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      Polychlorinated biphenyls impair dibutyryl cAMP-induced astrocytic differentiation in rat C6 glial cell line ☆

      research-article
      Author(s): a , 1 , b , 1 , c , d , e , *
      Publication date (Electronic):
      Journal: FEBS Open Bio
      Publisher: Elsevier
      Keywords: Astrocytic differentiation, C6 glial cell line, Aroclor1254, Glial fibrillary acidic protein (GFAP), Protein kinase C (PKC), Signal transducer and activator of transcription 3 (STAT3), PCBs, polychlorinated biphenyls, dbcAMP, N6,2′-O-dibutyryl cAMP, A1254, Aroclor 1254, DMSO, dimethyl sulfoxide, DMEM, Dulbecco’s Modified Eagle’s Medium, MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, NMDA, N-methyl-d-aspartate, nNOS, neuronal nitric oxide, CNS, central nervous system, ROS, reactive oxygen species, GFAP, glial fibrillary acidic protein, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, DAPI, 4′,6-diamidino-2-phenylindole, PKA, protein kinase A, PKC, protein kinase C, bis, 2-[1-(3-dimethylamino-propyl)indol-3-yl]-3-(indol-3-yl) maleimide, STAT3, signal transducer and activator of transcription 3, CRE, cAMP responsive element, CREB, cAMP-response element binding protein, TRE, CRE transcriptional response element

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          Abstract

          In the central nervous system, alteration of glial cell differentiation can affect brain functions. Polychlorinated biphenyls (PCBs) are persistent environmental chemical contaminants that exert neurotoxic effects in glial and neuronal cells. We examined the effects of a commercial mixture of PCBs, Aroclor1254 (A1254) on astrocytic differentiation of glial cells, using the rat C6 cell line as in vitro model. The exposure for 24 h to sub-toxic concentrations of A1254 (3 or 9 μM) impaired dibutyryl cAMP-induced astrocytic differentiation as showed by the decrease of glial fibrillary acidic protein (GFAP) protein levels and inhibition in change of cell morphology toward an astrocytic phenotype. The A1254 inhibition was restored by the addition of a protein kinase C (PKC) inhibitor, bisindolylmaleimide (bis), therefore indicating that PCBs disturbed the cAMP-induced astrocytic differentiation of C6 cells via the PKC pathway. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) is essential for cAMP-induced transcription of GFAP promoter in C6 cells. Our results indicated that the exposure to A1254 (3 or 9 μM) for 24 h suppressed cAMP-induced STAT3 phosphorylation. Moreover, A1254 reduced cAMP-dependent phosphorylation of STAT3 requires inhibition of PKC activity. Together, our results suggest that PCBs induce perturbation in cAMP/PKA and PKC signaling pathway during astrocytic differentiation of glial cells.

          Highlights

          • •

            A1254, a polychlorinated biphenyls mixture, exerts neurotoxic effects in C6 glial cells.

          • •

            Sub-toxic concentrations of A1254 decrease levels of glial fibrillary acidic protein.

          • •

            Sub-toxic concentrations of A1254 inhibit cAMP-induced astrocytic differentiation.

          • •

            A1254 reduces cAMP-dependent phosphorylation of STAT3 on Ser727 via protein kinase C.

          • •

            Polychlorinated biphenyls may affect astrocytic differentiation of glial cells.

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          Most cited references44

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          Differentiated rat glial cell strain in tissue culture.

          J H Lightbody, Raymond Sweet, Erica L Levine … (1968)
          Rat glial tumors, induced by injections of N-nitrosomethylurea, were plated and propagated in culture. Among a few cell strains obtained, one clone contains S-100 protein, which is unique to brain in vertebrates. Stationary-phase cultures contain approximately ten times more S-100 protein per cell than exponentially growing cells. When injected into newborn rats, cells producing S-100 grew as a glial tumor, which contained S-100 protein.
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            Effects of polychlorinated biphenyls on the nervous system.

            C De Bari, Walton Jones, O Faroon (2000)
            The neurological effects of polychlorinated biphenyls (PCBs) have been extensively investigated in humans and in animals. The main focus in human studies has been on the effects in neonates and young children, although studies of adults have also been conducted. A great deal of concern exists that even low levels of PCBs transferred to the fetus across the placenta may induce long-lasting neurological damage. Because PCBs are lipophilic substances, there is also concem that significant amounts might be transferred to nursing infants via breast milk. Studies in humans who consumed large amounts of Great Lakes fish contaminated with environmentally persistent chemicals, including PCBs. have provided evidence that PCBs are important contributors to subtle neurobehavioral alterations observed in newborn children and that some of these alterations persist during childhood. Some consistent observations at birth have been motor immaturity and hyporeflexia and lower psychomotor scores between 6 months and 2 years old. There is preliminary evidence that highly chlorinated PCB congeners, which accumulate in certain fish, are associated with neurobehavioral alterations seen in some newbom children. Subtle neurobehavioral alterations have also been observed in children bom to mothers in the general population with the highest PCB body burdens. Because of the limitations of epidemiological studies, these effects cannot be attributed entirely to PCB exposure. In one general population study, there was strong evidence that dioxins, as well as PCBs, were contributors to the neurobehavioral effects seen in exposed children. Children born to women who accidentally consumed rice oil contaminated with relatively high amounts of PCBs and chlorinated dibenzofurans (CDFs) during pregnancy also had neurodevelopmental changes. Studies in animals support the human data. Neurobehavioral alterations have been also observed in rats and monkeys following prenatal and/or postnatal exposure to commercial Aroclor mixtures, defined experimental congener mixtures, single PCB congeners, and Great Lakes contaminated fish. In addition, monkeys exposed postnatally to PCB mixtures of congeneric composition and concentration similar to that found in human breast milk showed learning deficits long after exposure had ceased. A few other generalizations can be made from the data in animals. It appears that ortho-substituted PCB congeners are more active than coplanar PCBs in modifying cognitive processes. In addition, one effect observed in both rats and monkeys--deficits on delayed spatial alternation--has been known to be induced by exposure to ortho-substituted PCBs, defined experimental mixtures, and commercial Aroclors. Both dioxin-like and non-dioxin-like PCB congeners have been shown to induce neurobehavioral alterations in animals. Changes in levels of neurotransmitters in various brain areas have also been observed in monkeys, rats, and mice. Of all the observed changes, the most consistent has been a decrease in dopamine content in basal ganglia and prefrontal cortex, but further research is needed before specific neurobehavioral deficits can be correlated with PCB-induced changes in specific neurotransmitters in specific brain areas.
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              Polychlorinated Biphenyls Disturb Differentiation of Normal Human Neural Progenitor Cells: Clue for Involvement of Thyroid Hormone Receptors

              Ellen Fritsche, Jason Cline, Ngoc-Ha Nguyen … (2005)
              Polychlorinated biphenyls (PCBs) are ubiquitous environmental chemicals that accumulate in adipose tissues over the food chain. Epidemiologic studies have indicated that PCBs influence brain development. Children who are exposed to PCBs during development suffer from neuropsychologic deficits such as a lower full-scale IQ (intelligence quotient), reduced visual recognition memory, and attention and motor deficits. The mechanisms leading to these effects are not fully understood. It has been speculated that PCBs may affect brain development by interfering with thyroid hormone (TH) signaling. Because most of the data are from animal studies, we established a model using primary normal human neural progenitor (NHNP) cells to determine if PCBs interfere with TH-dependent neural differentiation. NHNP cells differentiate into neurons, astrocytes, and oligodendrocytes in culture, and they express a variety of drug metabolism enzymes and nuclear receptors. Like triiodothyronine (T3), treatment with the mono-ortho-substituted PCB-118 (2,3′,4,4′,5-pentachlorobiphenyl; 0.01–1 μM) leads to a dose-dependent increase of oligodendrocyte formation. This effect was congener specific, because the coplanar PCB-126 (3,3′,4,4′,5-pentachlorobiphenyl) had no effect. Similar to the T3 response, the PCB-mediated effect on oligodendrocyte formation was blocked by retinoic acid and the thyroid hormone receptor antagonist NH-3. These results suggest that PCB-118 mimics T3 action via the TH pathway.
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                Author and article information

                Contributors
                Rosaria Arcone
                Journal
                Journal ID (nlm-ta): FEBS Open Bio
                Journal ID (iso-abbrev): FEBS Open Bio
                Title: FEBS Open Bio
                Publisher: Elsevier
                ISSN (Electronic): 2211-5463
                Publication date PMC-release: 29 October 2013
                Publication date (Electronic): 29 October 2013
                Publication date Collection: 2013
                Volume: 3
                Pages: 459-466
                Affiliations
                [a ]Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, Arcavacata di Rende, Cosenza (CS) 87036, Italy
                [b ]Department of Health Sciences, University of Catanzaro “Magna Graecia”, Viale Europa, Germaneto, Catanzaro (CZ) 88100, Italy
                [c ]Department of Neuroscience, Reproductive and Odontostomatologic Sciences, University of Naples “Federico II”, Via S. Pansini 5, Napoli (NA) 80131, Italy
                [d ]Department of Movement and Wellness Sciences, University of Naples “Parthenope”, Via Medina 40, Napoli (NA) 80133, Italy
                [e ]Department of Molecular Medicine and Medical Biotechonology, University of Naples “Federico II”, Via S. Pansini 5, Napoli (NA) 80131, Italy
                Author notes
                [* ]Corresponding author at: Department of Movement and Wellness Sciences, University of Naples “Parthenope”, Via Medina 40, Napoli(NA)80133, Italy. Tel.: +39 0817463146; fax: +39 0817464237. rosaria.arcone@ 123456uniparthenope.it
                [1]

                These authors contributed equally to this work.

                Article
                Publisher ID: S2211-5463(13)00065-X
                DOI: 10.1016/j.fob.2013.10.008
                PMC ID: 3829991
                PubMed ID: 24251112
                SO-VID: fd596011-9693-4a82-bb27-33b5c6635a3b
                Copyright © © 2013 The Authors
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 11 June 2013
                Date revision received : 20 October 2013
                Date accepted : 22 October 2013
                Categories
                Subject: Article

                Keywords: astrocytic differentiation,c6 glial cell line,aroclor1254,glial fibrillary acidic protein (gfap),protein kinase c (pkc),signal transducer and activator of transcription 3 (stat3),pcbs, polychlorinated biphenyls,dbcamp, n6,2′-o-dibutyryl camp,a1254, aroclor 1254,dmso, dimethyl sulfoxide,dmem, dulbecco’s modified eagle’s medium,mtt, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2h-tetrazolium bromide,nmda, n-methyl-d-aspartate,nnos, neuronal nitric oxide,cns, central nervous system,ros, reactive oxygen species,gfap, glial fibrillary acidic protein,gapdh, glyceraldehyde-3-phosphate dehydrogenase,dapi, 4′,6-diamidino-2-phenylindole,pka, protein kinase a,pkc, protein kinase c,bis, 2-[1-(3-dimethylamino-propyl)indol-3-yl]-3-(indol-3-yl) maleimide,stat3, signal transducer and activator of transcription 3,cre, camp responsive element,creb, camp-response element binding protein,tre, cre transcriptional response element
                Data availability:
                Keywords: astrocytic differentiation, c6 glial cell line, aroclor1254, glial fibrillary acidic protein (gfap), protein kinase c (pkc), signal transducer and activator of transcription 3 (stat3), pcbs, polychlorinated biphenyls, dbcamp, n6,2′-o-dibutyryl camp, a1254, aroclor 1254, dmso, dimethyl sulfoxide, dmem, dulbecco’s modified eagle’s medium, mtt, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2h-tetrazolium bromide, nmda, n-methyl-d-aspartate, nnos, neuronal nitric oxide, cns, central nervous system, ros, reactive oxygen species, gfap, glial fibrillary acidic protein, gapdh, glyceraldehyde-3-phosphate dehydrogenase, dapi, 4′,6-diamidino-2-phenylindole, pka, protein kinase a, pkc, protein kinase c, bis, 2-[1-(3-dimethylamino-propyl)indol-3-yl]-3-(indol-3-yl) maleimide, stat3, signal transducer and activator of transcription 3, cre, camp responsive element, creb, camp-response element binding protein, tre, cre transcriptional response element

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