The ability to alter the gap junction protein expression outside GST-P positive foci in liver of rats was associated to the tumour promotion potency of different polychlorinated biphenyls

Bager, Yvonne; Kato, Yoshihisa; Kenne, Kerstin; Wärngård, Lars

doi:10.1016/s0009-2797(97)03759-9

Cited by 20 publications

(4 citation statements)

References 38 publications

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“…Several groups have reported that PCBs inhibit gap junction intercellular communication (GJIC) and dislocalize the corresponding proteins in several cell types (Bager et al 1994(Bager et al , 1997aBrevini et al 2004;Hamers et al 2011;Hemming et al 1991;Kang et al 1996;Kato et al 1998;Machala et al 2003;Simeckova et al 2009). Gap junctions (GJ) are intercellular channels consisting of conniving oligomers.…”

Section: Introductionmentioning

confidence: 99%

A structure–activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins

et al. 2017

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Migration of neural crest cells (NCC) is a fundamental developmental process, and test methods to identify interfering toxicants have been developed. By examining cell function endpoints, as in the 'migration-inhibition of NCC (cMINC)' assay, a large number of toxicity mechanisms and protein targets can be covered. However, the key events that lead to the adverse effects of a given chemical or group of related compounds are hard to elucidate. To address this issue, we explored here, whether the establishment of two overlapping structure-activity relationships (SAR)-linking chemical structure on the one hand to a phenotypic test outcome, and on the other hand to a mechanistic endpoint-was useful as strategy to identify relevant toxicity mechanisms. For this purpose, we chose polychlorinated biphenyls (PCB) as a large group of related, but still toxicologically and physicochemically diverse structures. We obtained concentration-dependent data for 26 PCBs in the cMINC assay. Moreover, the test chemicals were evaluated by a new high-content imaging method for their effect on cellular re-distribution of connexin43 and for their capacity to inhibit gap junctions. Non-planar PCBs inhibited NCC migration. The potency (1-10 µM) correlated with the number of ortho-chlorine substituents; non-ortho-chloro (planar) PCBs were non-toxic. The toxicity to NCC partially correlated with gap junction inhibition, while it fully correlated (p < 0.0004) with connexin43 cellular re-distribution. Thus, our double-SAR strategy revealed a mechanistic step tightly linked to NCC toxicity of PCBs. Connexin43 patterns in NCC may be explored as a new endpoint relevant to developmental toxicity screening.

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Section: Introductionmentioning

confidence: 99%

A structure–activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins

et al. 2017

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“…Several studies have demonstrated that PCBs can inhibit gap-junctional intercellular communication (GJIC) both in vivo (Krutovskikh et al, 1995;Bager et al, 1997) and in vitro in rat liver epithelial cells, mouse and rat hepatocytes, human keratinocytes, and normal human breast epithelial cells (Ruch & Klaunig, 1986;Swierenga et al, 1990;Hemming et al, 1991;Kang et al, 1996). The ortho-substituted PCBs were potent inhibitors of GJIC at low micromolar concentrations, while the coplanar PCBs did not inhibit GJIC after a single dose (Machala et al, 2003).…”

Section: (B) Cell-cell Communicationmentioning

confidence: 99%

Polychlorinated Biphenyls and Polybrominated Biphenyls

Agudo

Aronson²,

Bonefeld-Jörgensen³

et al. 2008

Organic Pollutants

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initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestyle factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in carcinogenesis and related fields; and to indicate where additional research efforts are needed. The lists of IARC evaluations are regularly updated and are available on the Internet at http:// monographs.iarc.fr/.This programme has been supported since 1982 by Cooperative Agreement U01 CA33193 with the United States National Cancer Institute, Department of Health and Human Services. Additional support has been provided since 1986 by the European Commission Directorate-General for Employment, Social Affairs, and Inclusion, initially by the Unit of Health, Safety and Hygiene at Work, and since 2014 by the European Union Programme for Employment and Social Innovation "EaSI" (2014-2020) The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications -whether for sale or for non-commercial distribution -should be addressed to the IARC Communications Group at: publications@iarc.fr.The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.The IARC Monographs Working Group alone is responsible for the views expressed in this publication. IARC Library Cataloguing in Publication Data NOTE TO THE READERThe term 'carcinogenic risk' in the IARC Monographs series is taken to mean that an agent is capable of causing cancer. The Monographs evaluate cancer hazards, despite the historical presence of the word 'risks' in the title.Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a Monograph does not mean that...

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“…This effect appears to be due to reduced expression of connexins, the gap junction forming protein (Fitzgerald et al, 1989). However, the association is not complete and disruption of gap junctions and down-regulation of connexins, on one hand, and the expression of GSTp, on the other hand, may represent two distinct pathways to tumor formation (Bager et al, 1997). Toxaphene and other nongenotoxic carcinogens have been shown to disrupt GJIC (Kang et al, 1996;Kolaja et al, 2000).…”

Section: Toxaphene As a Tumor Promotermentioning

confidence: 99%

Development of a reference dose for the persistent congeners of weathered toxaphene based on in vivo and in vitro effects related to tumor promotion

Simon

Manning²

2006

Regulatory Toxicology and Pharmacology

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Toxaphene is a mixture of chlorinated camphenes and bornanes that was produced and used in the United States until 1982. 1.3 million tons of toxaphene have been released worldwide. "Technical" toxaphene (TT) consists of a mixture of up to 800 different chemicals, known as congeners. TT weathers in the environment by both biotic and abiotic processes. The human body burden of toxaphene consists of only five persistent congeners that are not metabolized; three of these occur in considerably greater amounts than the other two. Because of the rapid metabolism and excretion of the non-persistent congeners, the persistent congeners that make up the human body burden most likely play a role in eliciting any potential adverse effects. EPA's toxicity assessment for TT is based on the occurrence of liver cancer in rodents, and considerable doubt exists whether this assessment is applicable to weathered toxaphene (WT). Using experimental results from European Union scientists, a reference dose (RfD) was developed for WT based on the three most persistent congeners that comprise the human body burden. The critical effect chosen was tumor promotion and this endpoint is considered protective for other endpoints as well. Although RfDs are typically derived for non-carcinogenic effects, the endpoint of tumor promotion is appropriate for RfD development because the experimental data suggest a dose threshold. The RfD for weathered toxaphene represented by the sum of the three major persistent congeners ( summation 3PC) is 2E-05 mg/kg-day. To apply this reference dose to a particular WT mixture, information is needed regarding the percentage of summation 3PC in the mixture.

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The ability to alter the gap junction protein expression outside GST-P positive foci in liver of rats was associated to the tumour promotion potency of different polychlorinated biphenyls

Cited by 20 publications

References 38 publications

A structure–activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins

A structure–activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins

Polychlorinated Biphenyls and Polybrominated Biphenyls

Development of a reference dose for the persistent congeners of weathered toxaphene based on in vivo and in vitro effects related to tumor promotion

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