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Biomedical subjects

S Safe

Publications and source records attributed to S Safe.

At least 325 records · Page 18Linked to original sources
PubMedDate not supplied

Halogenated aryl hydrocarbon-induced suppression of the in vitro plaque-forming cell response to sheep red blood cells is not dependent on the Ah receptor.

The immunosuppressive effects of the halogenated aromatic hydrocarbons (HAHs), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,9-PeCDF and 1,3,6,8-TCDF were investigated utilizing the Mishell-Dutton model for in vitro immunization. The selected polychlorinated dibenzofuran congeners and 2,3,7,8-TCDD caused a concentration-dependent suppression of the splenic plaque-forming cell response to sheep red blood cells using cell cultures derived from C57BL/6 (Ah responsive) mice. Previous studies showed that there was up to a 14,900-fold difference in the in vivo immunotoxicity of these compounds, however in the in vitro studies, their immunosuppressive potencies were comparable. In addition, these congeners also exhibited similar potencies using spleen cell cultures from DBA/2 (Ah-nonresponsive) mice. Previous research demonstrated that alpha-naphthoflavone was relatively inactive in the in vitro splenic assay system and that co-treatment of cells from C57BL/6 mice with alpha-naphthoflavone (10 microM) plus 2,3,7,8-TCDD (20 mM) resulted in a significant inhibition of the immunotoxicity of 2,3,7,8-TCDD. In these studies, comparable interactive effects were also observed in cells treated with alpha-naphthoflavone plus 1,3,6,8-TCDF, a weak in vivo Ah receptor agonist. Collectively, the results from this study suggest that there may be mechanism(s) of action for HAH-induced suppression of the in vitro murine humoral response to sheep red blood cells which are independent of the Ah receptor protein.

Animals↗
PubMedDate not supplied

The bacterial mutagenicity of nitropolychlorinated dibenzo-p-dioxins.

The bacterial mutagenicity of 2-nitrodibenzo-p-dioxin, a mixture of 2-nitro-7-chloro- and 2-nitro-8-chlorodibenzo-p-dioxin, 7-nitro-2,3-dichloro-, 8-nitro-2,3,7-trichloro-, 2-nitro-1,3,7,8-tetrachloro- and 3-nitro-1,2,4,7,8-pentachlorodibenzo-p-dioxin was determined using Salmonella typhimurium tester strains TA98 and TA100 with and without rat hepatic S9 for metabolic activation. All the nitro-PCDDs exhibited some direct-acting mutagenicity with both tester strains, however, the activity was significantly lowered in the presence of exogenous S9 and the compounds were more mutagenic to tester strain TA98. The mutagenicity of the nitro-PCDDs was also dependent on structure because there was a marked decrease in activity with increasing chlorine content. Because nitro-PCDDs have recently been identified as incomplete combustion products of municipal waste, this study confirms that this new class of compounds contains some bacterial mutagens.

Dioxins↗
PubMedDate not supplied

Hepta-, hexa-, tetra- and dichloronaphthalene congeners as inducers of hepatic microsomal drug-metabolizing enzymes.

Pretreatment of immature male Wistar rats with 1,2,3,4,5,6,7-hepta-, 1,2,3,4,5,6,8-hepta- and 1,2,3,4,5,6-hexachloronaphthalene resulted in the induction of several hepatic microsomal drug-metabolizing enzymes. The enzymic activities, reduced cytochrome P-450:CO and ethylisocyanide binding difference spectra and electrophoretic mobilities of the induced microsomal proteins were comparable to those observed after administration of the classical inducer of microsomal aryl hydrocarbon hydroxylase, 3-methylcholanthrene. The 1,2,3,4,5,6,7-heptachloronaphthalene congener, which is fully substituted in the lateral 2,3,6 and 7 positions, was more potent than the 1,2,3,4,5,6,8-hepta- and the 1,2,3,4,5,6-hexachloronaphthalene congeners which contain only 3 lateral chloro substituents. 1,2,3,4-Tetra- and several lower chlorinated naphthalenes were inactive as inducers of microsomal aryl hydrocarbon hydroxylase. The effects of structure on the induction activities of the polychlorinated naphthalenes were similar to those observed for other halogenated aryl hydrocarbons.

Animals↗
PubMedDate not supplied

PCDD, PCDF, and PCB in farm-raised catfish from southeast United States--concentrations, sources, and CYP1A induction.

Nine catfish fillets, three catfish nuggets, two feed samples, and one pond sediment were analyzed for PCDD, PCDF, and PCB. Farm-raised catfish from Mississippi, Alabama, and Arkansas contained significant levels of 2,3,7,8-substituted PCDD and PCDF. In addition, a large number of non-2,3,7,8-substituted congeners were present in all samples. The catfish fillets and catfish nuggets also contained high concentrations of dioxin-like PCB, as well as a number of non-dioxin-like PCB. The TEQ based on PCDD and PCDF ranged from 9.5 to 43.0 pg/g lipid and the TEQ based on PCB ranged from 0.45 to 4.9 pg/g lipid for all catfish samples. The dioxin-like PCB contributed 4-16% to the total TEQ (PCDD/PCDF/PCB) for the catfish samples. The major source for the PCDD, PCDF, and PCB appears to be from feed and not from pond sediment. Immunoreactive CYP1A protein was elevated 2.5 fold in the pond-raised catfish compared to the aquarium-raised one. The results of this study suggest that the PCDD/PCDF are more important than the PCB in the CYP1A induction.

Agriculture↗
PubMedDate not supplied

Kinetics of the association of several tritiated polychlorinated dibenzo-p-dioxin and dibenzofuran congeners with hepatic cytosolic Ah receptor from the Wistar rat.

Several tritiated chlorinated dibenzo-p-dioxins and dibenzofurans have been prepared with specific activities in the range of 30-50 Ci/mmol in order to investigate the effects of structure on the kinetics of their association with the rat cytosolic Ah receptor. The compounds were 2,3,7-trichlorodibenzo-p-dioxin (TrCDD), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentchlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,7,8-TCDF, and 1,2,3,7,8-pentachlorodibenzofuran (PeCDF). Although these congeners differed by up to 2 orders of magnitude in their biochemical and toxic potencies, their affinities for the Ah receptor as determined by conventional Scatchard analysis varied by less than 2-fold (range of KD values 5.0-9.3 nM). The rate of association of these ligands with the Ah receptor was studied at several temperatures, taking into account the competing thermal inactivation of the unbound receptor. The equilibrium constants (KD) were also obtained as the ratio of the rate constants for dissociation and formation, respectively, of the receptor-ligand complexes. The following conclusions were derived from the kinetic studies: (1) 2,3,7-TrCDD and 1,2,7,8-TCDF bound significantly more slowly to the Ah receptor than the other radioligands at all temperatures (13.5-37 degrees C), and this paralleled the lower biochemical potencies of the congeners; (2) the KD values obtained kinetically were in the subnanomolar range, with the smallest KD values observed for those ligands which bound most rapidly to the receptor; and (3) the temperature dependence of the KD values indicated that receptor-ligand association was favorable both enthalpically and entropically.

Animals↗
PubMedDate not supplied

Effect of ligand structure on formation and DNA binding properties of the transformed rat cytosolic aryl hydrocarbon receptor.

The saturation binding of transformed rat hepatic aryl hydrocarbon (Ah) receptor with [32P]-dioxin responsive element was determined using gel mobility shift assays. The assay was carried out with ligands which exhibit both high and low Ah receptor agonist activity, namely: (high) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzo-p-dioxin, and 1,2,3,7,8-pentachlorodibenzofuran; and (low) 1,2,7,8-TCDF, 2,3,7-trichlorodibenzo-p-dioxin and 6-methyl-1,3,8-trichlorodibenzofuran (MCDF). Woolfplot analysis of the saturation binding data revealed that for the concentrations of ligands used in this study the Bmax values for the high-affinity ligands were significantly higher (36.9-39.4 fmol/mg) than observed for the low-affinity ligands (6.15-13.8 fmol/mg). In contrast, there was not a structure-dependent trend in the equilibrium constant for dissociation KD values or in the half-lives (t1/2) for decomposition of the transformed receptor complexes. MCDF, a partial Ah receptor agonist/antagonist, also transformed the cytosolic Ah receptor and inhibited TCDD-induced transformation as determined by gel mobility shift assays. However, the diagnostic value of this assay to detect partial Ah receptor antagonists is questionable since similar results were obtained with 1,2,7,8-TCDF, a ligand which does not exhibit partial antagonist activity.

Animals↗
PubMedDate not supplied

Synthesis of the Octa- and nonachlorobiphenyl isomers and congeners and their quantitation in commercial polychlorinated biphenyls and identification in human breast milk.

The synthesis of all possible Isomeric nona- and octachlorobiphenyls has been accomplished by the Cadogan coupling of commercially available or synthetic chlorinated anilines in the presence of excess chlorinated benzenes and isoamyl nitrite. 2, 3, 4, 6-Tetrachloraniline was prepared by the chlorination of 2, 4, 5-trichloroaniline. The synthetic polychlorinated biphenyls (PCBs) were characterized by their proton magnetic resonance and mass spectra and their purities determined by gas chromatographic analyses. The PCB standards were used to unambiguously identify the deca-, nona-, and octachlorobiphenyls present in human breast milk and in the commercial PCB preparations Arociors 1268, 1262, 1260, 1254, 1248, 1242, 1016, 1232 and 1221 utilizing high resolution glass capillary gas chromatography.

Aroclors↗
PubMedDate not supplied

Mechanisms of ligand-induced aryl hydrocarbon receptor-mediated biochemical and toxic responses.

The ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a member of a broad group of halogenated aromatic hydrocarbons (HAHs) that is known to induce a wide range of toxic and biochemical responses in laboratory animals and humans. The effects of HAH exposure are mediated by binding to the cytosolic aryl hydrocarbon receptor (AhR), which is expressed in a tissue- and cell type-specific manner. The AhR is a ligand-activated transcription factor belonging to the basic helix-loop-helix/Per-AhR-Arnt-Sim (bHLH/PAS) superfamily of proteins. The mechanism of induction of gene transcription by TCDD involves ligand recognition and binding by the AhR, nuclear translocation, and dimerization with the AhR cofactor, AhR nuclear translocator (Arnt). The nuclear heterodimer interacts with cognate xenobiotic responsive elements (XREs) in promoter/enhancer regions of multiple Ah-responsive genes. Subsequent changes in chromatin structure and/or interaction of the AhR complex with the basal transcriptional machinery play a significant role in AhR-mediated gene expression. Although Arnt is a necessary component of a functional nuclear AhR complex, this protein also forms transcriptionally active heterodimers with other bHLH/PAS factors, including those involved in the transcriptional response to hypoxia. Arnt is ubiquitously expressed in mammalian systems, and results from transgenic mouse studies suggest that this protein plays a vital role in early mammalian embryonic development. Similar experiments suggest that the AhR may be involved in development of various organ systems. Thus, molecular mechanistic studies of TCDD action have contributed significantly to an improved understanding of the role of at least 2 bHLH/PAS proteins, as well as organ- and tissue-specific biochemical and toxic responses to this class of environmental toxins.

Animals↗