Polymorphisms and functional differences in aryl hydrocarbon receptors (AhR) in Japanese field mice, Apodemus speciosus
Department of Environmental Science and Technology, Graduate School of Science and Technology, Niigata University, 8050, Ikarashi 2-no-cho, Nishi-ku, Niigata City 950-2181, Japan.Environmental toxicology and pharmacology 05/2010; 29(3):280-9. DOI: 10.1016/j.etap.2010.03.006
Dioxins, which are unintentionally generated toxic pollutants, exert a variety of adverse effects on organisms. The majority of these effects, which include teratogenesis, immunosuppression, tumor promotion, and endocrine disruption, are mediated through aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. Genetic variations in AhR result in different survivability under exposure to dioxin contamination, which might affect the genetic structure of wildlife populations through differential susceptibility to dioxin exposure. The aim of this study was to clarify the polymorphisms of AhR in Japanese field mice, Apodemus speciosus, and their functional differences in order to develop a molecular indicator for dioxin sensitivity. Wild Japanese field mice had abundant polymorphisms in AhR coding region. Seventy-one single nucleotide polymorphisms, 27 of which occur amino acid substitutions, and consequently 49 alleles were identified in 63 individuals. In the functional analysis of AhR variants using transient reporter assays, a Gln to Arg mutation at amino acid 799 exhibited a significant decrease in the level of transactivational properties (p=0.015) which might modify the dioxin susceptibility of an individual.
- [Show abstract] [Hide abstract]
ABSTRACT: Inflammation is often accompanied by hypoxia. However, crosstalk between signalling pathways activated by inflammation and signalling events that control adaptive response to hypoxia is not fully understood. Here we show that exposure to tumour necrosis factor-α (TNF-α) activates expression of the inhibitory PAS domain protein (IPAS) to suppress the hypoxic response caused by hypoxia-inducible factor (HIF)-1 and HIF-2 in rat pheochromocytoma PC12 cells but not in human hepatoma Hep3B cells. This induction of IPAS was dependent on the nuclear factor-κB (NF-κB) pathway and attenuated hypoxic induction of HIF-1 target genes such as tyrosine hydroxylase (TH) and vascular endothelial growth factor (VEGF). HIF-dependent reporter activity in hypoxia was also decreased following TNF-α treatment. Knockdown of IPAS mRNA by small interfering RNA (siRNA) restored the TNF-α-suppressed hypoxic response. These results indicate that TNF-α is a cell-type specific suppressor of HIFs and suggest a novel crosstalk between stimulation by inflammatory mediators and HIF-dependent hypoxic response.Journal of Biochemistry 05/2011; 150(3):311-8. DOI:10.1093/jb/mvr061 · 2.58 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The Chevrier's field mouse (Apodemus chevrieri) is an endemic species to China and is an important pest in agriculture and human diseases. In this study, the complete mitochondrial genome of this species was sequenced and its size was 16,298 bases (accession no.: HQ896683). The mitogenome structure was similar compared with other reported rodent mitochondrial genomes and includes 13 protein-coding genes, 2 rRNA genes (12S rRNA and 16S rRNA), 22 tRNA genes, and 1 control region. This was the first complete mitogenome sequenced in genus Apodemus. The phylogenetic analyses based on the sequences of 12 heavy-strand protein-coding genes demonstrated that A. chevrieri clustered together with genus Mus. Additionally, extremely high haplotype and nucleotide diversities (h=0.978, π=2.6%) were observed based on 44 mitochondrial cytochrome b (cyt b) gene sequences. This suggests adaptive divergence of this species to a variety of living habitats and potential refuges in the eastern margin of the Hengduan Mountains during the Quaternary ice ages. No population expansions or genetic bottlenecks were observed in demographic analyses. The phylogenetic analysis of cyt b sequences and haplotypes revealed a genetic differentiation between north and south populations. The divergence between north clade and south clade occurred probably in the middle Pleistocene 1.1815 million years ago (Mya) (95% highest posterior density 2.3189-0.2737 Mya), which was congruent with the periods of the most tense uplift events in the Tibetan Plateau.DNA and cell biology 08/2011; 31(4):460-9. DOI:10.1089/dna.2011.1301 · 2.06 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The sensitivity of avian species to the toxic effects of dioxin-like compounds (DLCs) varies up to 1000-fold among species and this variability has been associated with inter-species differences in aryl hydrocarbon receptor 1 ligand binding domain (AHR1 LBD) sequence. We previously showed that LD50 values, based on in ovo exposures to DLCs, were significantly correlated with in vitro EC50 values obtained with a luciferase reporter gene (LRG) assay that measures AHR1-mediated induction of cytochrome P4501A in COS-7 cells transfected with avian AHR1 constructs. Those findings suggest that the AHR1 LBD sequence and the LRG assay can be used to predict avian species sensitivity to DLCs. In the present study, the AHR1 LBD sequences of 86 avian species were studied and differences at amino acid sites 256, 257, 297, 324, 337 and 380 were identified. Site-directed mutagenesis, the LRG assay and homology modeling highlighted the importance of each amino acid site in AHR1 sensitivity to 2,3,8,8-tetrachlorodibenzo-p-dioxin and other DLCs. The results of the study revealed that: (1) only amino acids at sites 324 and 380 affect the sensitivity of AHR1 expression constructs of 86 avian species to DLCs and (2) in vitro luciferase activity in AHR1 constructs containing only the LBD of the species of interest is significantly correlated (r(2) = 0.93, p<0.0001) with in ovo toxicity data for those species. These results indicate promise for the use of AHR1 LBD amino acid sequences independently, or combined with the LRG assay, to predict avian species sensitivity to DLCs.Toxicological Sciences 08/2012; 131(1). DOI:10.1093/toxsci/kfs259 · 3.85 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.