PCBs alter gene expression of nuclear transcription factors and other heart-specific genes in cultures of primary cardiomyocytes: possible implications for cardiotoxicity.
1. Polychlorinated biphenyls (PCBs) are well-known environmental pollutants that bioaccumulate mainly in the fatty tissue of animals and humans. Although contamination occurs primarily via the food chain, waste combustion leads to airborne PCBs. From epidemiological studies, there is substantial evidence that cardiovascular disease is linked to air pollution, but little is known about the underlying molecular events. 2. We investigated the effects of Aroclor 1254, a complex mixture of >80 PCB isomers and congeners, on the expression of nuclear transcription factors (GATA-4, Nkx-2.5, MEF-2c, OCT-1) and of downstream target genes (atrial and brain natriuretic peptide, alpha- and beta-myosin heavy chain, alpha-cardiac and alpha-skeletal actin), which play an important role in cardiac biology. 3. We treated cultures of primary cardiomyocytes of adult rats with Aroclor 1254 (10.0 micro M) and found significant induction of the transcription factor genes GATA-4 and MEF-2c and of genes regulated by these factors, i.e. atrial natriuretic peptide, brain-type natriuretic peptide, alpha- and beta-myosin heavy chain, and skeletal alpha actin. 4. We have shown PCBs to modulate expression of genes coding for programmes of cellular differentiation and stress (e.g. atrial natriuretic peptide, brain-type natriuretic peptide) and these alterations may be important in the increase of cardiovascular disease in polluted areas.
Borlak
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J
Fraunhofer Institute of Toxicology and Aerosol Research, Center for Drug Research and Medical Biotechnology, Nicolai-Fuchs-Str. 1, D-30625 Hannover, Germany. borlak@ita.fhg.de
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D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004785:Environmental Pollutants / Q000494:pharmacology; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000096:biosynthesis; D051863:Host Cell Factor C1; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D008858:Microscopy, Phase-Contrast; D009206:Myocardium / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis; D050811:Octamer Transcription Factor-1; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D029867:Xenopus Proteins
D013956:Antithyroid Agents; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D050991:GATA4 Transcription Factor; C497692:HCFC1 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D051863:Host Cell Factor C1; D006838:Hydrocarbons; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; C095552:NKX2-5 protein, human; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; C494168:Pou2f1 protein, rat; D014157:Transcription Factors; D029867:Xenopus Proteins; D020111:Chlorodiphenyl (54% Chlorine); D012313:RNA; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1