Mechanistical studies of the inhibition of intercellular communication by organochlorine compounds

Wärngård, Lars; Bager, Yvonne; Kato, Yoshihisa; Kenne, Kerstin; Ahlborg, Ulf G.

doi:10.1007/978-3-642-61105-6_16

Cited by 17 publications

(17 citation statements)

References 16 publications

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“…The DEP extract was not found to induce significant hyperphosphorylation of connexin43 (Fig. 4), indicating similarity with the mechanism of chlorinated hydrocarbons such as chlordane or DDT (Kenne et al 1994;Warngard et al 1996). This similarity was strengthened by the finding of a similar time dependent effect on GJIC, i.e., no indication of downregulation of an effector mechanism resulting in recurrence of communication as seen with TPA following its own regulation of PKC (Fig.…”

Section: Discussionsupporting

confidence: 59%

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Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles

Rivedal

Myhre

Sanner

et al. 2003

Archives of Toxicology

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This study presents a new strategy for the carcinogenic evaluation of complex chemical mixtures based on genotoxic and nongenotoxic assays. We studied the ability of organic extracts of diesel exhaust particles (DEP) to induce point mutations in five different Salmonella typhimurium strains (Ames test) and to inhibit gap junction intercellular communication (GJIC) in rat liver epithelial cell lines. A crude extract of DEP was prepared by extraction with dichloromethane (DCM), and fractionated according to polarity into five fractions: aliphatic hydrocarbons, polycyclic aromatic hydrocarbons (PAH), nitro-PAH, dinitro-PAH, and polar compounds. Statistical experimental design, multivariate data analysis, and modeling were used to quantify the mutagenicity of individual and combined DEP fractions in the Ames assay. Quantitative determination of GJIC was carried out using a recently described combination of scrape loading and digital image analysis. Both assays responded to the DEP extract, but the responses were due to different fractions. The nitro-PAH fraction showed the strongest mutagenic potential, followed by the dinitro-PAH fraction. The effect on GJIC was due to the fraction containing the polar components, followed by the dinitro-PAH fraction. The extract was found to induce both basepair substitutions and frameshift mutations, through activation by bacterial nitroreductases. Hyperphosphorylation of connexin43, the major connexin in the epithelial cell lines, was less evident for DEP extract than for other communication inhibitors such as phorbol esters and growth factors, and consequently inhibitors of the protein kinase C (PKC) and mitogen-activated protein (MAP) kinase pathway were unable to counteract the inhibition by DEP extract. Since the Ames test is a well accepted method to screen for substances with genotoxic activity while inhibition of GJIC is associated with effect of tumor promoters and nongenotoxic carcinogens, it is not surprising but encouraging and interesting that the present data indicate that the two endpoints supplement each other as screening tests and in the evaluation of hazardous compounds in complex mixtures.

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Section: Discussionsupporting

confidence: 59%

“…The mechanism by which substances such as chlorinated hydrocarbons inhibit cell communication is unknown. It is, however, believed that the effect in some way is mediated by interference with cell membrane properties (Warngard et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles

Rivedal

Myhre

Sanner

et al. 2003

Archives of Toxicology

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“…Heptanol, a 7 carbon saturated alcohol, reversibly blocks GJIC between cells 14 . Endosulfan, a chlorthiepin that is used as an insecticide, also inhibits GJIC 15,16 . Histological evaluation of markers of granulation tissue maturation was the approach taken to investigate the effect of locally injected uncouplers upon the deposition of granulation tissue within polyvinyl alcohol (PVA) sponge implants in rats.…”

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confidence: 99%

Role for gap junctional intercellular communications in wound repair

Ehrlich

Diez

2003

Wound Repair Regeneration

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The participation of fibroblasts in wound repair is a coordinated effort requiring sequential cellular modulations to behavior including migration (entering), proliferation (increasing cell numbers), synthesis (depositing a collagen matrix), remodeling (organizing collagen), transformation into myofibroblasts, apoptosis, and elimination. Disruptions in that orderly sequence of behaviors will alter repair. Insights into controlling wound repair have focused on soluble factors such as cytokines and growth factors. Here we examine the direct communications between coupled cells through gap junctional intercellular communications. Molecules of less than 1000 MW pass directly between cells through gated gap junction channels. Sugars, amino acids, and oxygen, as well as second messengers such as cAMP, inositol phosphates, and calcium can pass directly between coupled cells. Does gap junctional intercellular communication affect fibroblast phenotype progression in granulation tissue maturation? In rats gap junctional intercellular communication uncouplers heptanol and endosulfan were injected daily into polyvinyl alcohol sponge implants. At 7 days, uncoupler-treated implants had capsules with increased fibroblast density, reduced cell penetration into the sponge, and diminished numbers of myofibroblasts. By polarized light, the uncouplers reduced the deposition and organization of collagen and thereby disrupted the coordinated phenotypic changes seen in fibroblasts during the repair process. It is proposed that gap junctional intercellular communication is critical for fibroblast progression from migratory cell to apoptosis as granulation tissue matures into scar.

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“…95,114,115 α-Endosulfan was also reported as a tumour promoter causing a significant and dose-related increase in hepatocytes, 95,116 and to rapidly inhibit gap junctional intercellular communication (GJIC) in liver cells. 95,117,118 Teratogenicity A relationship has been observed between maternal exposure and fetal malformations in the skull, ribs and spine of rats. 100,119 Similar teratogenic effects, as well as accumulation of cerebrospinal fluid in the brain, underdeveloped cerebrum, incomplete ossification of skull bones, and malformations of the liver, kidneys, ribs and renal pelvis were observed.…”

Section: Carcinogenicitymentioning

confidence: 99%

Clinical Aspects of the Poisoning by the Pesticide Endosulfan

Patočka¹,

Wu²,

França³

et al. 2016

Química Nova

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publicado na web em 06/06/2016 Endosulfan is an organochlorine insecticide, widely used in insect control. Unfortunately, it is also an acute neurotoxic compound to both insects and mammals, including humans, and has been responsible for many severe poisonings and several fatal cases. Endosulfan also imitates or enhances the effect of the female hormone estrogen, having the capability of causing reproductive and developmental damage in both, animals and humans, and its exposure has been linked to liver tissue injury. This persistent lipophilic compound is one of the most abundant organochlorine pesticides in the environment, capable of undergoing long range transport to remote locations such as the Arctic. It is practically water-insoluble, but readily adheres to clay particles and persists in soil and water for several years. Its indiscriminate and injudicious use in the control of insects on a wide range of agricultural products and in the extermination of household pests, has considerably increased the hazard risk for human health. Also, this compound has a high fatality rate in humans when ingested accidentally, from food or water contaminated, or in suicidal cases. The aim of this article is to review and summarize chemical, biochemical, environmental, and toxicological data of endosulfan and draw attention to its toxicological potential risk to human health.

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Mechanistical studies of the inhibition of intercellular communication by organochlorine compounds

Cited by 17 publications

References 16 publications

Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles

Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles

Role for gap junctional intercellular communications in wound repair

Clinical Aspects of the Poisoning by the Pesticide Endosulfan

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