Conventional biochemical and molecular techniques identified previously several genes whose expression is regulated by the aryl hydrocarbon receptor (AHR). We sought to map the complete spectrum of AHR-dependent genes in male adult liver using expression arrays to contrast mRNA profiles in Ahr-null mice (Ahr Ϫ/Ϫ ) with those in mice with wild-type AHR (Ahr ϩ/ϩ ). Transcript profiles were determined both in untreated mice and in mice treated 19 h earlier with 1000 g/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Expression of 456 ProbeSets was significantly altered by TCDD in an AHR-dependent manner, including members of the classic AHRE-I gene battery, such as Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1. In the absence of exogenous ligand, AHR status alone affected expression of 392 ProbeSets, suggesting that the AHR has multiple functions in normal physiology. In Ahr Ϫ/Ϫ mice, only 32 ProbeSets exhibited responses to TCDD, indicating that the AHR is required for virtually all transcriptional responses to dioxin exposure in liver. The flavin-containing monooxygenases, Fmo2 and Fmo3, considered previously to be uninducible, were highly induced by TCDD in an AHR-dependent manner. The estrogen receptor ␣ as well as two estrogen-receptor-related genes (␣ and ␥) exhibit AHR-dependent expression, thereby extending cross-talk opportunities between the intensively studied AHR and estrogen receptor pathways. p53 binding sites are over-represented in genes down-regulated by TCDD, suggesting that TCDD inhibits p53 transcriptional activity. Overall, our study identifies a wide range of genes that depend on the AHR, either for constitutive expression or for response to TCDD.Initial studies of the aryl hydrocarbon receptor (AHR) focused on its roles in regulating the induction of CYP1 enzymes (Nebert et al., 2004) and mediating toxicity of dioxinlike chemicals (Okey et al., 2005). More recently, the creation of mice with altered AHR signaling revealed phenotypic changes that implicate the AHR in multiple aspects of growth, development, differentiation, and physiology, irrespective of exposure to toxic environmental chemicals (Fernandez-Salguero et al., 1995;Lahvis et al., 2000;Bunger et al., 2003; Walisser et al., 2004a,b). The AHR is a member of the basic helix-loop-helix PAS superfamily and is located in the cytoplasm in association with chaperone proteins such as heat shock protein 90 and XAP2. The AHR is activated by binding to TCDD, translocates to the nucleus, and dimerizes with another basic helix-loop-helix protein, ARNT. The activated AHR/ARNT heterodimer complex interacts with AHresponsive elements and activates the expression of AHR target genes (Nebert et al., 2004).Mice in which the Ahr gene has been knocked out (Ahr Ϫ/Ϫ ) are extraordinarily resistant to TCDD toxicity (Mimura et al., 1997;Peters et al., 1999;Bunger et al., 2003). Major toxic effects in mice such as hepatic toxicity, thymic atrophy, and cleft palate formation (Bunger et al., 2003) require that the AHR have an intact nuclear translocation/transactiva...
The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL‐PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre‐ and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005‐TEQ/g fat in blood sampled at age 9 years based on PCDD/F‐TEQs. No association was observed when including DL‐PCB‐TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F‐TEQ only was on average 2.4‐ and 2.7‐fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL‐PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.
Background: Mouse and rat models are mainstays in pharmacology, toxicology and drug development -but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity. Several studies have shown that dioxins extensively alter hepatic mRNA levels. Surprisingly, though, analysis of a limited portion of the transcriptome revealed that rat and mouse responses diverge greatly (Boverhof et al. Toxicol Sci 94:398-416, 2006).
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent dioxin. There are exceptionally wide inter- and intraspecies differences in sensitivity to TCDD toxicity with Han/Wistar (H/W) (Kuopio) rats being the most resistant mammals tested. A peculiar feature of H/W rats is that despite their unresponsiveness to the acute lethality of TCDD, their sensitivity to other biological impacts of TCDD (e.g., CYP1A1 induction) is preserved. The biological effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR). We recently found that the AhR of H/W rats (about 98 kDa) is smaller than the receptor in other rat strains (106 kDa). In the present study, molecular cloning and sequencing of the H/W rat AhR revealed that the reason for its smaller size is a deletion/insertion-type change at the 3' end of exon 10 in the receptor cDNA. This change emanates from a single point mutation at the first nucleotide of intron 10, resulting in altered mRNA splicing. At the protein level, the mutation leads to a total loss of either 43 or 38 amino acids (with altered sequence for the last seven amino acids in the latter case) toward the carboxyl-terminal end in the trans-activation domain of the AhR. H/W rats also harbor a point mutation in exon 10 that will cause a Val-to-Ala substitution in codon 497, but this occurs in a variable region of the AhR. These findings suggest that there is a relatively small region in the AhR trans-activation domain that may be capable of providing selectivity to its function.
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