benzofurans and 1-2-3-7-8-pentachlorodibenzo-p-dioxin

Topics: Air Pollutants; Benzofurans; Dibenzofurans, Polychlorinated; Environmental Monitoring; Environmental Pollutants; Incineration; Industrial Waste; Polychlorinated Dibenzodioxins; Soil; Soil Pollutants; Taiwan

Obesity, a risk factor for developing metabolic complications, is a major public health problem. Abdominal obesity is strongly accompanied by a cluster of metabolic abnormalities characterized by insulin resistance. The link between persistent organic pollutants (POPs) and insulin resistance has been investigated in animal and epidemiological studies. We aimed to examine whether insulin resistance is greater in people with abdominal obesity (AO) and concomitant exposure to serum dioxins (PCDD/Fs). We conducted a cross-sectional descriptive study of 2876 participants living near a PCDD/Fs contaminated area. Seventeen 2,3,7,8-substituted PCDD/Fs congeners were measured, and then the associations between the main predictor variable, serum TEQDF-1998, abdominal obesity (AO), dependent variables, and insulin resistance were examined. Twelve of the 17 congeners, widely distributed among PCDDs, and PCDFs, had trends for associations with abdominal adiposity. In men, the highest quintiles of 1,2,3,7,8-PeCDF; 1,2,3,7,8-PeCDD; 2,3,7,8-TCDD; 2,3,7,8-TCDF; and 2,3,4,7,8-PeCDF had the top five adjusted odds ratios (AORs) + 95% confidence intervals (CIs):[4.2; 2.7-6.4], [3.6; 2.3-5.7], [3.2; 2.1-5.0], [3.0; 2.0-4.5], and [2.9; 1.9-4.7], respectively. In women, the highest quintiles of 1,2,3,4,7,8,9-HpCDF; 1,2,3,6,7,8-HxCDF; and 1,2,3,4,6,7,8-HpCDF had the top three AORs + 95% CIs:[3.0; 1.9-4.7], [2.0; 1.3-3.1], and [1.9; 1.3-2.9], respectively. After confounding factors had been adjusted for, men, but not women, with higher serum TEQDF-1998 levels or abdominal obesity had a significantly (Ptrend < 0.001) greater risk for abnormal insulin resistance. The groups with the highest joint serum TEQDF-1998 and abdominal obesity levels were associated with elevated insulin resistance at 5.0 times the odds of the groups with the lowest joint levels (AOR 5.23; 95% CI: 3.53-7.77). We hypothesize that serum TEQDF-1998 and abdominal obesity affect the association with insulin resistance in general populations.

Topics: Adult; Benzofurans; Cross-Sectional Studies; Environmental Exposure; Environmental Pollutants; Female; Humans; Insulin Resistance; Male; Middle Aged; Obesity, Abdominal; Polychlorinated Dibenzodioxins; Sex Factors

Risk assessment for mixtures of dioxin-like compounds uses the toxic equivalency factor (TEF) approach. Although current WHO-TEFs are mostly based on oral administration, they are commonly used to determine toxicity equivalencies (TEQs) in human blood or tissues. However, the use of "intake" TEFs to calculate systemic TEQs in for example human blood, has never been validated. In this study, intake and systemic relative effect potencies (REPs) for 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3',4,4',5-pentachlorobiphenyl (PCB-118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB-156) were compared in rats. The effect potencies were calculated based on administered dose and liver, adipose or plasma concentrations in female Sprague-Dawley rats 3 days after a single oral dose, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatic ethoxyresorufin-O-deethylase activity and gene expression of Cyp1a1, 1a2, 1b1 and aryl hydrocarbon receptor repressor in liver and peripheral blood lymphocytes were used as endpoints. Results show that plasma-based systemic REPs were generally within a half log range around the intake REPs for all congeners tested, except for 4-PeCDF. Together with our previously reported systemic REPs from a mouse study, these data do not warrant the use of systemic REPs as systemic TEFs for human risk assessment. However, further investigation for plasma-based systemic REPs for 4-PeCDF is desirable.

Topics: Administration, Oral; Animals; Benzofurans; Body Weight; Cytochrome P-450 CYP1A1; Dioxins; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Lymphocytes; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Tissue Distribution

The toxic equivalent (TEQ) approach is traditionally used in risk evaluation of dioxins. Non-dioxin-like PCBs are not included in this approach and TEQ can therefore underestimate toxicity. In this study, a factorial design and multiple endpoint strategy have been used to evaluate the combined toxicity and possible interactions between the non-dioxin-like PCB 138 and the potent AhR agonists 2,3,7,8-TCDF (TCDF) and 1,2,3,7,8-PeCDD (PCDD). Primary hepatocyte cultures from Atlantic salmon were exposed for 24h and qPCR was employed to create CYP1A dose-response curves and to quantify the transcriptional levels of eight genes (CYP1A, UDPGT, HSP70, GR, GPX, MnSOD, GST and p53). Principal component analysis (PCA) was used to evaluate response similarities between genes. PLS regression was used to model CYP1A and UDPGT responses to the three chemicals. The contour plot examinations of the CYP1A model indicated an antagonism between PCDD and TCDF and in the UDPGT model a possibly synergistic interaction between PCB 138 and PCDD. The results indicate that PCB 138, in combination with TCDF and PCDD, can contribute to the measured CYP1A and UDPGT responses. Using primary cell cultures, multivariate data analysis of qPCR data is shown to be a useful tool in toxicological studies. A multiple endpoints strategy can enhance the quality of risk evaluation of chemical compounds.

Topics: Animals; Benzofurans; Cells, Cultured; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Endpoint Determination; Glucuronosyltransferase; Hepatocytes; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Principal Component Analysis; RNA, Messenger; Salmo salar

The human population is exposed to dioxins (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) mainly through diet; bioaccumulation and biomagnification in aquatic environment results in fishery products and by-products being an important vector to humans. The determination of PCDD/Fs and dl-PCBs in fillets of young turbots (Psetta maxima) (0-2 years) from aquaculture plant (Galicia, Spain) (N = 21) and in feeding stuffs were carried out, and dietary accumulation values and lipid-normalized biomagnification factors (BMF) relating concentration in fish and in feed were calculated. Levels found in feeding stuffs (0.5 pg TEQ-PCDD/F/g and 1.6 pg TEQ-dl-PCB/g), and turbots (0.13-0.27 pg TEQ-PCDD/F/g fresh weight and 0.35-1.2 pg TEQ-dl-PCB/g fresh weight) were below maximum permitted levels set by EC. Levels of toxic compounds in feeding stuff are reflected in fish fillets; predominant isomers are 2,3,7,8-TCDF, OCDD, 1,2,3,7,8-PeCDF, 2,3,4,7,8-PeCDF and 1,2,3,4,6,7,8-HpCDD, and PCBs 118, 105, 156 and 167. Relevant compounds accounting for total toxicity are the same congeners in feeding stuff and turbots: 2,3,4,7,8- PeCDF; 2,3,7,8-TCDF; 2,3,7,8-TCDD and 1,2,3,7,8-PeCDD, and PCB 126. Higher accumulation efficiency values were obtained for dl-PCBs (30-46%); tetra- and penta-chloro substituted PCDD/Fs showed the highest values (27-34%) of the PCDD/F group. Biomagnification was shown for these compounds (BMF around 1.5).

Topics: Animal Feed; Animals; Aquaculture; Benzofurans; Dibenzofurans, Polychlorinated; Diet; Flatfishes; Food Contamination; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Safety; Spain; Water Pollutants, Chemical

Exposure to the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produces hydronephrosis in developing mice, the etiology of which involves hyperplasia within the ureteric luminal epithelium. Dysregulation of epidermal growth factor receptor (EGFR), EGF, and transforming growth factor-alpha expression has been implicated as playing a role in TCDD-induced hydronephrosis. In this study, changes in the expression of genes encoding the EGFR and its cognate ligands in response to TCDD were evaluated within the developing ureter. C57BL/6 dams were injected ip with 30 mug/kg TCDD on gestational day (GD) 13 or 16 and fetal tissues removed on GD 17. Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator messenger RNA (mRNA) were expressed in control and treated fetal tissues at GD 14 and 17. Prototypical AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1 were upregulated in TCDD-exposed fetal tissues, demonstrating AHR transcriptional activity at these developmental stages. Amphiregulin (AREG) and epiregulin, ligands for the EGFR, were induced at the transcriptional level in ureters of fetuses exposed to TCDD for 24 h. AREG mRNA was also induced by TCDD dose- and time-dependently in the mouse hepatoma cell line Hepa-1c1c7 (Hepa-1), mimicking the induction patterns of CYP1A1 mRNA. Other AHR ligands also induced AREG mRNA in Hepa-1 cells. Furthermore, variant Hepa-1 cells (TAOBP(r)c1 cells) virtually deficient in the AHR failed to display an increase in AREG mRNA in response to TCDD. Taken together, these data suggest that the AHR cross talks with the EGFR signaling pathway by directly inducing the expression of growth factors that are important for EGFR signaling in the developing mouse ureter.

Topics: Amphiregulin; Animals; Benz(a)Anthracenes; Benzo(a)pyrene; Benzofurans; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; EGF Family of Proteins; Female; Gene Expression Regulation, Developmental; Gestational Age; Glycoproteins; Injections, Intraperitoneal; Intercellular Signaling Peptides and Proteins; Male; Maternal Exposure; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Teratogens; Ureter

To develop an enzyme-linked immunosorbent assay (ELISA) for monitoring the toxicity due to polychlorinated dibenzo-p-dioxins and dibenzofurans contaminated in human breast milk, we have generated novel monoclonal antibodies using some haptenic derivatives linked to bovine serum albumin via the C-1 or C-2 position on the dioxin skeleton. BALB/c or A/J mice were repeatedly immunized with the immunogen, and spleen cells were fused with P3/NS1/1-Ag4-1 myeloma cells. After five fusion experiments, a hybridoma clone was established that secretes an antibody D9-36 group specifically recognizing the major toxic congeners, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin, and 2,3,4,7,8-pentachlorodibenzofran. An ELISA is developed on the basis of the competitive and labeled-antigen format. The toxic congeners extracted from butter or milk specimens by a novel extraction cartridge and a peroxidase-labeled dioxin analogue were sequentially reacted with a fixed amount of D9-36 in the presence of Triton X-100. The bound fraction was captured on a microtiter plate, immobilizing a second antibody, and the enzyme activity was colorimetrically determined. This ELISA afforded a practical sensitivity (measurable range, 1-100 pg/assay; detection limit, 1.0 pg/assay as 2,3,7,8-TCDD equivalent). The assay values for milk and butter samples were in reasonable accordance with the sum of the toxicity-equivalent quantity of each congener, which had been determined by a high-resolution gas chromatography/high-resolution mass spectrometry method.

Topics: Animals; Antibodies, Monoclonal; Benzofurans; Cattle; Dioxins; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Humans; Mice; Milk, Human; Polychlorinated Dibenzodioxins

Topics: Bacteria, Anaerobic; Benzofurans; Biodegradation, Environmental; Chlorine; Dioxins; Environmental Pollutants; Oxidation-Reduction; Polychlorinated Dibenzodioxins; Species Specificity

The hepatic tumor-promoting activity of a mixture of polyhalogenated aromatic hydrocarbons (PHAHs) was studied in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats. The PHAH mixture contained 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), 2,3,3',4,4', 5-hexachlorobiphenyl (PCB 156), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) and covered >90% of the total toxic equivalents (TEQ) present in Baltic herring. To determine possible interactive effects of di-ortho-substituted PCBs, the PHAH mixture was tested with (PHAH+) and without (PHAH-) PCB 153. Rats were initiated by a diethylnitrosamine injection (30 mg/kg body wt i.p.) 24 h after a partial 23 hepatectomy. Six weeks after initiation, the PHAH mixtures were administered once a week by subcutaneous injections for 20 weeks. Treatment with the PHAH mixtures caused liver enlargement and an increased activity of the hepatic cytochrome P4501A1/2 and P4502B1/2. All PHAH exposure groups exhibited an increased occurrence of hepatic foci positive for the placental form of glutathione-S-transferase. In the PHAH-group dosed 1 microgram TEQ/kg body wt/week, the volume fraction of the liver occupied by foci was significantly lower compared to the TEQ equivalent dosed TCDD group (3.8 vs 8.7%). The volume fraction was significantly increased in the groups treated with 0.5, 1, or 2 micrograms TEQ/kg body wt/week of the PHAH+ mixture (4.5, 5.2, and 6.6%, respectively) compared to the corn oil group (2.0%), but to a lower extent than expected on basis of the TEQ doses. Overall, the TEQ-based administered dose overestimated the observed tumor-promoting effects of this PHAH mixture. The applicability of the toxic equivalency factor concept, the role of differences in toxicokinetic properties and interactive effects of PCB 153 on hepatic deposition of the dioxin-like congeners are discussed.

Topics: Animals; Benzofurans; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Liver; Liver Neoplasms, Experimental; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Precancerous Conditions; Rats; Rats, Sprague-Dawley

A defined mixture of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) was subcutaneously administered to a pregnant marmoset monkey (Callithrix jacchus) 11 weeks prior to delivery. Transfer of PCDDs and PCDFs via placenta and mother's milk was investigated by measurement of concentrations in a newborn 1 day after birth and in an infant of the same litter after a lactation period of 33 days. Furthermore, comparative measurements were performed in different tissues of the mother at the end of the lactation period, and in addition, in two groups of four adult monkeys each 1 and 6 weeks after treatment. Deposition of the PCDDs and PCDFs into fetal liver was very low for most of the 2,3,7,8-substituted congeners. Highest deposition was observed for 2,3,7,8-T4CDD and 1,2,3,7,8-P5CDD. For all other compounds concentrations in the hepatic tissue of newborn shortly after birth were lower than one tenth of corresponding concentrations in adults. Especially for PCDFs, prenatal deposition in fetal liver was extremely low. Fetal liver is apparently largely unable to accumulate PCDDs/PCDFs. In contrast to liver, concentrations of 2,3,7,8-substituted PCDDs/PCDFs in adipose tissue of the newborn were at least one third of the levels in adults. However, concentrations of OCDD and OCDF were about three times higher in the newborn than in adult adipose tissue. Transfer of some of the 2,3,7,8-substituted PCDDs and PCDFs to the offspring via mother's milk was considerable, leading to hepatic concentrations in the suckled infant at the end of the 33-day nursing period well above corresponding concentrations in the dam. When hepatic concentrations in the infant and dam were compared 2- to 4-fold higher concentrations were found in the infant's liver for 2,3,7,8-T4CDD/F and for 1,2,3,7,8-P5CDD. In the case of the 2,3,7,8-substituted H6CDDs, P5CDFs, and most of the H6CDFs, hepatic concentrations in the infant and dam were in the same range at the end of the suckling period. In contrast to this, less than one tenth the concentration of OCDD was found in the infant's liver when compared with adult liver. A corresponding phenomenon was observed for PCDFs. At the maximum absorption, 1 week after injection, for almost all 2,3,7,8-substituted congeners highest concentrations were measured in hepatic tissue of adult monkeys. This is especially true for those substances with six and more chlorine atoms. Besides adipose tissue, comparatively high levels were found in

Topics: Animals; Benzofurans; Callitrichinae; Dibenzofurans, Polychlorinated; Female; Male; Maternal-Fetal Exchange; Milk; Placenta; Polychlorinated Dibenzodioxins; Pregnancy; Tissue Distribution

Treatment of 25-day-old female Sprague-Dawley rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly lowered constitutive uterine peroxidase activity and decreased uterine wet weights in a dose-response fashion. In cotreatment studies with 17 beta-estradiol, 2,3,7,8-TCDD antagonized the increase in uterine peroxidase activity and uterine wet weights, and these effects persisted for up to 156 hr. In the rat uterus, the antiestrogenic affects of two potent Ah receptor agonists, 2,3,7,8-TCDD and 2,3,4,7,8-pentachlorodibenzofuran, were comparable at a dose of 80 micrograms/kg, whereas the weaker Ah receptor agonist, 1,2,4,7,8-pentachlorodibenzo-p-dioxin, was relatively inactive at this dose. These results show that 2,3,7,8-TCDD antagonizes a well-characterized estrogen-induced response (uterine peroxidase activity), and the structure-activity data suggest that the Ah receptor is involved in mediating the antiestrogenic responses in target cells/organs.

Topics: Animals; Benzofurans; Dioxins; Estradiol; Estrogen Antagonists; Female; Kinetics; Organ Size; Peroxidase; Polychlorinated Dibenzodioxins; Rats; Rats, Inbred Strains; Receptors, Aryl Hydrocarbon; Receptors, Drug; Structure-Activity Relationship; Uterus