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Query: UNIPROT:P06889 (Mol)
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PCBs are persistent environmental contaminants that cause a variety of adverse health effects in wildlife and humans. This article describes the use of signature gene expression patterns that link increased PCB exposure with progressive, adverse biological effects. Developing Xenopus laevis tadpoles of two age classes were exposed to the PCB mixture Aroclor 1254 for 2 days. Real-time PCR was used to quantitate mRNA expression for 11 physiologically relevant, potential bioindicator genes. Younger tadpoles (5 days postfertilization) were resistant to Aroclor 1254 and showed few changes in gross morphology, swimming behavior, survival, or gene expression. Older tadpoles (11 days postfertilization) were more susceptible to Aroclor 1254. Exposure to 25 and 50 ppm Aroclor 1254 caused alterations in gross morphology and swimming behavior and statistically significant decreases in survival. These tadpoles showed statistically significant decreases in gene expression for 9 out of the 11 genes measured. Tadpoles exposed to 10 ppm showed incipient health changes but had gene expression profiles similar to the tadpoles treated with higher doses of Aroclor 1254. Tadpoles exposed to 1 ppm did not exhibit any observable adverse health effects, yet statistically significant decreases in gene expression occurred in these tadpoles (4 out of 11 genes). After prolonged exposure, tadpoles exposed to 1 and 10 ppm Aroclor 1254 exhibited health effects similar to those exposed to higher concentrations. Therefore, changes in expression of specific genes may serve not only as molecular bioindicators of Aroclor 1254 exposure but also as predictors of impending adverse health effects.
Environ Mol Mutagen 2002
PMID:Aroclor 1254 alters morphology, survival, and gene expression in Xenopus laevis tadpoles. 1221 Oct 73

The CHH/MIH/GIH peptide family of black tiger prawn (Paneaus monodon) is important in shrimp reproduction and growth enhancement. In this study, the cDNA that encodes the complete peptide that is related to the CHH/MIH/GIH family (so-called, Pem-CMG) in the eyestalk of P. monodon was successfully expressed in a methylotrophic yeast Pichia pastoris under the control of an alcohol oxidase promoter. In order to obtain the secreted Pem-CMG, a secretion signal of either the Saccharomyces cerevisiae alpha-factor or Pem-CMG was employed. The results demonstrated that alphaPem-CMG, either with (alpha2EACMG) or without (alphaCMG) the Glu-Ala repeats, was secreted into the medium, while Pem-CMG with its own secretion signal failed to be secreted. The total protein amount that was secreted from the transformant that contained either alpha2EACMG or alphaMG was approximately 60 mg/l and 150 mg/l, respectively. The N-terminus of the Pem-CMG peptide of both alpha2EACMG and alphaCMG was correctly processed. This produced the mature Pem-CMG peptide.
J Biochem Mol Biol 2002 Sep 30
PMID:Secretion of Pem-CMG, a peptide in the CHH/MIH/GIH family of Penaeus monodon, in Pichia pastoris is directed by secretion signal of the alpha-mating factor from Saccharomyces cerevisiae. 1235 89

Population-level studies using the major histocompatibility complex (Mhc) have linked specific alleles with specific diseases, but data requirements are high and the power to detect disease association is low. A novel use of Mhc population surveys involves mapping allelic substitutions onto the inferred structural molecular model to show functional differentiation related to local selective pressures. In the estuarine fish Fundulus heteroclitus, populations experiencing strong differences in antigenic challenges show significant differences in amino acid substitution patterns that are reflected as variation in the structural location of changes between populations. Fish from a population genetically adapted to severe chemical pollution also show novel patterns of DNA substitution at a highly variable Mhc class II B locus including strong signals of positive selection at inferred antigen-binding sites and population-specific signatures of amino acid substitution. Heavily parasitized fish from an extreme PCB-contaminated (U.S. Environmental Protection Agency Superfund) site show enhanced population-specific substitutions in the a-helix portion of the inferred antigen-binding region. In contrast, fish from an unpolluted site show a significantly different pattern focused on the first strand of the B-pleated sheet. Whether Mhc population profile differences represent the direct effects of chemical toxicants or indirect parasite-mediated selection, the result is a composite habitat-specific signature of strong selection and evolution affecting the genetic repertoire of the major histocompatibility complex.
Mol Biol Evol 2002 Nov
PMID:Strong positive selection and habitat-specific amino acid substitution patterns in MHC from an estuarine fish under intense pollution stress. 1241 96

PCBs have been shown to alter several neurochemical end-points and are implicated in the etiology of some neurological diseases. Recent in vivo studies from our laboratory indicated that developmental exposure to a commercial PCB mixture, Aroclor 1254, caused perturbations in calcium homeostasis and changes in protein kinase C (PKC) activities in rat brain. However, it is not known which molecular substances are targets for PCB-induced developmental neurotoxicity. Since the PKC signaling pathway has been implicated in the modulation of motor behavior as well as learning and memory, and the roles of PKC are subspecies specific, the present study attempted to analyze the effects on selected PKC isozymes in the cerebellum and the hippocampus following developmental exposure (gestational day 6 through postnatal day 21) to a PCB mixture, Aroclor 1254. The results indicated that the developmental exposure to PCBs caused significant hypothyroxinemia and age-dependent alterations in the translocation of PKC isozymes; the effects were greatly significant at postnatal day (PND) 14. Immunoblot analysis of PKC-alpha (alpha) from both cerebellum and hippocampus revealed that developmental exposure to Aroclor 1254 caused a significant decrease in cytosolic fraction and an increase in particulate fraction. There was no significant difference between these two brain regions on the level of fractional changes. However, the ratio between the fractions (particulate/cytosol) from cerebellum only was increased in a dose-dependent manner. Analysis of PKC-gamma (gamma) in cerebellum on PND14 showed a decrease in cytosolic fraction in both dose groups and an increase in particulate fraction at high dose (6 mg/kg) only. The ratio between the two fractions was increased in a dose-dependent manner. In the hippocampus, there was a significant decrease in PKC-gamma in cytosolic fraction of the high-dose group and a significant increase in particulate fraction of the low-dose group. But, the ratio between the fractions showed a significant increase (2.6-fold increase in high dose on PND14). Analysis of PKC-epsilon (epsilon) in cerebellum showed a significant decrease in cytosolic fraction at PND14, while particulate PKand an increase in ratio between fractions at 6 mg/kg on PND14. The results from this study indicate that the patterns of subcellular distributions of PKC isoforms following a developmental PCB exposure were PKC isozyme- and developmental stage-specific. Considering the significant role of PKC signaling in motor behavior, learning and memory, it is suggested that altered subcellular distribution of PKC isoforms at critical periods of brain development may be a possible mechanism of PCB-induced neurotoxic effects and that PKC-alpha, gamma, and epsilon may be among the target molecules implicated with PCB-induced neurological impairments during developmental exposure. It is believed that this is the first report successfully identifying PKC isoforms responding to PCBs during developmental exposure.
Brain Res Mol Brain Res 2003 Mar 17
PMID:Alterations in brain protein kinase C isoforms following developmental exposure to a polychlorinated biphenyl mixture. 1265 12

The B cell, a major component of humoral immunity, is a sensitive target for the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), possibly by rendering cells less responsive to antigenic or mitogenic stimulation. Potential mechanisms of TCDD action on B cells were examined in murine B cell lymphoma cells (CH12.LX) treated with 3 nM TCDD or dimethyl sulfoxide vehicle using sequence-verified cDNA microarrays. One transcript that was significantly induced by TCDD was suppressor of cytokine signaling 2 (Socs2). Changes in Socs2 mRNA levels paralleled that of Cyp1a1 with a maximal 3-fold induction observed at 4 h, as determined by quantitative real-time polymerase chain reaction. Socs2 induction seems B cell-specific, because no induction was observed in TCDD-responsive mouse hepatoma cells or human breast cancer cells. TCDD-mediated induction of Socs2 mRNA was dose-dependent and exhibited the characteristic structure-activity relationships observed for the aryl hydrocarbon receptor (AhR) ligands 3,3',4,4',5-pentachlorobiphenyl (PCB-126), indolo[3,2-b]-carbazole, and beta-naphthoflavone. Experiments with cycloheximide and AhR-deficient B cells indicated that Socs2 mRNA induction is a primary effect that is AhR-dependent. Western blot analysis confirmed that Socs2 and Cyp1a1 protein levels were also induced in CH12.LX cells. Promoter analysis revealed the presence of four dioxin-response elements within 1000 base pairs upstream of the Socs2 transcriptional start site, and a reporter gene regulated by the Socs2 promoter was inducible by TCDD. Promoter activity was also dependent on a functional AhR signaling pathway. These results indicate that Socs2 is a primary TCDD-inducible gene that may represent a novel mechanism by which TCDD elicits its immunosuppressive effects.
Mol Pharmacol 2004 Dec
PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells. 1537 57

Endocrine disrupting chemicals (EDCs) are widespread in the environment and suspected to interfere with the function of thyroid hormones (THs). We investigated the TH disrupting activity of different classes of EDCs including plasticizers (bisphenol A, bisphenol A dimethacrylate), alkylphenols (4-n-nonylphenol, 4-octylphenol), pesticides (prochloraz, iprodion, chlorpyrifos), PCB metabolites (OH-PCB 106, OH-PCB 121, OH-PCB 69) and brominated flame-retardants (tetrabromobisphenol A). The ED potential of a chemical was determined by its effect on the cell proliferation of TH-dependent rat pituitary GH3 cell line. All tested chemicals significantly interfered with the cell proliferation alone or upon co-treatment with T3. The growth of GH3 cells was stimulated by all tested chemicals, but 4-n-nonylphenol, 4-octylphenol, prochloraz and iprodion elicited an inhibitory effect on cell growth. In conclusion, these EDCs have the potential to exert TH disruption increasing the risk or a negative impact on fetal brain development, resulting in cognitive dysfunctions.
Mol Cell Endocrinol 2005 Dec 01
PMID:Impact of environmental chemicals on the thyroid hormone function in pituitary rat GH3 cells. 1622 24

17beta-Estradiol (E2) activates non-genomic pathways in MCF-7 cells, and this study investigates the effects of structurally-diverse estrogenic compounds on activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3-K), protein kinase C (PKC), PKA, and calcium calmodulin-dependent kinase IV (CaMKIV). Activation of kinases was determined by specific substrate phosphorylation and transactivation assays that were diagnostic for individual kinases. The compounds investigated in this study include E2, diethylstilbestrol (DES), the phytoestrogen resveratrol, and the following synthetic xenoestrogens, bisphenol-A (BPA), nonylphenol, octylphenol, endosulfan, kepone, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), and 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB-Cl(4)). With the exception of resveratrol, all the compounds activated PI3-K and MAPK. Activation of PKC by the xenoestrogens was structure-dependent since resveratrol, kepone and HO-PCB-Cl(4) were inactive and only minimal activation of PKA was observed. CaMKIV was activated only by E2 and DES, and HO-PCB-Cl(4) was a potent inhibitor of CaMKIV-dependent activity. These results demonstrate that activation of estrogen receptor-alpha-mediated non-genomic pathways by estrogenic compounds in MCF-7 cells is structure-dependent and can result in activation or inhibition of kinase activities.
J Steroid Biochem Mol Biol 2006 Feb
PMID:Activation of kinase pathways in MCF-7 cells by 17beta-estradiol and structurally diverse estrogenic compounds. 1641 91

Acidovorax sp. (formally Pseudomonas sp.) strain KKS102 carries a bph operon for the degradation of PCB/biphenyl. Transcription from the pE promoter for the bph operon was found to be under catabolite control, i.e. the promoter activity was at a lower level when succinate, fumarate or acetate was added to the culture. Some mutations in the immediate upstream region of the pE promoter resulted in catabolite-insensitive and constitutively low promoter activity, suggesting that a transcriptional activator was involved in catabolite control. A genetic screen for a pE promoter activator identified two tandemly arranged genes, bphP and bphQ, that encoded proteins homologous to the sensor kinases and response regulators, respectively, of two-component regulatory system. In the bphPQ double mutant, pE promoter activity was weak and catabolite-insensitive, and a supply of the bphQ gene alone led to the restoration of the catabolite response. The mechanism of catabolite repression in KKS102 is explained in terms of inhibition of activation by BphQ. The genes highly similar to bphQ were found from several beta-proteobacteria, such as Burkholderia cenocepacia J2315, B. multivorans ATCC17616, B. xenovorans LB400 and Ralstonia solanacearum RS1085.
Mol Microbiol 2006 Jun
PMID:Identification of a response regulator gene for catabolite control from a PCB-degrading beta-proteobacteria, Acidovorax sp. KKS102. 1679 88

Quantitative structure-activity relationship (QSAR) models were developed for the in vitro potencies to downregulate gap junctional intercellular communication (GJIC) of hydroxylated polychlorinated biphenyls (OH-PCBs) and PCB quinines using partial least squares (PLS) regression. Quantum chemical descriptors computed by the semiempirical AM1, PM3 and MNDO methods were used as predictor variables. The cross-validated Q2cum values for the three optimal QSAR models are 0.784, 0.789 and 0.755, respectively, indicating good predictive capabilities for the acute inhibition of GJIC (IC(50)) of oxygenated PCB derivatives. The slightly higher Q2cum value of the model using computed molecular descriptors from the PM3 Hamiltonian suggested a slightly better predictive power than the models developed using AM1 or MNDO. However, given these dispersion parameters in these three optimal models, there would not be a significant difference between the Q2cum values. Results from this study showed that the logarithmic scale of IC(50) is affected by different molecular structural descriptors.
J Mol Model 2007 Jan
PMID:Quantitative structure-activity relationships for prediction of the toxicity of hydroxylated and quinoid PCB metabolites. 1696 66

The polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and dioxin-like polychlorinated biphenyls (dioxin-like PCB) are ubiquitous in food of animal origin and accumulate in fatty tissues of animals and humans. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The toxic responses include dermal toxicity, immunotoxicity, carcinogenicity, and reproductive and developmental toxicity. Toxic equivalency factors have been established for the other PCDD, PCDF and dioxin-like PCB relative to TCDD, and the combined toxicity of a sample can be expressed as toxic equivalent (WHO-TEQ). The EC Scientific Committee for Food evaluated these compounds in 2001. The assessment used the most sensitive adverse toxicological end-points of TCDD in experimental animals. These were developmental and reproductive effects in the male offspring of rats administered TCDD during pregnancy. Because of the large difference between rats and humans in the biological half-life of TCDD, the assessment used a body burden approach to compare across species and derived a tolerable weekly intake of 14 pg TCDD/kg of body weight (bw), which was extended to include all the 2,3,7,8-substituted PCDD and PCDF, and the dioxin-like PCB, and expressed as a group tolerable weekly intake of 14 pg WHO-TEQ/kg bw. The FAO/WHO Joint Expert Committee on Food Additives (JECFA) performed a similar assessment whereas the US Environmental Protection Agency (US EPA) has paid more attention to human data on carcinogenicity.
Mol Nutr Food Res 2006 Oct
PMID:Risk assessments of polychlorinated dibenzo- p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in food. 1700 11


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