| 1. |
- Fletcher, Nick, et al.
(författare)
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Altered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treatment
- 2005
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 86:2, s. 264-272
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the effects of long-term low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on retinoid, thyroid hormone, and vitamin D homeostasis in Long-Evans and Han/Wistar rats using a tumor promotion exposure protocol. Female rats (ten/group) were partially hepatectomized, initiated with nitrosodiethylamine (NDEA), and given TCDD once per week by sc injection for 20 weeks at calculated daily doses of 0, 1, 10, 100, or 1000 ng/kg bw/day. Groups of nonhepatectomized/uninitiated rats (five/group) were identically maintained. After 20 weeks, the rats were killed, and apolar retinoid levels were determined in the liver and kidneys. No consistent differences were seen between partially hepatectomized/initiated and nonhepatectomized/uninitiated animals with respect to apolar retinoid levels or hepatic TCDD concentration. Further analyses of polar and apolar retinoid levels in liver, plasma, and kidney, as well as free thyroxine (FT4) and vitamin D (25-OH-D(3)) concentrations were carried out in partially hepatectomized/inititated animals. In Long-Evans rats, TCDD exposure dose-dependently decreased hepatic retinyl ester concentrations at doses of 1-100 ng/kg bw/day. Likewise, hepatic all-trans-retinoic acid (all-trans-RA) concentration was decreased 39 and 54% at 10 and 100 ng/kg bw/day respectively, whereas 9-cis-4-oxo-13,14-dihydro-retinoic acid (9-cis-4-oxo-13,14-dihydro-RA), a recently discovered retinoic acid metabolite, was decreased approximately 60% in the liver at 1 ng/kg bw/day. TCDD dose-dependently increased plasma retinol and kidney retinol concentrations, whereas all-trans-RA concentration was also increased in the plasma and kidney at 10 and 100 ng/kg bw/day. Plasma 9-cis-4-oxo-13,14-dihydro-RA was decreased to below detection limits from doses of 1 ng/kg bw/day TCDD. A qualitatively similar pattern of retinoid disruption was observed in the Han/Wistar rat strain following TCDD exposure. FT4 was decreased to a similar extent in both strains, whereas 25-OH-D(3) was decreased only at 100 ng/kg bw/day in Long-Evans rats. Together these results show that TCDD disrupts both retinoid storage and metabolism of retinoic acid and retinoic acid metabolites in liver, kidney, and plasma from doses as low as 1 ng/kg bw/day. Furthermore, 9-cis-4-oxo-13,14-dihydro-RA was identified as a novel and sensitive indicator of TCDD exposure, in a resistant and sensitive rat strain, thereby extending the database of low-dose TCDD effects.
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| 2. |
- Herlin, Maria, et al.
(författare)
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Quantitative characterization of changes in bone geometry, mineral density and biomechanical properties in two rat strains with different Ah-receptor structures after long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
- 2010
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 273:1-3, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Both industrial chemicals and environmental pollutants can interfere with bone modeling and remodeling. Recently, detailed toxicological bone studies have been performed following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which exerts most of its toxic effects through the aryl hydrocarbon receptor (AhR). OBJECTIVES: The aims of the present study were to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following long-term exposure to TCDD, and to further investigate the role of AhR in TCDD-induced bone alterations. To this end, tissue material used in the study was derived from TCDD-exposed Long-Evans (L-E) and Han/Wistar (H/W) rats, which differ markedly in sensitivity to TCDD-induced toxicity due to a strain difference in AhR structure. METHODS: Ten weeks old female L-E and H/W rats were administered TCDD s.c. once per week for 20 weeks, at doses corresponding to calculated daily doses of 0, 1, 10, 100 and 1000ngTCDD/kgbw (H/W only). Femur, tibia and vertebra from the L-E and H/W rats were analyzed by peripheral quantitative computed tomography (pQCT) and biomechanical testing at multiple sites. Dose-response modeling was performed to establish benchmark doses for the analyzed bone parameters, and to quantify strain sensitivity differences for those parameters, which were affected by TCDD exposure in both rat strains. RESULTS: Bone geometry and bone biomechanical parameters were affected by TCDD exposure, while bone mineral density parameters were less affected. The trabecular area at proximal tibia and the endocortical circumference at tibial diaphysis were the parameters that showed the highest maximal responses. Significant strain differences in response to TCDD treatment were observed, with the L-E rat being the most sensitive strain. For the parameters that were affected in both strains, the differences in sensitivity were quantified, showing the most pronounced (about 49-fold) strain difference for cross-sectional area of proximal tibia. CONCLUSION: The study provides novel information about TCDD-induced bone alterations at doses, which are of relevance from a health risk assessment point of view. In addition, the obtained results provide further support for a distinct role of the AhR in TCDD-induced bone alterations, and suggest that the benchmark dose modeling approach is appropriate for quantitative evaluation of bone toxicity parameters.
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| 3. |
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| 4. |
- Tuomisto, Jouko, et al.
(författare)
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Maternal smoking during pregnancy and testicular cancer in the sons: A nested case-control study and a meta-analysis
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 45:9, s. 1640-1648
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Tidskriftsartikel (refereegranskat)abstract
- Some large ecological studies have noted a significant association of testicular cancer (TC) with maternal smoking during pregnancy, while several more controlled studies have been negative. It has been difficult to obtain reliable data on exposure because of the long lag time to cancer diagnosis. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal smoking in the risk of TC in the offspring. After reviewing the literature, we also performed a meta-analysis of published studies. For each index mother of the TC patient, three to nine matched control mothers with a cancer-free son born at the same time as the TC case were identified within each cohort. First trimester sera were retrieved from the 70 index mothers and 519 control mothers and were tested for cotinine level by a novel HPLC-MS-MS method developed. No statistically significant association between maternal cotinine level and risk of TC in the offspring was found (OR 0.68; 95% CI 0.35, 1.34). This is the first study based on individual exposure measurements. Its results agree with our meta-analysis of seven previous epidemiological studies (total number of 2149 cases, 2762 controls) using indirect exposure assessment (OR 1.0; 95% CI 0.88, 1.12). (c) 2009 Elsevier Ltd. All rights reserved.
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| 5. |
- Van den Berg, Martin, et al.
(författare)
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The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds
- 2006
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Ingår i: Toxicological Sciences. - : Oxford University Press. - 1096-6080 .- 1096-0929. ; 93:2, s. 223-241
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Tidskriftsartikel (refereegranskat)abstract
- In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic" TEFs for blood and adipose tissue and TEQ for body burden.
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