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3 Toxicology
Pages 47-138

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From page 47...
... Toxic effects are influenced by dosage (magnitude and frequency of administration) ; by exposure to other substances, including compounds other than herbicides; by pre-existing health status; and by genetic factors.
From page 48...
... High concentrations usually are required to alter cellular and biochemical processes. In contrast, experimental data reviewed in previous reports led to the conclusion that TCDD elicits a spectrum of toxic effects that vary with exposure level and the age, sex, and species of the animals studied.
From page 49...
... Male and female rats were given different doses of 2,4-D in drinking water and food for 30 days, and kidney tissue was analyzed for residues of 2,4D and 2,4-DCP. Both compounds were found in kidney with all dose regimens,
From page 50...
... Genotoxic Effects and Mechanisms Related to Carcinogenicity Carcinogenicity may occur as a result of mutations (genotoxicity) or epigenetic effects involving promotion of tumor-cell proliferation and tumor growth.
From page 51...
... . Two human prostatic-cancer cell lines were exposed to the chemicals at various doses with or without the AR agonist DHT.
From page 52...
... Reproductive and Developmental Toxicity Previous studies have indicated that 2,4-D is embryotoxic in vivo and that the fetus may be more sensitive than adults to its toxic effects. Since Update 2004, studies continue to indicate that 2,4-D has effects in developing animals, including multiple effects on the developing central nervous system.
From page 53...
... As in the previous study, 9-day-old primaparous female Wistar rats were exposed by intraperitoneal injection to 2,4-D at 70 or 100 mg/kg per day for 14 days (postnatal days 9–22) , and control female rats received carrier.
From page 54...
... Mechanisms Related to Effects on Energy Metabolism or Mitochondrial Function Several reports cited in previous updates suggested that the toxicity of relatively high concentrations of 2,4-D might be related, at least in part, to its effect on calcium homeostasis and energy metabolism. Those effects might be mediated by a direct action on mitochondria.
From page 55...
... Together, the data implicate oxidative stress as a factor in the toxicity of 2,4-D. Gene-Expression Profiling The first expression-profiling study of 2,4-D effects was that of Bharadwaj et al.
From page 56...
... Earlier studies also indicated membrane disruption and possibly oxidative stress as effects of 2,4,5-T. A few studies relevant to mechanisms of toxicity of 2,4,5-T have been published since Update 2004; most of them included assessment of 2,4-D as well as 2,4,5-T, and those studies are discussed in the sections on each of these herbicides.
From page 57...
... . The study examined the effects of 2,4,5-T and 2,4,5-TCP on indexes of oxidative stress in human red blood cells (RBCs)
From page 58...
... UPDATED TOXICITY PROFILE OF CACODYLIC ACID Cacodylic acid, or DMA, and its sodium salt constituted about 30 percent of Agent Blue, one of the mixtures used for defoliation in Vietnam. DMA is a metabolic product of exposure to inorganic arsenic.
From page 59...
... Both DMAIII and DMAV have been shown to induce DNA damage by increasing oxidative stress. Chronic exposure of ddY mice to DMAV at 400 ppm in drinking water increased staining for 4-hydroxy-2-nonenal adducts, which are indicative of oxidative stress, and for 8-oxo-2 -deoxyguanosine (8-oxodG)
From page 60...
... In a recent study, gene-expression profiling of bladder urothelium after chronic exposure to DMAV in the drinking water showed significant increases in genes that regulate apoptosis, the cell cycle, and oxidative stress (Sen et al., 2005)
From page 61...
... based on non-neoplastic changes was 40 ppm in male mice and 8 ppm in female mice; the rat NOEL based on neoplastic and nonneoplastic changes was 10 ppm in both sexes. UPDATED TOXICITY PROFILE OF PICLORAM Picloram (4-amino-3,5,6-trichloropyridine-2-carboxylic acid or 4-amino3,5,6-trichloropicolinic acid)
From page 62...
... Studies in animals have indicated that picloram is sparingly toxic at very high doses. UPDATED TOXICITY PROFILE OF TCDD Toxicokinetics Unlike the herbicides described earlier in this chapter, which tend to be rapidly excreted from the body and do not accumulate to any substantial degree in tissues, TCDD is poorly metabolized and highly lipid-soluble, so it can accumulate in the body and distribute among tissues.
From page 63...
... (2006) demonstrated that distribution of TCDD is highest in adipose, mammary gland, and serum of pregnant mice lacking CYP1A2 expression compared with wildtype mice that show the highest TCDD concentrations in liver.
From page 64...
... Thus, the authors suggest that at low TCDD exposures the diffusion from adipose is the rate-limiting step in TCDD elimination, whereas at higher TCDD exposures metabolic elimination is the rate-limiting step. Human Studies Efforts have continued to identify dietary or other approaches that can enhance the elimination of dioxins, decreasing their uptake and half-life, and previous studies over the last several years have attempted to enhance elimination of TCDD, for example, with activated charcoal, crude dietary fiber, Olestra, and seaweed (reviewed in previous updates)
From page 65...
... They found that the model predicted cumulative serum TCDD concentrations 4–5 times higher than those obtained with the first-order elimination model and an 8.7-year fixed-half-life model. Further use of the PBPK model failed to find a significant relation between untransformed TCDD exposure and cancer response using any lag period, but did identify a positive association between logarithmically transformed TCDD exposure and cancer mortality when a lag period of 1–15 years was applied and when the individuals with the most extreme exposures (i.e., highest 5 percent)
From page 66...
... In summary, the new concentration-dependent PBPK models, which predict that TCDD elimination is considerably faster after high exposure, suggest that (1) previous back-extrapolation of peak serum TCDD concentrations may be significantly underestimated and result in a potential for exposure misclassifications and (2)
From page 67...
... TOXICOLOGY 67 TABLE 3-1 Estimates of TCDD Half-Life in Humans and Animals Confidence Reference Half-Lifea Interval Comment Human Studies Leung et al., 2006 0.4 years Breast-fed infants, 0–1 year PE Aylward et al., 2005a 3 years Calculated for exposures 10,000 pg/g serum lipid 10 years Calculated for exposures 50 pg/g serum lipid Kumagai and Koda, 2005 1.1–2.3 years Adult men, incinerator workers, 0–1.3 years PE Geusau et al., 2002 1.5 yearsb Adult women, severe exposure 0–3 years PE 2.9 yearsb Adult women, severe exposure 0–3 years PE Michalek et al., 2002 0.34 yearsb Adult men, Seveso cohort, 0–3 months PE 6.9 years Adult men, Seveso cohort, 3–16 years PE 9.8 years Adult women, Seveso cohort, 3–16 years PE 7.5 years Adult men, Ranch Hands 9–33 years PE Flesch-Janys et al., 1996 7.2 years Adult men, Boehringer cohort Needham et al., 1994 7.8 years 7.2–9.7 years Adults, Seveso cohort Pirkle et al., 1989 7.1 years 5.8–9.6 years Adult men, Ranch Hands 9–23 years PE Animal Studies Hurst et al., 1998 8 days Rats, Long-Evans, excretion from liver Viluksela et al., 1996 20.2 days Rats, Long-Evans TurkuAB strain 28.9 daysd Rats, Long-Evans Charles River strain DeVito and Birnbaum, 1995 15 days Mice, female B6C3F1 Weber et al., 1993 16.3 3.0 days Rats, male Sprague-Dawley Neubert et al., 1990 73.7 days 60.9–93.8 days Monkeys, Marmoset, single injection Pohjanvirta et al., 1990 21.9 days Rats, male Han/Wistar resistant strain Koshakji et al., 1984 20 days Mice, male ICR/Ha Swiss Gasiewicz et al., 1983 11.0 daysc Mice, C5BL/6J 24.4 daysc Mice, DBA/2J 12.6 daysc Mice, B6D2F1/J ABBREVIATION: PE, postexposure. a Half-lives of TCDD in humans based on measurement of TCDD in serum samples.
From page 68...
... It will be important to continue to refine PBPK models for evaluating tissue distribution in humans. The information on TCDD toxicokinetics is expanding, and new studies are beginning to challege the previous paradigm of a one-compartment, firstorder elimination model to back-extrapolate to earlier exposure estimates.
From page 69...
... The AhR signaling pathway may be viewed as regulating multiple physiologic processes that may not be mutually exclusive, including the adaptive pathway that mediates the metabolism of xenobiotics, such as the polycyclic aromatic hydrocarbons; a toxic pathway that mediates the deleterious effects of xenobiotic exposure; and pathways that regulate developmental and adult cardiovascular homeostasis and adult fertility. The finding that many AhR-regulated genes are modulated in a species-, cell-, and developmental-stage-specific pattern suggests that the molecular and cellular pathways that lead to a particular toxic event are complex.
From page 70...
... that are altered by TCDD exposure are: metabolism of xenobiotics, carbohydrates, glucose, fatty acids, and cholesterol and transport of small molecules (Yueh et al., 2005) ; cell-cycle control [cyclin E1, cyclin G2]
From page 71...
... TABLE 3-2 Overview of TCDD-Induced Changes in Gene Expression as Identified by Microarray Analysis Biological Model Conditions Outcomes Major Pathways Affected Example References Three-day-old 0.5 or 5 nM TCDD-induced Metabolic processes Handleyzebrafish TCDD, expression pericardial Xenobiotic metabolism CYP1A1 Goldstone in heart analyzed edema/circulatory Fatty acid metabolism Acyl-coenzyme A dehydrogenase et al., 2005 after 24 hr impairment Steroid synthesis Sarcomeric components Myosin heavy chain Mitrochondrial energy transfer NADH dehydrogenase Ribosomal machinery Mitochondrial 12S rRNA C57BL/6N 1.5, 3, and 6 g/kg TCDD- Metabolic processes Thackaberry pregnant mice, TCDD, expression induced cardiac Xenobiotic metabolism CYP1A1 et al., 2005a GD 12.5 in hearts at GD tetratogenicity, Carbohydrate metabolism Fbp1 17.5 impaired Organic transporters Abcc3 cardioproliferation Cell cycle (G1/S) Cyclin E1 Extracellular matrix MMP13 C57BL/6 20 g/kg TCDD, TCDD-induced Metabolic processes Fujita et al., pregnant mice, expression in brain decrease in Xenobiotic metabolism CYP1A1 2006 ED 7 at ED 12 neocortical Organogenesis Mab21L2 neurogenesis (Mitsuhashi et al., 2003)
From page 72...
... TABLE 3-2 Continued 72 Biological Model Conditions Outcomes Major Pathways Affected Example References 6–8 wk female 150 and 1500 Gene expression Metabolic processes Puga et al., C57BL/6J ng/kg TCDD, consistently altered Xenobiotic metabolism CYP1B1 2004 mice expression in aorta in both systems Glycolysis Glyoxalase after 40 weeks by TCDD was Insulin signaling Igfbp2 OR emphasized Cell cycle Cyclin G2 Signal transduction/mitogenesis Slp65 Vascular 5 nM TCDD, Membrane channels Scn5a smooth muscle expression after Growth arrest/DNA damage GADD45g cells 8 hr Transcription factors Jmy Immune function Ly4911 Platelet function Clec2 10-wk female 1 and 10 g/kg Metabolic processes Watanabe C57BL/6J TCDD / E2, Xenobiotic CYP1A1 et al., 2005 ovariectomized expression in Fatty acid metabolism Fabp1 uterus after 6 hr Cell structure Connexin 26 Proliferation PCNA Immune function Immunoglobulin heavy chains 28 PND female 30 g/kg TCDD No TCDD-induced TCDD Only Boverhof C57BL/6 / E2 (100 effect on E2 Metabolic processes et al., 2006 mice, ovari- g/kg) , expression induced uterine Xenobiotic metabolism CYP1A1 ectomized in uterus after wet weight, Protein/small molecular transport Kpna6 2–72 hr luminal epithelial Amino acid metabolism Asns cell height or Fatty acid transport/metabolism Lrp2 stromal thickness
From page 73...
... EE TCDD Metabolic processes Amino acid metabolism Asns Small molecule transport Slc 25a5 Proliferation PCNA Signal transduction Inpp5a Protease function Serpinh1 Microtubule structure Dctn2 Transcription factors Rcor3 Rat ovarian 100 pM TCDD, FSH induced Metabolic processes Miyamato, granuloa cells expression after differentiation Xenobiotic metabolism CYP1B1 2004 24 hr Cell cycle Cyclin G Cell structure proteins -actin Cell adhesion Filamin A Ovarian differentiation LH receptor Steroidogenesis P450 scc C3H 10 T1/2 10 nM TCDD IDMB-induced IDMB-induced change inhibited Hanlon cells (mouse treatment during differentiation by TCDD et al., 2005 embryonic adipogenesis, into adipocytes, Metabolic processes fibroblasts) expression after cooperative Oxidation-linked Metabolism Cytosolic epoxide hydrolase 24 hr enhancement with Triglyceride synthesis ADRP the addition of Cholesterol regulation Phospholipid transferase protein EGF Cell structure Extracellular matrix Procollagen VI Proteoglycans Osteoglycin Protease function Plasminogen activator inhibitor 1 Secreted proteins Adiponectin Transcription factors C/EBP Plasma membrane receptors Anion carrier protein 4 Signal transduction ERK3 Cytokines Clustein 73 continued
From page 74...
... treatment with changes in genes not altered by EGF and IDMB IDMB alone Metabolic processes Xenobiotic metabolism CYP1B1 Glucose-linked energy metabolism Phosphoglycerate kinase 1 Iron metabolism Coproporphyrinogen oxidase Cytokines Interleukin receptor type 1 Oxidative stress response Superoxidase dismutase 3 Growth factor signaling Glypican 1 HPL1A 0.1–10 nM TCDD, Metabolic processes Toyoshiba lung airway expression after Xenobiotic metabolism CYP1A1 et al., 2004 epithelial cells 24 hr Fatty acid -oxidation Human peroxisomal acyl-CoA oxidase Retinoic acid transport Cellular retinoic acid binding protein 1 Differentiation Retinoic acid receptor
From page 75...
... 30 PND female 30 g/kg TCDD, liver weight at Metabolic processes Boverhof C57BL/6 mice, expression in liver 24, 72, and 168 hr, Xenobiotic metabolism CYP1A1 et al., 2005 ovariectomized after 2–168 hr apoptosis, immune Fatty acid uptake/Metabolism Apolipoprotein A-1 cell accumulation Glucogenogenesis Gpd2 or at 168 hr Oncogenesis Myc Apoptosis Hip1 0.001–300 g/kg liver weight at Immune function Cd44 TCDD, expression 100 and 300 g/kg, in liver after 24 hr mild to moderate cytoplasmic vacuolization (0.001–.1 g/kg) (lipid accumulation)
From page 76...
... Protein/small molecule transport Slc17a1 total protein, Cell cycle Ccnd1 globulin (40 g/kg, Cell signaling Tgfb1i4 7 day) Immune response Fkb4 hemoglobin (40 Cell structure MPL3 g/kg, 6hr, 24 hr, and 7 day)
From page 77...
... Female Harlan 1–100 ng/kg/day Liver hypertrophy, Metabolic processes Vezina SD rats TCDD, expression multinucleated Xenobiotic metabolism CYP1A1 et al., 2004 in liver after 13 hepatocytes and Oxidative stress Cytochrome c oxidase subunit VIII-H weeks diffuse fatty Cell adhesion C-Cam 4 change in 100 ng Protease function Serpin 7A dose (NTP, 2004a) Immune response Ig non-productively rearranged lamda-chain Cell structure CAP2 Signal transduction iNO synthatase Cell signaling EGF 10-wk male 1,000 g/kg AHR effects independent of Tijet et al., Ahr / or TCDD, expression TCDD 2006 wild-type Ahr in liver after 19 hr Metabolic processes / C57BL/6J Xenobiotic metabolism CYP1A2 mice Steroid metabolism CYP17a1 Glucose metabolism Pck1 Protein/small molecule transport Slc16a5 Protease function Serpina 12 Retinoic acid signaling Retinal binding protein 1 Cell structure Tuba 8 AHR-Dependent effects of TCDD Metabolic processes Xenobiotic metabolism CYP1A1 Immune response TNF 19 Apoptosis Ti-PARP Protease function Serpina 7 Cell structure Tuba 8 77 continued
From page 78...
... Metabolic processes or Xenobiotic metabolism CYP1A1 0.001–300 g/kg Fatty acid synthesis Ptgs 1 TCDD, expression Small molecule transport Slc20a1 in liver after 24 hr Growth arrest/DNA damage GADD45b Cell cycle Cda5 Mitochondrial function Mrp137 Development Cfdp 1 Immune response Irf1 , Tnfaip2 Cell structure Col1a1 TCDD repressed both in vivo and in vitro Metabolic processes Gyk DNA modification Dnmt 1 Proliferation Tk1 TCDD induced in vivo and repressed in vitro CO2 hydration Carbonic anhydrase 2 Fatty acid signaling Fabp5 Growth arrest/DNA damage GADD45gip1 Oncogenesis Myc TCDD repressed in vivo and induced in vitro Small molecule transport Slco Ib2 Immune function Btg2
From page 79...
... TCDD-elicited gene expression responses unique to C57BL/6 hepatic tissue Metabolic processes Xenobiotic metabolism Gsta2 Fatty acid metabolism Elovl5 Glucose metabolism Gpd2 CO2 hydration Car3 Growth arrest Gas1 Development Notch1 Immune response Cd3d Mouse 10 nM TCDD, hepatoma cells expression after (Hepa1c1c7 1–48 hr wild-type and or c4 ARNT- 0.001 nM–100 deficient) nM, expression after 168 hr Mouse Basal conditions Differences in Relative to wild-type Fong et al., hepatoma cells, morphology and Cell structure/cytoskeleton 2005 Hepa1c1c7 proliferation C1 Anxa7 (c1, CYP1A1 (c1 WT c4,c12)
From page 80...
... TABLE 3-2 Continued 80 Biological Model Conditions Outcomes Major Pathways Affected Example References Bioenergetics C1 Nadufv C4 Cox6b Ndufs2 C12 Cox8a Proliferation C1 Banf1 Lyar tgfb1i4 C4 Degs Oaz1 C12 Arg2 Cdkn1a Ranbp1 Human 50 nM TCDD, Metabolic processes CYP1A1 Kim et al., hepatoma cell expression after Proliferation JUN 2006 lines, Hep3B 1–4 hr Signal transduction SOS1 and HepG2 Development TBX3 Long-Evans 100 g/kg TCDD, TCDD modulated AHRE-II genes and Sprague expression in liver Metabolic processes Dawley rats after 3 and 19 hr Xenobiotic metabolism CYP2b19 Cell signaling Tgf 3 Proteosome function Proteasome type5 Circadian rhythm Period 2 Ribosomal proteins Rib L 29
From page 81...
... expression Hypothetical protein: high homology with NADH in liver and ubituinone oxidoreductase, 42 kDa subunit ovary in Ovary (p < 0.05) 1-day-old 60 kDa heat shock protein chicks Regucalcin continued
From page 82...
... , mitochondrial precursor Ribosomal proteins 60 S ribosomal protein L7a Elongation factors Eukaryotic translation initiation factor 4B Nucleolus biogenesis Nucleophosmin (B23) Glycolysis Mitochondrial hexokinase I Xenobiotic metabolism Aldehyde dehydrogenase
From page 83...
... effects of TCDD. Additional transcription factors that have been recently reported to interact with the AhR include SMRT (Widerak et al., 2006)
From page 84...
... In the lung, AhR expression has recently been shown to be higher in bronchiolar Clara cells than in the progenitor human small-airway epithelial cells (Chang et al., 2006)
From page 85...
... . Effect of Pharmacologic Agents, Dietary Factors, and Environmental Exposures on the AhR and TCDD's Adverse Effects It is predicted that coexposure to agents that act as AhR agonists or AhR antagonists that may be encountered pharmacologically, via the diet, and in the environment may modulate a person's response to TCDD.
From page 86...
... Recently, it has been shown that although 2-(1 H-indole-3 -carbonyl) -thiazole-4-carboxylic acid methyl ester can act as a potent AhR agonist both in vitro and in vivo, it failed to incur adverse effects typically associated with TCDD exposure, that is, cleftpalate formation, hydronephrosis, and thymic atrophy (Henry et al., 2006)
From page 87...
... that examined the ligand-binding capabilities of the human AhR compared with that obtained from the mAhRd and mAhRb-1 are consistent with that statement and show that the mAhRd and mAhRb-1 have 2 and 10 times the relative binding affinity of the human AhR, respectively. That the species-specific effects of TCDD toxicity are due largely to differences in amino acid composition was also recently confirmed in a study of avian species, which display one of the most dramatic differences in sensitivity to TCDD (Karchner et al., 2006)
From page 88...
... Although the exact biologic mechanisms of those endpoints and the observed differences are not yet understood, recent data show the possibility that at least some of the effects are mediated by TCDD's ability, through the AhR, to modulate cell-cycle control, signaling pathways that lead to cell death or inappropriate cell activation, hormones and growth factors and the responses to them, or the biochemical pathways that lead to oxidative stress. Those mechanisms are implicated in many of the toxic endpoints discussed below.
From page 89...
... A microarray study performed with liver mRNA isolated from male rats treated with a relatively high dose of TCDD supports the idea that TCDD alters cell adhesion and demonstrated that in the liver TCDD exposure results in major deregulation of cholesterol metabolism and bile acid synthesis and transport (Fletcher et al., 2005a)
From page 90...
... A number of recent animal studies confirm the effects of developmental TCDD exposure on tooth development. Offspring of female mink exposed in utero and via lactation to dioxin, dioxin-like chemicals, and non-dioxin-like chemicals (including non-dioxin-like PCBs and polybrominated diphenyl ethers)
From page 91...
... In a third study, global gene-expression profiling after TCDD exposure of mouse aorta in vivo or cultured vascular smooth muscle cells in vitro showed that more than 4,500 genes differed in expression between the two models but that a subset of 35 genes showed similar responses to dioxin exposure (Puga et al., 2004)
From page 92...
... . Several published reports have suggested an association between TCDD exposure and chronic obstructive pulmonary disease, but the present committee found insufficient evidence to support a relationship between herbicide exposure and respiratory disorders that are not considered cancer, noting the lack of toxicity to the pulmonary system in laboratory animals exposed acutely to low doses (1–10 g/kg)
From page 93...
... The authors suggest that Clara cells may be the most sensitive lung-cell type responsive to TCDD. Previous toxicogenomic studies identified EGR1 as a potential novel target for TCDD and other AhR agonists in human lung epithelial cells (IOM, 2005)
From page 94...
... (2005) examined oxidative stress in mouse liver after one dose of TCDD (5 /kg body weight)
From page 95...
... (2005b) examined the effects of long-term low-dose TCDD exposure on retinoid, thyroid hormone, and vitamin D homeostasis in Long-Evans and Han/ Wistar rats, given a tumor initiation regimen.
From page 96...
... neurons in the substantia nigra and movement defects. Oxidative stress has been implicated in the pathogenesis of PD based on its role in the cascade of biochemical changes that lead to DA neuronal death.
From page 97...
... The study suggests that granule neuroblasts are direct targets for developmental AhRmediated TCDD neurotoxicity and that TCDD exposure may disrupt granule cell neurogenesis.
From page 98...
... Studies published since Update 2004 have investigated the effects of TCDD exposure on the thymus. Nottebrock et al.
From page 99...
... However, the expression of several other genes associated with cell survival or death was increased in the T cells by TCDD exposure. Many of the upregulated genes belong to the
From page 100...
... NFkB signaling in B cells is also affected by TCDD exposure. Recent studies indicate that the dioxinresponse element overlaps with an NFkB-response element in the enhancer region of the gene for immunoglobulin heavy chain.
From page 101...
... . Further evidence that TCDD exposure may contribute to the formation of squamous-cell carcinoma is provided by a study performed by Wyde et al.
From page 102...
... Although it is apparent that TCDD can participate in genotoxic events by inducing such enzymes as CYP1A1, CYP1A2, and CYP1B1 -- which are responsible for the metabolic activation of many promutagens, increasing oxidative stress and increasing DNA methylation of tumor-suppressor genes (Ray and Swanson, 2004; Wu et al., 2004) -- a large body of evidence indicates that TCDD's carcinogenic actions occur primarily by nongenotoxic means that would facilitate a damaged cell's progression through Weinberg's six requisite changes (Table 3-4)
From page 103...
... . In vivo evidence that TCDD exposure may lead to chromosomal abnormalities was found in studies of sheep flocks that reside in the provinces of Naples and Caserta, Italy (Perucatti et al., 2006)
From page 104...
... However, the effect of TCDD on cell proliferation may be cell-dependent or dose-dependent inasmuch as TCDD has also been reported to increase proliferation of nontumorigenic human breast luminal epithelial cells (Ahn et al., 2005)
From page 105...
... and other genes involved in vascularization. The degree to which CYP1A1 induction or oxidative stress in the vascular endothelium contributes to inhibition of angiogenesis remains unclear.
From page 106...
... gene was expressed exclusively in murine testis and that its expression was suppressed by TCDD exposure.
From page 107...
... characterized the regulation of AhR expression in rat granulosa cells by the endogenous hormones follicle-stimulating hormone and estradiol and by the exogenous AhR ligand -naphthaflavone. Both folliclestimulating hormone and estradiol reduced AhR protein and mRNA expression in a time-dependent manner, and -naphthaflavone induced a rapid decrease in AhR protein via proteasomal degradation but also induced a delayed increase in AhR mRNA after prolonged exposure.
From page 108...
... (2006) reported that a single TCDD exposure of female rats before puberty delayed the onset of puberty and induced premature reproductive senescence; life-long TCDD exposure resulted in a loss of cyclicity and accelerated the transition to reproductive senescence.
From page 109...
... (2005) showed that TCDD exposure of normal human endometrial stromal cells significantly reduced the ratio of the expression of progesterone receptor B (PR-B)
From page 110...
... . TCDD exposure of primary porcine thymocytes significantly downregulated mRNA expression of the sodium iodide symporter, which is required for accumulation of iodide in the thyroid, and cathepsin B, which is required for proteolysis of thyroglobulin and release of thyroid hormones from the thyroid gland.
From page 111...
... Further study has shown that reduced angiogenesis in the chick embryo after TCDD exposure is associated with reduced secretion of VEGF and reduced responsiveness of endothelial cells to angiogenic stimuli (Ivnitski-Stele et al., 2005)
From page 112...
... Electrocardiographic (ECG) recordings in chick embryos in ovo after TCDD exposure showed an increased incidence of arrhythmias, normal basal heart rate, and decreased responsiveness to -adrenergic-stimulated tachycardia (Sommer et al., 2005)
From page 113...
... In another study, in utero and lactational TCDD exposure of rats reduced ventral prostate weight without affecting the weight of other male reproductive organs or reducing sperm number. However, when the TCDD-exposed male offspring were mated to unexposed females, the percentage of male pups in F2 generation (38/100, 38 percent)
From page 114...
... reported that perinatal TCDD exposure decreased neuron number and reduced or reversed sexual dimorphic brain development, and these changes were associated with altered sexual behavior and learning. Recent studies confirm and extend those observations.
From page 115...
... Altered brain development after perinatal TCDD exposure was associated with other behavioral changes later in life. Rainbow trout swim-up fry that had been exposed to TCDD as newly fertilized eggs exhibited decreased densities of retinal ganglion and corresponding deficits in visual and motor function that resulted in decreased prey-capture rate (Carvalho and Tillitt, 2004)
From page 116...
... (2006) studied the effects of perinatal TCDD exposure of C57BL/6 mice on immune
From page 117...
... 2003. Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells.
From page 118...
... 2004. Recruitment of thyroid hormone receptor/retinoblastoma-interacting protein 230 by the aryl hydrocarbon receptor nuclear translocator is required for the transcriptional response to both dioxin and hypoxia.
From page 119...
... 2004. 2,3,7,8-Tetrachlorodibenzo-p-dioxin activation of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator pathway causes developmental toxicity through a CYP1A-independent mechanism in zebrafish.
From page 120...
... 2006. TCDD exposure response analysis and risk assessment.
From page 121...
... 1997. Lesions of aryl-hydrocarbon receptor-deficient mice.
From page 122...
... 2004. Presence and functional activ ity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes.
From page 123...
... 2006. Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide.
From page 124...
... 2006. The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen.
From page 125...
... 2004. A constitutively active arylhydrocarbon receptor induces growth inhibition of jurkat T cells through changes in the expression of genes related to apoptosis and cell cycle arrest.
From page 126...
... despite the identical primary structure of the aryl hydrocarbon receptor. Toxicology and Applied Pharmacology 212(3)
From page 127...
... 2004. Histomorphometric alteration and cell-type specific modulation of arylhydrocarbon receptor and estrogen receptor expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in mouse experimental model of endometriosis.
From page 128...
... 2005. The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis.
From page 129...
... 2005. Effects of in utero and lactational TCDD exposure on bone development in differen tially sensitive rat lines.
From page 130...
... 2004. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice.
From page 131...
... 2005. Constitutively active aryl hydrocarbon receptor expressed spe cifically in T-lineage cells causes thymus involution and suppresses the immunization-induced increase in splenocytes.
From page 132...
... 2004. Phosphorylation analysis of 90 kDa heat shock protein within the cytosolic arylhydrocarbon receptor complex.
From page 133...
... 2002. Role of the aryl hydrocarbon receptor in cell cycle regulation.
From page 134...
... 2005. Association of micrope nis with pro185Ala polymorphism of the gene for aryl hydrocarbon receptor repressor involved in dioxin signaling.
From page 135...
... 2005. Induction and activation of the aryl hydrocarbon receptor by IL-4 in B cells.
From page 136...
... c ˇ r 2005. Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.
From page 137...
... 2005. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: Implications for development and dioxin neurotoxic ity.
From page 138...
... 2005. The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells.


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