benzofurans and 2-4-5-2--4--5--hexachlorobiphenyl

Emerging evidence supports that exposure to persistent organic pollutants (POPs) can impact the interaction between the gut microbiota and host. Recent efforts have characterized the relationship between gut microbiota and environment pollutants suggesting additional research is needed to understand potential new avenues for toxicity. Here, we systematically examined the direct effects of POPs including 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,7,8-tetrachlorodibenzo-

Topics: Animals; Bacteria; Benzofurans; Carbon; Cecum; Citric Acid Cycle; Gastrointestinal Microbiome; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Persistent Organic Pollutants; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Protein Transport; Pyruvic Acid

Within our research project, 34 river bottom sediments were collected in 2006-2007 at five areas across Slovakia with industrial sources of persistent organic pollutants (Košice, Krompachy, Nemecká, Šala, Nováky) and one background area (Starina). Sediments were analyzed for seven 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDDs) and 10 dibenzofurans (PCDFs), 12 dioxin-like and 6 indicator polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and 1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) with 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE). Analytical procedure based on accelerated solvent extraction followed by a semi-automated clean-up and fractionation was used. Determination of target compounds was performed by HRGC-HRMS analysis. Total WHO toxic equivalent WHO1998-PCDD/F/dl-PCB-TEQ concentrations ranged from 0.26 to 559 pg TEQ g(-1) dry matter (dm), with a median 2.2 pg TEQ g(-1) dm. The sums of six indicator PCBs were in the range 0.56-1014 ng g(-1) dm, with a median 11.8 ng g(-1) dm. The concentrations of organochlorine pesticides HCB and p,p'-DDE/DDT varied from 0.15 to 34.8 ng g(-1) dm, with a median 0.91 ng g(-1) dm and 0.46-34.1 ng g(-1)dm, with a median 6.7 ng g(-1)dm, respectively. The most abundant congeners in all sediment samples among dioxins, furans and PCBs were OCDD, 1,2,3,4,6,7,8-HpCDF, PCB-118 and PCB-153.

Topics: Benzofurans; Dichlorodiphenyl Dichloroethylene; Environmental Monitoring; Geologic Sediments; Hexachlorobenzene; Hydrocarbons, Chlorinated; Pesticides; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polymers; Rivers; Slovakia; Water Pollutants, Chemical

Dioxins and PCBs accumulate in the food chain and might exert toxic effects in animals and humans. In large epidemiologic studies, exposure estimates of these compounds based on analyses of biological material might not be available or affordable.. To develop and then validate models for predicting concentrations of dioxins and PCBs in blood using a comprehensive food frequency questionnaire and blood concentrations.. Prediction models were built on data from one study (n=195), and validated in an independent study group (n=66). We used linear regression to develop predictive models for dioxins and PCBs, both sums of congeners and 33 single congeners (7 and 10 polychlorinated dibenzo-p-dioxins and furans (PCDDs/PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs: 4 non-ortho and 8 mono-ortho), sum of all the 29 dioxin-like compounds (total TEQ) and sum of 4 non dioxin-like PCBs (∑ CB-101, 138, 153, 183=PCB(4)). We used the blood concentration and dietary intake of each of the above as dependent and independent variables, while sex, parity, age, place of living, smoking status, energy intake and education were covariates. We validated the models in a new study population comparing the predicted blood concentrations with the measured blood concentrations using correlation coefficients and Weighted Kappa (К(W)) as measures of agreement, considering К(W)>0.40 as successful prediction.. The models explained 78% (sum dioxin-like compounds), 76% (PCDDs), 76% (PCDFs), 74% (no-PCBs), 69% (mo-PCBs), 68% (PCB(4)) and 63% (CB-153) of the variance. In addition to dietary intake, age and sex were the most important covariates. The predicted blood concentrations were highly correlated with the measured values, with r=0.75 for dl-compounds 0.70 for PCB(4), (p<0.001) and 0.66 (p<0.001) for CB-153. К(W) was 0.68 for sum dl-compounds 0.65 for both PCB(4) and CB-153. Out of 33 congeners 16 (13dl-compounds and 3 ndl PCBs) had К(W)>0.40.. The models developed had high power to predict blood levels of dioxins and PCBs and to correctly rank subjects according to high or low exposure based on dietary intake and demographic information. These models underline the value of dietary intake data for use in investigations of associations between dioxin and PCB exposure and health outcomes in large epidemiological studies with limited biomaterial for chemical analysis.

Topics: Adult; Aged; Aged, 80 and over; Animals; Benzofurans; Diet; Dioxins; Environmental Exposure; Female; Food Contamination; Humans; Male; Middle Aged; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Young Adult

Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For fourteen, thirty-one, or fifty-three weeks or for two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); 2,3',4,4',5-pentachlorobiphenyl (PCB118); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118. The ranges of treatment-related changes in the reproductive system included chronic active inflammation in the ovary that occurred in the 1,000 and 3,000 microg/kg core groups (two-year exposure) of PCB153 and in the 300 ng/3,000 microg/kg core group of binary mixture of PCB126 and PCB153. Increases in the incidence of acute and/or chronic active inflammation of the uterus were observed in all dosed groups, including the stop-exposure group (withdrawal after thirty-week exposure) of PeCDF and the 1,000 microg/kg and/or higher group dosed with PCB153. The incidence of cystic endometrial hyperplasia was marginally increased in the 92 PeCDF ng/kg group at two years. The incidence of squamous metaplasia was significantly increased in the 44 ng/kg and higher dose group, including the stop-exposure group. The incidence of uterine squamous cell carcinoma was significantly or marginally increased in the 6 ng/kg core and 100 ng/kg stop-exposure groups of TCDD and in the 300 ng/300 microg/kg core group that received the binary mixture of PCB126 and 153. The incidence of uterine carcinoma was marginally increased in the 92 ng/kg PeCDF group at two years and clearly increased in the 1,000 and 4,600 microg/kg PCB118 core group and the 4,600 microg/kg stop group. In the studies of PCB 126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurr

Topics: Administration, Oral; Animals; Benzofurans; Carcinogens; Carcinoma, Squamous Cell; Dioxins; Endometrial Hyperplasia; Female; Metaplasia; Ovary; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests; Uterine Neoplasms; Uterus

We employed DNA microarray to identify unique hepatic gene expression patterns associated with subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other halogenated aromatic hydrocarbons (HAHs). Female Harlan Sprague-Dawley rats were exposed for 13 weeks to toxicologically equivalent doses of four different HAHs based on the toxic equivalency factor of each chemical: TCDD (100 ng/kg/day), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF; 200 ng/kg/day), 3,3',4,4',5-pentachlorobiphenyl (PCB126; 1,000 ng/kg/day), or 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153; 1,000 microg/kg/day). Global gene expression profiles for each exposure, which account for 8,799 gene probe sets contained on Affymetrix RGU34A GeneChips, were compared by principal components analysis. The aryl hydrocarbon receptor (AhR) ligands TCDD, PeCDF, and PCB126 produced very similar global gene expression profiles that were unique from the nonAhR ligand PCB153, underscoring the extensive impact of AhR activation and/or the resulting hepatic injury on global gene expression in female rat liver. Many genes were co-expressed during the 13-week TCDD, PeCDF, or PCB126 exposures, including classical AhR-regulated genes and some genes not previously characterized as being AhR regulated, such as carcinoembryonic-cell adhesion molecule 4 (C-CAM4) and adenylate cyclase-associated protein 2 (CAP2). Real-time reverse-transcriptase polymerase chain reaction confirmed the increased expression of these genes in TCDD-, PeCDF-, and PCB126-exposed rats as well as the up- or down-regulation of several other novel dioxin-responsive genes. In summary, DNA microarray successfully identified dioxin-responsive genes expressed after exposure to AhR ligands (TCDD, PeCDF, PCB126) but not after exposure to the non-AhR ligand PCB153. Together, these findings may help to elucidate some of the fundamental features of dioxin toxicity and may further clarify the biologic role of the AhR signaling pathway.

Topics: Administration, Oral; Animals; Benzofurans; DNA Primers; Female; Gene Expression Profiling; Gene Expression Regulation; Hydrocarbons, Halogenated; Liver; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA

The ubiquitous and persistent nature of polychlorinated aromatic hydrocarbons (PCAHs) in our environment and the risk of exposure to PCAHs have provoked concern over their potential toxicity. In humans, exposure to PCAHs is aimed chiefly at epithelial cells residing in the intestinal mucosa, because oral intake of contaminated food is a major source of PCAHs. The purpose of this study, therefore, was to examine the effects of chronic exposure to various PCAHs [i.e. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), and 2,2'4,4'5,5'-hexachlorobiphenyl (PCB-153)], given alone or as mixtures, on intestinal cholecystokinin (CCK) peptide and messenger RNA levels. We show that chronic PCAH treatment significantly lowers intestinal levels of stored CCK peptide. Intestinal CCK messenger RNA levels are not affected. In addition, 3,3',4,4',5-pentachlorobiphenyl treatment increased intestinal insulin-like growth factor-binding protein-3 levels in a dose-related manner. Acute 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment of intestinal CCK cells lowered levels of CCK-processing enzymes (i.e. prohormone convertase-1 and -2). Together, these data indicate that PCAHs may decrease intestinal levels of stored CCK peptide by affecting the intestinal insulin-like growth factor system and CCK processing.

Topics: Animals; Aspartic Acid Endopeptidases; Benzofurans; Cell Line; Cholecystokinin; Chromogranin A; Chromogranins; Duodenum; Female; Hydrocarbons, Aromatic; Hydrocarbons, Chlorinated; Insulin-Like Growth Factor Binding Protein 3; Intestinal Mucosa; Intestines; Mice; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Proprotein Convertase 2; Proprotein Convertases; Rats; Rats, Sprague-Dawley; RNA, Messenger; Subtilisins

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

Hepatic microsomes derived from Cypla2(-/-) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As expected, microsomes from untreated 1a2 KO mice did not have immunodetectable CYP1A2 protein; however, methoxyresorufin-O-demethylase (MROD, 25.5+/-6.1 pmol/min/mg protein) and acetanilide-4-hydroxylation (ACOH, 0.64+/-0.04 nmol/min/mg protein) activities were still present. Furthermore, induction of ethoxyresorufin-O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 1a2 KO mice was accompanied by a greater than 70-fold increase in MROD activity. In contrast, ACOH was only induced 2-fold by TCDD. As with 1a2 KO mice, the parental strains exposed to TCDD or 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) showed substantial EROD and MROD induction, whereas ACOH activity was induced to a lesser degree. PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) resulted in low levels of both EROD and MROD induction. Results indicate that both substrates are subject to metabolism by non-CYP1A2 sources, and the apparent contribution of CYP1A1 activity to methoxyresorufin metabolism makes MROD unsuitable for differentiating CYP1A1 and CYP1A2 activities in the mouse.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Enzyme Induction; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Microsomes, Liver; Oxazines; Oxidoreductases; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Substrate Specificity

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), most potent of the polyhalogenated aromatic hydrocarbons, has been studied in a variety of genetically normal species. Transgenic mice lacking a cytochrome P450 1A2 gene were used to study the influence of the CYP1A2 gene on the hepatic sequestration and distribution of TCDD, 4-PeCDF (2,3,4,7,8-pentachlorodibenzofuran; dioxin-like compound), and PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl; non-dioxin-like PCB (polychlorinated biphenyl)). The knock-out mice were compared to their age-matched lineage strains of C57BL/6N (1A2+/+; Ah(b)) and 129/Sv (1A2+/+; Ah(d)) for each compound. As demonstrated by the liver-to-adipose tissue (L/F) concentration ratios, there was no hepatic sequestering of TCDD and 4-PeCDF in the transgenic knock-out mice.

Topics: Adipose Tissue; Animals; Benzofurans; Cytochrome P-450 CYP1A2; Dibenzofurans, Polychlorinated; Dioxins; Enzyme Induction; Fats; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

Topics: Adipose Tissue; Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Dioxins; Liver; Lung; Male; Mice; Mice, Inbred Strains; Polychlorinated Biphenyls