ToxSci Advance Access originally published online on August 13, 2007
Toxicological Sciences 2007 99(2):470-487; doi:10.1093/toxsci/kfm189
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microRNAs in Adult Rodent Liver Are Refractory to Dioxin Treatment
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* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8
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 To whom correspondence should be addressed at Department of Pharmacology, Room 4302 Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario Canada M5S 1A8. Fax: (416) 978-6395. E-mail: allan.okey{at}utoronto.ca.
Received June 4, 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 reverse transcriptase–polymerase chain reaction to measure miRNA levels in wild-type (WT) versus Ahr-null mice, in dioxin-sensitive Long-Evans (L-E; Turku/AB) rats versus dioxin-resistant Han/Wistar (H/W; Kuopio) 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 WT AHR or between L-E rats (that have WT 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 adult rodent liver.
Key Words: aryl hydrocarbon receptor; dioxin; 2,3,7,8-tetrachlorodibenzo-p-dioxin; microRNA; microarray.
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