Ototoksične tvari na radnom mjestu: kratak uvid u stanje

Ototoxic chemicals can impair the sense of hearing and balance. Lately, efforts have been intensifi ed to compile evidence-based lists of workplace agents with ototoxic properties. This article gives a rough overview of the latest relevant publications, which confirm that toluene, styrene, and lead should receive particular attention as ototoxic substances at the workplace. Moreover, there is sufficient evidence that occupational exposure to trichloroethylene, mercury, carbon monoxide, and carbon disulfide can affect the ear. Based on the existing information, industrial hygienists should make sure that occupational health professionals and the workforce are made aware of the risks posed by ototoxic substances; support their replacement or new technical measures to reduce exposure; make these substances a part of regular screening, develop tools that can early diagnose chemically induced hearing impairment, and investigate further into the ototoxic properties of these substances. Further research should focus on quantifying the combined effects of ototoxic substances and noise.Ototoksične kemikalije mogu narušiti osjetilo sluha i ravnotežu. Nedavno su uloženi dodatni napori u izradu znanstveno utemeljenih popisa tvari koje su prisutne na radnom mjestu, a koje imaju ototoksična svojstva. Ovaj rad daje kratak uvid u najnovije publikacije objavljene na ovu temu. Usporedba navedenih publikacija potvrđuje da bi toluen, stiren i olovo trebalo razmatrati kao izrazito bitne ototoksične tvari koje postoje na radnom mjestu. Nadalje, postoje dovoljni dokazi koji potvrđuju da ototoksične tvari poput trikloretilena, žive, ugljikova monoksida i disulfida u radnom okruženju mogu oštetiti sluh. Temeljem postojećih informacija stručnjaci u području higijene rada trebali bi upozoravati stručnjake u području medicine rada i same radnike na rizike koje ototoksične tvari predstavljaju; poticati ih na zamjenu takvih tvari ili uvođenje novih mjera za smanjenje izlaganja; uključiti ototoksične tvari u redoviti program praćenja i osmisliti mjere za rano otkrivanje oštećenja sluha zbog izloženosti kemijskim tvarima; dodatno istražiti ototoksična svojstva ovih tvari. Buduća istraživanja trebala bi se usredotočiti na izračun ukupnih učinaka ototoksičnih tvari i buke

Functional Hair Cell Mechanotransducer Channels Are Required for Aminoglycoside Ototoxicity

Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss

Gentamicin affects the bioenergetics of isolated mitochondria and collapses the mitochondrial membrane potential in cochlear sensory hair cells

Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) – a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures

Dimethyl Sulfoxide (DMSO) Exacerbates Cisplatin-induced Sensory Hair Cell Death in Zebrafish (Danio rerio)

Inner ear sensory hair cells die following exposure to aminoglycoside antibiotics or chemotherapeutics like cisplatin, leading to permanent auditory and/or balance deficits in humans. Zebrafish (Danio rerio) are used to study drug-induced sensory hair cell death since their hair cells are similar in structure and function to those found in humans. We developed a cisplatin dose-response curve using a transgenic line of zebrafish that expresses membrane-targeted green fluorescent protein under the control of the Brn3c promoter/enhancer. Recently, several small molecule screens have been conducted using zebrafish to identify potential pharmacological agents that could be used to protect sensory hair cells in the presence of ototoxic drugs. Dimethyl sulfoxide (DMSO) is typically used as a solvent for many pharmacological agents in sensory hair cell cytotoxicity assays. Serendipitously, we found that DMSO potentiated the effects of cisplatin and killed more sensory hair cells than treatment with cisplatin alone. Yet, DMSO alone did not kill hair cells. We did not observe the synergistic effects of DMSO with the ototoxic aminoglycoside antibiotic neomycin. Cisplatin treatment with other commonly used organic solvents (i.e. ethanol, methanol, and polyethylene glycol 400) also did not result in increased cell death compared to cisplatin treatment alone. Thus, caution should be exercised when interpreting data generated from small molecule screens since many compounds are dissolved in DMSO.National Institutes of Health (U.S.) (DC010998)National Institutes of Health (U.S.) (NIH DC010231)Harvard College (1780- )Sarah Fuller Foundation for Little Deaf Childre

Uptake of Gentamicin by Bullfrog Saccular Hair Cells in vitro

Vertebrate sensory hair cells in the inner ear are pharmacologically sensitive to aminoglycoside antibiotics. Although the ototoxicity of aminoglycosides is well known, the route of drug uptake by hair cells and mechanisms of cytotoxicity remain poorly understood. Previously published studies have documented the intracellular distribution of gentamicin using immunocytochemical, electron microscopic, and autoradiographic methods. In this article, we compare the subcellular distribution of fluorescently conjugated gentamicin (gentamicin–Texas Red, GTTR) with immunolabeled gentamicin using confocal or electron microscopy. Gentamicin (detected by postfixation immunocytochemistry) and GTTR were rapidly taken up by hair cells throughout the bullfrog saccular explant in vitro and preferentially in peripheral hair cells. Immunolabeled gentamicin and GTTR were observed at the apical membranes of hair cells, particularly in their hair bundles. GTTR was also identified within a variety of subcellular compartments within hair cells, including lysosomes, mitochondria, Golgi bodies, endoplasmic reticulum, and nuclei, and in similar structures by immunoelectron microscopy. The distributions of GTTR and immunolabeled gentamicin are largely identical and corroborate a variety of published immunocytochemical and autoradiography studies. Thus, GTTR is a valid fluorescent probe with which to investigate the pharmacokinetics and mechanisms of gentamicin accumulation