Quantitative and statistical analysis of differences in sensitivity between Long–Evans and Han/Wistar rats following long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Sand, Salomon; Fletcher, Nicholas; Rosen, Dietrich von; Kalantari, Fereshteh; Viluksela, Matti; Tuomisto, Jouni T.; Tuomisto, Jouko; Falk‐Filipsson, Agneta; Håkansson, Helen

doi:10.1016/j.yrtph.2010.01.006

Cited by 9 publications

(2 citation statements)

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“…In both strains, the greatest size reductions occurred within the highest dose groups, i.e., 1000 ng/kg bw/day in H/W rats and 100 ng/kg bw/day in L–E rats, consistent with reductions in length, cross-sectional area, and circumference of the femur, tibia, and lumbar vertebrae observed at the same exposure levels in other studies [11] , [12] . Furthermore, comparable to other studies showing about 10-fold greater sensitivity in L–E rats for decreased body weight [39] and reduced tibial length [11] , the dose–response models for the face and base modules produced CED values that were about 10 times lower for the L–E rats ( Table 3 ). These modules showed significant positive correlations with femoral and tibial size for both rat strains, and even stronger correlations with body weight gain during TCDD treatment ( Table 4 ).…”

Section: Discussionsupporting

confidence: 86%

Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR) structures

et al. 2015

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Mammalian bone has shown a variety of responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in experimental and wildlife studies. Although many responses have been well characterized in the postcranial skeleton, dioxin-induced effects on the cranium are largely unknown. In this study, we investigated the effects of chronic adult exposure to TCDD on cranial size and shape in dioxin-resistant Han/Wistar (H/W) and dioxin-sensitive Long–Evans (L–E) rat strains. Three-dimensional landmark configurations for the face, vault, and base of the cranium were recorded and analyzed using geometric morphometrics (GM) and dose–response modeling. The strongest effects were shown by L–E and H/W rats with daily exposures of 100 and 1000 ng TCDD/kg bw/day, respectively, resulting in significant reductions in centroid size (CS) in all three cranial modules for both strains except for the vault in H/W rats. Consistent with previous evidence of intraspecific variation in TCDD resistance, the benchmark doses (CEDs) for cranial size reduction in L–E rats were roughly 10-fold lower than those for H/W rats. For both strains, the face showed the greatest size reduction from the highest doses of TCDD (i.e., 3.6 and 6.3% decreases in H/W and L–E rats, respectively), most likely related to dose-dependent reductions in limb bone size and body weight gain. However, intrinsic morphological differences between strains were also observed: although the control groups of H/W and L–E rats had vaults and bases of comparable size, the face was 6.4% larger in L–E rats. Thus, although H/W rats possess an altered aryl hydrocarbon receptor (AhR) that appears to mediate and provides some resistance to TCDD exposure, their smaller reductions in facial size may also relate to strain-specific patterns of cranial development and growth. Future research will be aimed at understanding how ontogenetic factors may modulate toxic effects of prenatal and lactational exposure on the mammalian skeleton.

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Section: Discussionsupporting

confidence: 86%

Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR) structures

et al. 2015

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“…Although not considered hepatocarcinogenic themselves, endogenous ligands of AhR (e.g., kynurenine, kynurenic acid and indoles) may modulate the activation of AhR and thus the hepatocarcinogenic process (Budinski et al, 2013). Short-term liver toxicity is not observed in either Ahr -null mice (Gonzalez and Fernandez-Salguero, 1998) or TCDD-resistant Han Wistar/Kupio rats at doses of TCDD that are hepatotoxic in sensitive strains such as Sprague-Dawley rats (Sand et al, 2010). Recent studies with an AHR- null rat model demonstrated that AhR was required for TCDD to induce liver weights and liver xenobiotic metabolism genes (Harrill et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR)

et al. 2015

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dioxin-like compounds (DLC) as well as some drugs and endogenous tryptophan metabolites. Short-term activation of AhR can lead to hepatocellular steatosis, and chronic activation can lead to liver cancer in mice and rats. Analytical approaches were developed to identify biosets in a genomic database in which AhR activity was altered. A set of 63 genes was identified (the AhR gene expression biomarker) that was dependent on AhR for regulation after exposure to TCDD or benzo[a]pyrene and includes the known AhR targets Cyp1a1 and Cyp1b1. A fold-change rank-based test (Running Fisher's test; p-value ≤ 10(-4)) was used to evaluate the similarity between the AhR biomarker and a test set of 37 and 41 biosets positive or negative, respectively for AhR activation. The test resulted in a balanced accuracy of 95%. The rank-based test was used to identify factors that activate or suppress AhR in an annotated mouse liver/mouse primary hepatocyte gene expression database of ∼ 1850 comparisons. In addition to the expected activation of AhR by TCDD and DLC, AhR was activated by AP20189 and phenformin. AhR was suppressed by phenobarbital and 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) in a constitutive activated receptor (CAR)-dependent manner and pregnenolone-16α-carbonitrile in a pregnane X receptor (PXR)-dependent manner. Inactivation of individual genes in nullizygous models led to AhR activation (Pxr, Ghrhr, Taf10) or suppression (Ahr, Ilst6st, Hnf1a). This study describes a novel screening strategy for identifying factors in mouse liver that perturb AhR in a gene expression compendium.

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The point of transition on the dose‐effect curve as a reference point in the evaluation of in vitro toxicity data

Sand

Ringblom

Håkansson

et al. 2012

J of Applied Toxicology

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Dose-effect evaluation is an increasingly important step of health risk assessment. The foreseen increase of in vitro methods argues for the development and evaluation of a clearly defined reference points for dose-effect modelling of in vitro data. In the present study, the traditional use of a concentration corresponding to 10% or 50% of the maximal effect (EC₁₀ or EC₅₀) is compared with a strategy, under which, a reference point (Benchmark dose, BMD(T) ) is calculated that represents the dose where the slope of the dose-effect curve changes the most (per unit log-dose) in the low dose region. To illustrate the importance of the reference point, dose-effect data on CYP1A1 enzyme activity for 30 polychlorinated biphenyl (PCB) congeners were evaluated in order to calculate relative potencies, in relation to 2,3,7,8-TCDD, with confidence intervals (CIs). The present study shows that the interpretation of the results as potency and rank orders potentially depends on the choice and definition of the reference point (BMD(T) , EC₁₀ or EC₅₀). This is important as potency ranking may be used as a method for screening and prioritization, in research, in policy development or in pharmaceutical development. The use of the BMD(T) implies a focus on the change of structure in the parameter's dose-response rather than a particular percentage change in the response in such a parameter. In conclusion, the BMD(T) may be used as an alternative base for evaluation of dose-effect relationships in vitro. It offers an objective geometrical definition of a reference point in the low-dose region of the dose-effect curve.

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Quantitative and statistical analysis of differences in sensitivity between Long–Evans and Han/Wistar rats following long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Cited by 9 publications

References 30 publications

Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR) structures

Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR) structures

Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR)

The point of transition on the dose‐effect curve as a reference point in the evaluation of in vitro toxicity data

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