Interruption of cell-cell communication in Chinese hamster V79 cells by various alkyl glycol ethers: implications for teratogenicity.

Abstract

Intercellular communication most likely plays a significant coordinating role in morphogenesis. Blockage of a specific type of intercellular communication, that mediated by gap junctions, has been proposed as a mechanism of action of some teratogens. Several glycol ethers have recently been shown to be teratogenic in laboratory animals. Because these compounds are negative in genotoxic assays, it is suggested that they may act by nongenetic, perhaps membrane-mediated mechanisms.In the present study several structurally related alkyl glycol ethers were examined for their ability to block junction-mediated intercellular communication. Interruption of intercellular communication was measured in vitro by an assay that depends on the transfer of metabolites via gap junctions, i.e., metabolic cooperation. All compounds tested-ethylene glycol (EG), ethylene glycol monomethyl ether (EGME), ethylene glycol monoethyl ether (EGEE), ethylene glycol monopropyl ether (EGPE), and ethylene glycol monobutyl ether (EGBE)-were able to block metabolic cooperation in vitro. The potencies of the compounds were inversely related to the length of the aliphatic chain, the dose required for maximum blockage increasing as the aliphatic chain shortened. Some differences in the maximum amount of blockage were detected, but these were not consistent and hence were not considered significant. Cytotoxicity, as measured by cell survival, was also related to the structure of the compound, generally increasing with increased length of the aliphatic chain. There were structurally related differences in the concentration ranges over which the compounds were effective. The noncytotoxic ranges over which communication was blocked became reduced as the length of the aliphatic chain increased. EG was effective over the broadest range, followed by EGME. The remaining compounds had very narrow effective ranges relative to EG and EGME. Because they are effective over such broad noncytotoxic ranges, blockage of intercellular communication may be most significant as a teratogenic mechanism for EG and EGME. Although the other compounds in the series also blocked communication, they were more cytotoxic and they interrupted communication in a relatively narrow window of concentrations. Consequently, interrupted intercellular communication may be mixed with cytotoxicity in the embryo and the mother, and thus be less specific as a mechanism of teratogenesis for EGEE, EGPE and EGBE.

Final Report on the Safety Assessment of Ethoxyethanol and Ethoxyethanol Acetate

“…Ethoxyethanol was described as an effective blocker of intercellular communication. The researchers noted that the blockage of a speci c type of intercellular communication, mediated by gap junctions, has been proposed as a mechanism of action of some teratogens (Loch-Caruso, Trosko, Corcos 1984). Ethoxyethanol-induced inhibition of metabolic cooperation in Chinese hamster V79 cells also has been demonstrated in other studies (Chen et al 1984;Welsch and Stedman 1984).…”

Reproductive toxic agents in work environments and related cases in Korea

“…Some of the mechanisms of each reproductive toxicity factor is known, but most are unknown. Ethylene glycol ethers are known to cause reproductive toxicity by breaking the gap junctions of cells [28,35]. Some substances, such as cadmium, act as an asphyxiant or placental toxin [36].…”

Concurrent teratogenic and mutagenic action of 2‐methoxyethanol in Drosophila melanogaster larvae resulted in similar phenotypes: Close resemblance to directed mutations

“…2). Inhibition of intercellular communication by a gap-junction breakdown has been observed as well [58,59]. More recently electron paramagnetic resonance (EPR) has been employed as a tool to resolve the mechanism of teratogenicity of 2-ME and MAA.…”

“…2-ME and its oxidation products MAALD and MAA are dispersed simultaneously throughout the larva, where a variety of cell types are exposed. The teratogenicity of compounds like 2-ME or MAA is thought to act via inhibition of cell-cell interactions [58,59], probably by disturbing transport or receptor proteins [60], and by inhibition of flavoproteins sarcosine dehydrogenase and dimethylglycine dehydrogenase [25,57,78]. Some downstream targets of Notch signalling are beginning to be elucidated, which suggests relatively direct signal transmission from the cell surface to the nucleus [75].…”