Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, alpha-2-HS-glycoprotein alpha and beta chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, alpha-2-macroglobulin precursor, prothymosin alpha and alpha-fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TRalpha1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T(3)) induced time- and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TRalpha1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.
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PMID:Plasma protein regulation by thyroid hormone. 1465 6

Thyroid hormone (T(3)) regulates growth, development, and differentiation. These activities are mediated by the nuclear thyroid hormone receptors (TRs), which belong to the steroid/TR superfamily of ligand-dependent transcription factors. The effect of T(3) treatment on target gene regulation was investigated in a TRalpha-overexpressing hepatoma cell line (HepG2-TRalpha), by performing cDNA microarrays. We demonstrate that 148 of the 7597 genes represented were up-regulated by T(3), including fibrinogen and several other components of the coagulation factor system. To confirm the microarray results, fibrinogen and a small number of the blood clotting components were further investigated using quantitative RT-PCR. The T(3)-induction ratios observed with quantitative RT-PCR for factors such as thrombin (8-fold), coagulation factor X (4.9-fold), and hepatoglobin (30-fold) were similar to those observed by the cDNA microarray analysis. Further investigation, using HepG2-TRalpha (cell lines, revealed a 2- to 3-fold induction of fibrinogen transcription after 24 h of T(3) treatment. In addition, T(3) treatment increased the level of fibrinogen protein expression 2.5- to 6-fold at 48 h. The protein synthesis inhibitor, cycloheximide, did not inhibit the induction of fibrinogen by T(3), indicating that this regulation was direct. Furthermore, transcription run-on experiments indicate that the induction of fibrinogen by T(3) is regulated largely at the level of transcription. Similar observations were made on the regulation of fibrinogen by T(3) using rats that received surgical thyroidectomy (TX) as an in vivo model. These results suggest that T(3) plays an important role in the process of blood coagulation and inflammation and may contribute to the understanding of the association between thyroid diseases and the misregulation of the inflammatory and clotting profile evident in the circulatory system of these patients.
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PMID:Thyroid hormone receptor-dependent transcriptional regulation of fibrinogen and coagulation proteins. 1497 60

Oxygen is of vital importance for the metabolism and function of all cells in the human body. Hypoxia, the reduction of oxygen supply, results in adaptationally appropriate alterations in gene expression through the activation of hypoxia-inducible factor 1 (HIF-1) to overcome any shortage of oxygen. Thyroid hormones are required for normal function of nearly all tissues, with major effects on oxygen consumption and metabolic rate. Thyroid hormones have been found to augment the oxygen capacity of the blood by increasing the production of erythropoietin (EPO) and to improve perfusion by vasodilation through the augmented expression of adrenomedullin (ADM). Because the hypoxic expression of both genes depends on HIF-1, we studied the influence of thyroid hormone on HIF-1 activation in the human hepatoma cell line HepG2 under normoxic and hypoxic conditions. We found that thyroid hormones increased HIF-1alpha protein accumulation by increasing HIF-1alpha protein synthesis rather than attenuating its proteasomal degradation. HIF-1alpha expression directly correlated with augmented HIF-1 DNA binding and transcriptional activity of luciferase reporter plasmids, whereas HIF-1beta levels remained unaffected. Knocking down HIF-1alpha by short interfering RNA (siRNA) clearly demonstrated that thyroid hormone-induced target gene expression required the presence of HIF-1. Although an increased association of the two known coactivators of HIF-1, p300 and SRC-1, was found, thyroid hormone did not affect the activity of the isolated COOH-terminal transactivating domain of HIF-1alpha. Increased synthesis of HIF-1alpha may contribute to the adaptive response of increased oxygen demand under hyperthyroid conditions.
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PMID:Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxia-inducible factor-1. 1515 77

Thyroid hormones regulate growth, development, differentiation, and metabolic processes by interacting with and activating thyroid hormone receptors and associated pathways. We investigated the triiodothyronine (T3) modulation of gene expression, in human hepatocellular carcinoma cell lines, via a PCR-based cDNA subtraction method. Here we present further data on one of the T3-upregulated genes, fibronectin (FN). We demonstrate that the induction of FN protein expression by T3 in TRalpha1 and TRbeta1 over-expressing cells was time and dose-dependent at the mRNA and protein levels. Blockade of protein synthesis by cycloheximide almost completely inhibited the concomitant induction of FN mRNA by T3, indicating that T3 indirectly regulates FN. Furthermore, nuclear-run on and FN promoter assay clearly can specifically increase the number of FN transcriptional demonstrated that the presence of T3 initiations. In addition, we further confirmed that the up-regulation of FN by T3 was mediated, at least in part, by transforming growth factor-beta (TGF-beta), because the induction of FN was blocked in a dose-dependent manner by the addition of TGF-beta neutralizing antibody. In an effort to elucidate the we demonstrated the involvement of the signaling pathways involved in the activation of FN by T3, mitogen activated protein kinase/c-Jun N-terminal kinase/p38 MAPK (MAPK/JNK/p38) pathway. Although T3 induces the expression of TGF-beta, neither wild-type nor dominant-negative Smad3 or Smad4 over-expression affected the activation of FN by T3. Thus, we demonstrate that T3 regulates FN gene expression indirectly at the transcriptional level, with the participation of the MAPK/JNK/p38 pathway and the TGF-beta signaling pathway but independent of Smad3/4.
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PMID:Regulation of fibronectin by thyroid hormone receptors. 1552

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that regulate the transcription of multiple thyroid hormone (TH)-responsive genes. Our study aimed to identify TH-responsive genes in an estrogen-responsive chicken hepatoma cell line, LMH. RNA was prepared from cells treated with or without 10(-8) M 3,3',5-triiodothyronine (T3) for 24 h and was analyzed by differential display. At least six cDNAs were detected whose transcript increased in the presence of T3, and four of them were cloned. The four candidate TH-responsive genes that were identified had high similarity (>83%) to known chicken or mammalian genes, which included the ribosomal protein L7 gene; the cytoplasmic dynein heavy chain gene; the scaffold attachment factor A (SAF-A) gene, also known as heterogeneous nuclear ribonucleoprotein U (hnRNP U); and a gene for an unknown protein. Real-time PCR confirmed that the transcription of the four genes was responsive to T3; their transcript levels increased from four to eleven times with the administration of T3. The amount of TRbeta transcript did not change with the administration of T3. The physiological reasons for the activation of these genes and the utility of this cell line are discussed.
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PMID:Identification of thyroid hormone-responsive genes in a chicken hepatoma cell line, LMH. 1628 25

Thyroid hormone (triiodothyronine, T3) regulates growth, development and differentiation. To examine the influence of T3 on hepatoma cell growth, thyroid receptor (TR)alpha1 or TRbeta1 over-expressing HepG2 cell lines were used. Growth of the HepG2-TR stable cell line was inhibited by over 50% following treatment with T3. However, transforming growth factor (TGF)-beta neutralizing antibody, but not the control antibody can reverse the cell growth inhibition effect of T3. Flow cytometric analysis indicated that the growth inhibition was apparent at the transition point between the G1 and S phases of the cell cycle. The expression of major cell cycle regulators was used to provide further evidence for the growth inhibition. Cyclin-dependent kinase 2 (cdk2) and cyclin E were down-regulated in HepG2-TR cells. Moreover, p21 protein or mRNA levels were up-regulated by around 5-fold or 7.3-fold respectively following T3 treatment. Furthermore, phospho-retinoblastoma (ppRb) protein was down-regulated by T3. The expression of TGF-beta was studied to delineate the repression mechanism. TGF-beta was stimulated by T3 and its promoter activity was enhanced six- to eight-fold by T3. Furthermore, both T3 and TGF-beta repressed the expression of cdk2, cyclin E and ppRb. On the other hand, TGF-beta neutralizing but not control antibody blocked the repression of cdk2, cyclin E and ppRb by T3. These results demonstrated that T3 might play a key role in liver tumor cell proliferation.
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PMID:Mediation of the inhibitory effect of thyroid hormone on proliferation of hepatoma cells by transforming growth factor-beta. 1646 23

Thyroid hormone, T(3), regulates cell metabolism, differentiation, and development. cDNA microarrays were performed to study the mechanism of target gene regulation after T(3) treatment in a thyroid hormone receptor-alpha (TRalpha)-overexpressing hepatoma cell line (HepG2-TRalpha). The differentially expressed target genes are several metabolic enzymes, including dehydroepiandrosterone-sulfotransferase family 1A member 2 (SULT2A1). Enzyme SULT2A1 was elevated roughly 5-fold at the protein level and 9-fold increase at the mRNA level after 48 h T(3) treatment in HepG2-TRalpha cells. Cycloheximide inhibited T(3)-induced SULT2A1 expression, suggesting that regulation was indirect. SULT2A1 has been reported to be regulated by the two transcription factors, steroidogenic factor 1 (SF1) and GATA, in the human adrenal gland. T(3) induced a 2.5- to 3.5-fold elevation of SF1 at the protein level and a 6.2-fold increase at the RNA level in HepG2-TRalpha cells. About seven SF1 binding sites exist on the SULT2A1 gene. To identify and localize the critical SF1 binding site, series of deletion mutants of SULT2A1 promoter fragments in pGL2 plasmid were constructed. The promoter activity of the SULT2A1 gene was enhanced about 2.8- to 7.1-fold by T(3). The -228 SF1 binding site was identified as the most critical site because deleting this region reduced T(3)-induced expression. Transcription factor SF1 application enhanced the -228 but not -117 reporter plasmid activities. SULT2A1 and SF1 up-regulation at protein and RNA levels in thyroidectomized rats occurred after T(3) application. In summary, this work demonstrated that the SULT2A1 gene was mediated by SF1 and indirectly regulated by T(3). Further study is required to elucidate the physiological importance of SULT2A1 induction mediated by T(3).
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PMID:Indirect regulation of human dehydroepiandrosterone sulfotransferase family 1A member 2 by thyroid hormones. 1646 13

DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bio-concentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in body tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2-YEAR STUDY: The 2-year study of a binary mixture of PCB 126 and PCB 153 was designed to assess the carcinogenicity of a constant ratio mixture of PCB 126 and PCB 153. In addition, varying ratio mixture groups were used to assess the impact of increasing PCB 153 on the carcinogenicity of PCB 126. Dose groups were divided into two study arms (Figure 1). TCDD equivalent (TEQ) doses are based on the PCB 126 doses after adjustment for the PCB 126 TEF of 0.1. Groups of 81 (Groups 2, 3, 5, and 7) or 80 (Groups 4 and 6) female rats received a mixture of PCB 126 and PCB 153 in corn oil:acetone (99:1) by gavage 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle only and served as the vehicle control (Group 1). Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of Groups 4 and 5 were generally less than those of the vehicle controls after week 25. The mean body weights of Group 6 were less after week 12, and those of Group 7 were less after week 8. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. In the constant ratio groups, serum total thyroxine (T(4)) and free T(4) generally showed a treatment-related decrease relative to controls. Serum total triiodothyronine (T(3)) exhibited a treatment-related increase at the 14-, 31-, and 53-week interim evaluations, but serum thyroid stimulating hormone (TSH) levels were increased at the 14-week time point only. In the varying ratio groups, the decrease in total and free T(4) was more pronounced in those groups dosed with the increasing proportion of PCB 153 at the 31- and 53-week time points. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. At 31 and 53 weeks, a significant increase in the hepatocellular labeling index occurred in Group 7. In the varying ratio groups, the labeling index at the 53-week interim time point was significantly higher in Group 6, which had the highest proportion of PCB 153 compared to the other varying ratio groups. Cytochrome P450 Enzyme Activities: To evaluate the expression of known PCB 126-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, PCB 153-inducible CYP2B-associated 7-pent-oxyresorufin-O-dealkylase (PROD) activity was analyzed. In the constant ratio Groups 2, 3, 5, and 7, hepatic and pulmonary EROD (CYP1A1) activities, hepatic A4H (CYP1A2) activities, and hepatic PROD (CYP2B) activities were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. In the varying ratio groups, hepatic EROD, A4H, and PROD activities at 14 weeks were higher in groups receiving a greater proportion of PCB 153 in the PCB mixture. At 31 and 53 weeks, hepatic CYP1A1 and CYP1A2 enzyme activities in Group 6 were generally lower than in Groups 4 and 5. Determinations of PCB 126 and PCB 153 Concentrations in Tissues: Concentrations of PCB 126 and PCB 153 were determined in fat, liver, lung, and blood at the 14-, 31-, and 53-week interim evaluations and at the end of the 2-year study (105 weeks). PCB 126 was not detectable in vehicle control animals, but increased with increasing dose of PCB 126 and duration of exposure; the highest concentrations were found in liver and fat, and lower levels were seen in lung and blood. Increasing the proportion of PCB 153 in the mixture relative to PCB 126 led to a general decrease in the amount of PCB 126 in liver and lung at the later time points, whereas in fat and blood, there was generally either no effect of PCB 153 on the disposition of PCB 126, or there was an increase in the amount of PCB 126 in the tissue. In vehicle control animals, PCB 153 was detectable in the fat at all time points, in the lung at all time points except 53 weeks, and in the liver and blood at 2 years. PCB 153 was measurable in all examined tissues of treated animals, with the highest concentrations found in fat at the end of the 2-year study in groups administered the highest doses of PCB 153. Pathology and Statistical Analyses -- Constant Ratio Mixture of PCB 126 and PCB 153: At 14, 31, and 53 weeks, the absolute and relative liver weights of all dosed groups were generally greater than those of the vehicle controls. Exposure to the PCB mixture led to significant toxicity in the liver. At 14 weeks, the incidences of several nonneoplastic liver lesions were increased compared to the vehicle controls including hepatocyte hypertrophy, pigmentation, multinucleated hepatocytes, and diffuse fatty change. The spectrum and severity of effects increased with dose and duration of exposure. At the end of the 2-year study, there were significantly increased incidences and severities of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, diffuse and focal fatty change, eosinophilic focus, nodular hyperplasia, cholangiofibrosis, oval cell hyperplasia, bile duct cysts, bile duct hyperplasia, necrosis, and portal fibrosis. Significantly increased incidences of hepatocellular adenoma, cholangiocarcinoma, and hepatocholangioma were observed in the study. In addition, two animals in the highest dose group had hepatocellular carcinoma. The incidences of these lesions generally exceeded the historical vehicle control ranges. At 2 years, a significantly increased incidence of cystic keratinizing epithelioma of the lung was observed in Group 7. In addition, single occurrences of squamous cell carcinoma were seen in the top two dose groups. Nonneoplastic effects whose incidences were increased in the lung included bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia. Significantly increased incidences of squamous cell carcinoma (gingival) of the oral mucosa were seen at the end of the 2-year study and were accompanied by increased incidences of gingival squamous hyperplasia. In the pancreas at 53 weeks, the incidence of acinar cytoplasmic vacuolization was significantly increased in the highest dose group. At 2 years, increased incidences of acinar atrophy and acinar cytoplasmic vacuolization were seen in addition to pancreatic acinar neoplasms in dosed groups. In Groups 5 and 7, these incidences exceeded the historical vehicle control ranges. In the uterus at 2 years, there was a marginal increase in the incidence of squamous cell carcinoma in Group 5. Numerous nonneoplastic effects were seen in other organs at the interim time points including atrophy of the thymus and follicular cell hypertrophy of the thyroid gland. These responses were also affected by administration of the mixture of PCB 126 and PCB 153 at the end of the 2-year study and were accompanied by additional nonneoplastic responses in numerous organs including atrophy of the adrenal cortex and cortical hyperplasia, severity of nephropathy, and incidences of pigmentation of the kidney. Other nonneoplastic lesions that were treatment related were forestomach hyperplasia, hyperplasia of the nasal respiratory epithelium, metaplasia of the olfactory epithelium, and ectasia of the mandibular lymph node. Varying Ratio Mixture of PCB 126 and PCB 153: An effect of increasing the proportion of PCB 153 in the PCB mixture was seen in several tissues, most notably in the liver. Treatment-related nonneoplastic effects seen across the varying ratio groups were generally the same as those seen in the constant ratio groups. In general there was a positive effect of PCB 153 in the mixture on the incidences and severities of these lesions with higher incidences and higher severities being seen in Group 6, which had the highest proportion of PCB 153. (ABSTRACT TRUNCATED).
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PMID:Toxicology and carcinogenesis studies of a binary mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (gavage studies). 1716 Jan 4

DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. Mixtures of polychlorinated biphenyls (PCBs) including 3,3',4,4',5-pentachlorobiphenyl (PCB 126) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) were produced commercially before 1977 for the electric industry as dielectric insulating fluids for transformers and capacitors. Manufacture and use of these chemicals were stopped because of increased PCB residues in the environment, but they continue to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, during combustion of some waste materials, and during atmospheric recycling. This PCB mixture study was conducted as part of the dioxin TEF evaluation that includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. This study was originally a study of PCB 118 alone. However, midway through the study PCB 126 was identified as one of the minor contaminants (0.622%) of the bulk PCB 118 (98.5% pure). Given the 1,000-fold higher potency of PCB 126 for inducing dioxin-like effects (based on the TEFs for PCB 126 and PCB 118 of 0.1 and 0.0001, respectively), it was expected that the effects of administration of this compound would be due to the combined dioxin-like effects of both PCB 126 and PCB 118. Therefore, this study was reclassified as a mixture study of PCB 126 and PCB 118. 2-YEAR STUDY: Groups of female Harlan Sprague-Dawley rats were administered the PCB mixture containing PCB 126 and PCB 118 by gavage in corn oil:acetone (99:1) or vehicle alone, 5 days per week for up to 104 weeks. Dose groups are referred to by the total levels of TCDD toxic equivalents (TEQ) provided by the PCBs in the mixture in each dose group. Groups of 81 female rats were administered 7, 22, 72, or 216 ng TEQ/kg; a group of 86 female rats was administered 360 ng TEQ/kg; and a group of 81 female rats was administered the corn oil:acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. No animals in the 360 ng TEQ/kg group were examined at 53 weeks. A group of 50 female rats was administered 360 ng TEQ/kg for 30 weeks and then the vehicle alone for the remainder of the study. Nominal doses of PCB 118 and levels of PCB 126 in each dose group used were: 7 ng TEQ/kg dose group: 62 ng/kg PCB 126 and 10 microg/kg PCB 118 7 ng TEQ/kg dose group: 62 ng/kg PCB 126 and 10 microg/kg PCB 118 22 ng TEQ/kg dose group: 187 ng/kg PCB 126 and 30 microg/kg PCB 118 72 ng TEQ/kg dose group: 622 ng/kg PCB 126 and 100 microg/kg PCB 118 216 ng TEQ/kg dose group: 1,866 ng/kg PCB 126 and 300 microg/kg PCB 118 360 ng TEQ/kg dose group: 3,110 ng/kg PCB 126 and 500 microg/kg PCB 118 No animals in the 216 or 360 ng TEQ/kg core study groups survived to the end of the study, and survival in the 360 ng TEQ/kg stop-exposure group was significantly less than in the vehicle control group. Mean body weights of 72 ng TEQ/kg rats were less than those of the vehicle controls after week 33 of the study, and mean body weights of the 216 and 360 ng TEQ/kg core study rats and the 360 ng TEQ/kg stop-exposure group rats were less than those of the vehicle controls throughout most of the study. Clinical findings related to the administration of the binary mixture of PCB 126 and PCB 118 included abnormal breathing, thinness, and ruffled hair. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. Total thyroxine (T4) and free T4 were significantly lower in most dose groups than in vehicle controls at the 14- and 31-week interim evaluations. Serum T3 was significantly lower in the 360 ng TEQ/kg group compared to vehicle controls at 31 weeks only. TSH levels were higher in the 216 and 360 ng TEQ/kg groups than in vehicle controls at 31 weeks only. Hepatic Cell Proliferation Data To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. Labeling indices were elevated at doses above 216 ng TEQ/kg at 31 weeks and at doses above 72 ng TEQ/kg at 53 weeks. Cytochrome P450 Enzyme Activities: CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations to evaluate the expression of known dioxin-responsive genes. In addition, CYP2B-associated pentoxyresorufin-O-deethylase (PROD) activity was also analyzed. Hepatic and pulmonary EROD (CYP1A1) activity, hepatic A4H (CYP1A2) activity, and hepatic PROD (CYP2B1) activity were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. Determinations of PCB 126 and PCB 118 Concentrations in Tissues: The tissue disposition of PCB 126 and PCB 118 was analyzed in the liver, lung, fat, and blood of up to 10 rats in each group at the 14-, 31-, and 53-week interim evaluations, except for the 360 ng TEQ/kg group at 53 weeks. The tissue disposition of PCB 126 and PCB 118 was also analyzed in 10 rats per group at the end of the 2-year study in the vehicle control, 7, 22, and 72 ng TEQ/kg core study groups and the 360 ng TEQ/kg stop-exposure group. Detectable concentrations of PCB 126 and PCB 118 were observed in the liver, fat, lung, and blood. The highest levels of PCB 126 were seen in the liver whereas the highest levels of PCB 118 were seen in the fat. In general, tissue concentrations increased with increasing doses of the mixture and increasing duration of exposure. Hepatic levels of PCB 126 and PCB 118 in the 72 ng TEQ/kg group at the end of the 2-year study were 284 ng/g and 3,769 ng/g, respectively. On a TCDD equivalents basis this corresponds to 28 ng TEQ/g and 0.4 ng TEQ/g for PCB 126 and PCB 118, respectively. Cessation of administration of the mixture in the stop-exposure group led to declines in the tissue concentrations of both PCB 126 and PCB 118 to levels comparable to those observed in the 7 ng TEQ/kg group at the end of the 2-year study. Pathology and Statistical Analyses: At 14, 31, and 53 weeks, liver weights were significantly increased in treated groups with more pronounced effects occurring in the higher dose groups. At 14 weeks, hepatocyte hypertrophy and pigmentation were seen at doses less than 72 ng TEQ/kg. Exposure to the PCB mixture led to significant toxicity in the liver. At higher doses, the incidences of toxic hepatopathy were increased as indicated by increased incidences of multinucleated hepatocytes and diffuse fatty change. At 31 weeks, most rats in the 216 and 360 ng TEQ/kg groups had multiple hepatic nonneoplastic lesions. At 53 weeks all animals administered 216 ng TEQ/kg had multiple nonneoplastic lesions. The spectrum of effects and the severity of effects at the interim and 2-year time points increased with dose and duration of exposure. At the end of the 2-year study in all dosed groups, there were significantly increased incidences and severity of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, toxic hepatopathy, diffuse fatty change, nodular hyperplasia, centrilobular fibrosis, cholangiofibrosis, oval cell hyperplasia, bile duct cyst, bile duct hyperplasia, and portal fibrosis. There were also increased incidences of hepatocyte glandular structures, necrosis, centrilobular degeneration, eosinophilic focus, and metaplasia. The incidences of cholangiocarcinoma (multiple and/or single) were significantly increased in groups administered 22 ng TEQ/kg or greater at 2 years. The incidences of hepatocellular adenoma were also significantly increased in the 216 and 360 ng TEQ/kg core study groups. In addition, single occurrences of hepatocholangioma, cholangioma, or hepatocellular carcinoma were observed in some dosed groups administered 72 ng TEQ/kg or greater. In the lung at 53 weeks, the incidences of cystic keratinizing epithelioma and bronchiolar metaplasia were significantly increased in the 216 ng TEQ/kg group. (ABSTRACT TRUNCATED).
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PMID:Toxicology and carcinogenesis studies of a binary mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) (Cas No. 31508-00-6) in female Harlan Sprague-Dawley rats (gavage studies). 1734 96

Thyroid hormone (T3) regulates multiple physiological processes during development, growth, differentiation, and metabolism. Most T3 actions are mediated via thyroid hormone receptors (TRs) that are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. The effects of T3 treatment on target gene regulation was previously examined in TRalpha1-overexpressing hepatoma cell lines (HepG2-TRalpha1). Androgen receptor (AR)-associated protein 70 (ARA70) was one gene found to be up-regulated by T3. The ARA70 is a ligand-dependent coactivator for the AR and was significantly increased by 4- to 5-fold after T3 treatment by Northern blot analyses in the HepG2-TRalpha1 stable cell line. T3 induced a 1- to 2-fold increase in the HepG2-TRbeta1 stable cell line. Both stable cell lines attained the highest fold expression after 24 h treatment with 10 nM T3. The ARA70 protein was increased up to 1.9-fold after T3 treatment in HepG2-TRalpha1 cells. Similar findings were obtained in thyroidectomized rats after T3 application. Cycloheximide treatment did not suppress induction of ARA70 transcription by T3, suggesting that this regulation is direct. A series of deletion mutants of ARA70 promoter fragments in pGL2 plasmid were generated to localize the thyroid hormone response element (TRE). The DNA fragments (-234/-190 or +56/+119) gave 1.55- or 2-fold enhanced promoter activity by T3. Thus, two TRE sites exist in the upstream-regulatory region of ARA70. The TR-TRE interaction was further confirmed with EMSAs. Additionally, ARA70 could interfere with TR/TRE complex formation. Therefore, the data indicated that ARA70 suppresses T3 signaling in a TRE-dependent manner. These experimental results suggest that T3 directly up-regulates ARA70 gene expression. Subsequently, ARA70 negatively regulates T3 signaling.
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PMID:Direct regulation of androgen receptor-associated protein 70 by thyroid hormone and its receptors. 1741 1


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