ToxSci Advance Access published online on August 13, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm189
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Micro-RNAs in Adult Rodent Liver are Refractory to Dioxin Treatment
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* Department of Pharmacology, University of Toronto, Toronto, Canada
Department of Food and Environmental Hygiene, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
Finnish Food Safety Authority EVIRA, Kuopio Research Unit, Kuopio, Finland
1 Corresponding author: Allan B. Okey, Department of Pharmacology, Room 4302 Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario CANADA M5S 1A8, Phone: (416) 978-7243; FAX (416) 978-6395, email: allan.okey{at}utoronto.ca
Received June 4, 2007; revision received July 13, 2007; accepted July 17, 2007
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Abstract |
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Dioxin-like chemicals are well-known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We used two miRNA array platforms as well as quantitative RT-PCR to measure miRNA levels in wildtype vs. Ahr-null mice, in dioxin-sensitive Long-Evans (Turku/AB; L-E) rats vs. dioxin-resistant Han/Wistar(Kuopio; H/W) rats, and in rat 5L and mouse Hepa-1 hepatoma cells in culture. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo caused few changes in miRNA levels in mouse or rat livers and those changes that were statistically significant were of modest magnitude. Hepatoma cells in culture also exhibited few changes in miRNA levels in response to TCDD. AHR genotype had little effect on hepatic miRNA levels, either in constitutive expression or in response to TCDD – only a few miRNAs differed in expression between Ahr-null mice compared to mice with wildtype AHR or between L-E rats (that have wildtype AHR) compared to H/W rats (whose AHR has a large deletion in the transactivation domain). It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adultrodent liver.
Key Words: aryl hydrocarbon receptor; dioxin; 2,3,7,8-tetrachlorodibenzo-p-dioxin; microRNA; microarray.
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