Effects of TCDD on the expression of nuclear encoded mitochondrial genes.
Generation of mitochondrial reactive oxygen species (ROS) can be perturbed following exposure to environmental chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Reports indicate that the aryl hydrocarbon receptor (AhR) mediates TCDD-induced sustained hepatic oxidative stress by decreasing hepatic ATP levels and through hyperpolarization of the inner mitochondrial membrane. To further elucidate the effects of TCDD on the mitochondria, high-throughput quantitative real-time PCR (HTP-QRTPCR) was used to evaluate the expression of 90 nuclear genes encoding mitochondrial proteins involved in electron transport, oxidative phosphorylation, uncoupling, and associated chaperones. HTP-QRTPCR analysis of time course (30 microg/kg TCDD at 2, 4, 8, 12, 18, 24, 72, and 168 h) liver samples obtained from orally gavaged immature, ovariectomized C57BL/6 mice identified 54 differentially expressed genes (/fold change/ > 1.5 and P-value < 0.1). Of these, 8 exhibited a sigmoidal or exponential dose-response profile (0.03 to 300 microg/kg TCDD) at 4, 24 or 72 h. Dose-responsive genes encoded proteins associated with electron transport chain (ETC) complexes I (NADH dehydrogenase), III (cytochrome c reductase), IV (cytochrome c oxidase), and V (ATP synthase) and could be generally categorized as having proton gradient, ATP synthesis, and chaperone activities. In contrast, transcript levels of ETC complex II, succinate dehydrogenase, remained unchanged. Putative dioxin response elements were computationally found in the promoter regions of all 8 dose-responsive genes. This high-throughput approach suggests that TCDD alters the expression of genes associated with mitochondrial function which may contribute to TCDD-elicited mitochondrial toxicity.
Forgacs
Agnes L
AL
Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
Burgoon
Lyle D
LD
Lynn
Scott G
SG
LaPres
John J
JJ
Zacharewski
Timothy
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D045222:Electron Transport Chain Complex Proteins / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D050259:Genes, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
D045222:Electron Transport Chain Complex Proteins; D000072317:Polychlorinated Dibenzodioxins
Toxicology. 1994 Sep 6;92(1-3):39-51
7940568
Hepatology. 2006 Sep;44(3):592-601
16941708
J Biol Chem. 2005 Jul 8;280(27):25305-12
15883162
IUBMB Life. 2001 Sep-Nov;52(3-5):159-64
11798028
Toxicol Sci. 2008 Aug;104(2):412-8
18441342
Mutat Res. 2004 Sep 12;563(1):71-9
15324750
Free Radic Biol Med. 1989;6(4):369-74
2540069
J Bioenerg Biomembr. 2000 Apr;32(2):153-62
11768748
Toxicol Lett. 2009 Dec 1;191(1):79-87
19686823
Xenobiotica. 1990 Sep;20(9):979-88
2238714
Annu Rev Pharmacol Toxicol. 1982;22:517-54
6282188
Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
12184808
Biochem Pharmacol. 2000 Jan 1;59(1):65-85
10605936
Toxicology. 2002 Jun 14;175(1-3):73-82
12049837
J Biol Chem. 2003 Aug 15;278(33):30525-33
12756242
Genome Biol. 2002;3(12):REVIEWS3015
12537581
Toxicol Appl Pharmacol. 2002 Jan 1;178(1):15-21
11781075
Free Radic Biol Med. 1990;9(1):79-90
2210442
Toxicol Sci. 2005 Jun;85(2):1048-63
15800033
Biochem Biophys Res Commun. 1998 Dec 9;253(1):44-8
9875217
Toxicol Appl Pharmacol. 2006 Dec 15;217(3):363-74
17109908
FASEB J. 1997 Aug;11(10):809-15
9271366
Adv Exp Med Biol. 1986;197:357-65
3020934
J Cell Physiol. 2008 Aug;216(2):413-8
18314881
Toxicology. 2002 Feb 28;171(2-3):117-25
11836018
Nucleic Acids Res. 2004 Aug 24;32(15):4512-23
15328365
Free Radic Biol Med. 2002 Nov 1;33(9):1268-78
12398935