title: Effects of TCDD on the expression of nuclear encoded mitochondrial genes.
abstract: 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.
authors.affiliation: Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Forgacs
authors.forename: Lyle D
authors.initials: LD
authors.lastname: Burgoon
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lynn
authors.forename: John J
authors.initials: JJ
authors.lastname: LaPres
authors.forename: Timothy
authors.initials: T
authors.lastname: Zacharewski
mesh_terms: 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
chemical_list: D045222:Electron Transport Chain Complex Proteins; D000072317:Polychlorinated Dibenzodioxins
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