocarbon receptor activation. We found mRNA transcripts of CCAAT/enhancer binding protein alpha and gamma, hepatic nuclear factor 1, and hepatic nuclear factor 4 to be increased up to 62-fold, whereas albumin gene expression and secretion was increased 3-fold. Noticeably, expression of c-fos, c-jun (AP-1), HNF-6, CCAAT/enhancer binding protein beta and delta, tissue-specific enhancer-1, Ah-receptor, and albumin D-site-binding protein was unchanged. We show coordinate albumin gene expression and protein secretion in primary rat hepatocyte cultures and propose a relationship between induction of certain liver-enriched transcription factors and of the albumin gene via an Ahr-mediated mechanism.
Borlak
Jürgen
J
Center for Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Aerosol Research, Germany. Borlak@ita.fhg.de
Dangers
Marc
M
Thum
Thomas
T
D000418:Albumins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D000418:Albumins; D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496489:Hnf1a protein, rat; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D020111:Chlorodiphenyl (54% Chlorine); D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D019363:Cytochrome P-450 CYP1A1