Effects of co-exposure to CS2 and noise on hearing and balance in rats: continuous versus intermittent CS2 exposures

Background: carbon disulfide (CS2) exacerbates the effect of noise on hearing, and disrupts the vestibular system. The goal of this study was to determine whether these effects are also observed with intermittent CS2 exposure. Methods: rats were exposed for 4 weeks (5 days/week, 6 h/day) to a band noise at 106 dB SPL either alone or combined with continuous (63 ppm or 250 ppm) or intermittent (15 min/h or 2 × 15 min/h at 250 ppm) CS2. Hearing function was assessed by measuring distortion product otoacoustic emissions (DPOAEs); balance was monitored based on the vestibulo-ocular reflex (VOR). Functional measurements were performed before, at the end of exposure and 4 weeks later. Histological analyses of the inner ear were also performed following exposure and after the 4-week recovery period. Results: the results obtained here confirmed that CS2 exposure exerts two differential temporary effects on hearing: (1) it attenuates the noise-induced DPOAE decrease below 6 kHz probably through action on the middle ear reflex when exposure lasts 15 min per hour, and (2) continuous exposure to 250 ppm for 6 h extends the frequency range affected by noise up to 9.6 kHz (instead of 6 kHz with noise alone). With regard to balance, the VOR was reversibly disrupted at the two highest doses of CS2 (2 × 15 min/h and continuous 250 ppm). No morphological alterations to the inner ear were observed. Conclusion: these results reveal that short periods of CS2 exposure can alter the sensitivity of the cochlea to noise at a dose equivalent to only 10 times the short-term occupational limit value, and intermittent exposure to CS2 (2 × 15 min/h) can alter the function of the vestibular system

Biomarkers of toluene exposure in rats: mercapturic acids versus traditional indicators (urinary hippuric acid and o -cresol and blood toluene)

International audience1. Toluene (TOL) is a neurotoxic, ototoxic and reprotoxic solvent which is metabolized via the glutathione pathway, producing benzylmercapturic, o-, m-and p-toluylmercapturic acids (MAs). These metabolites could be useful as biomarkers of TOL exposure. 2. The aims of this work were 1) to provide data on MAs excretion in rat urine following TOL exposure by inhalation, 2) to compare them to data from traditional TOL biomarkers i.e., TOL in blood (Tol-B), and urinary hippuric acid (HA) and o-cresol (oCre), and 3) to establish the relationships between these different indicators and the airborne TOL concentration (Tol-A). 3. Sprague-Dawley rats were exposed to a range of TOL concentrations. Blood and urine were collected and analyzed to determine biomarker levels. 4. Levels of the four MAs correlate strongly with Tol-A (comparable to the correlation with Tol-B). 5. MAs are thus clearly superior to oCre and HA as potential markers of exposure to TOL.Le toluène (TOL) est un solvant CMR qui peut être métabolisé par la voie du glutathion, ce qui conduit à la production de quatre acides mercapturiques (AMs) : les acides benzylmercapturique et o-, m-et p-toluylmercapturique. Ces métabolites peuvent être utiles en tant que d’indicateurs biologiques d'exposition au TOL. Les objectifs de ce travail étaient : de fournir des données sur l'excrétion des AMs dans l'urine de rat après une exposition par inhalation au TOL ; de les comparer aux données obtenues avec les biomarqueurs traditionnels du TOL i.e. le toluène sanguin (Tol-S), et les indicateurs urinaires que sont l'acide hippurique (AH) et l’o-crésol (oCre) et d'établir les relations entre ces différents indicateurs et la concentration atmosphérique en TOL (Tol-A). Pour cela, des rats Sprague-Dawley ont été exposés à différents niveaux de TOL. Leur sang et leurs urines ont été prélevés et analysés afin de déterminer les niveaux de chaque biomarqueur. Il a ainsi été établi que les niveaux des quatre AMs étaient fortement corrélés avec ToL-A (comparable à la celle observée avec Tol-S). En conclusion, il apparait que les AMs sont nettement supérieurs à AH et oCre en tant que marqueurs potentiels de l'exposition au TOL

Neurobehavioral toxicity of a repeated exposure (14 days) to the airborne polycyclic aromatic hydrocarbon fluorene in adult Wistar male rats.

Fluorene is one of the most abundant polycyclic aromatic hydrocarbons in air and may contribute to the neurobehavioral alterations induced by the environmental exposure of humans to PAHs. Since no data are available on fluorene neurotoxicity, this study was conducted in adult rats to assess the behavioral toxicity of repeated fluorene inhalation exposure. Male rats (n = 18/group) were exposed nose-only to 1.5 or 150 ppb of fluorene 6 hours/day for 14 consecutive days, whereas the control animals were exposed to non-contaminated air. At the end of the exposure, animals were tested for activity and anxiety in an open-field and in an elevated-plus maze, for short-term memory in a Y-maze, and for spatial learning in an eight-arm maze. The results showed that the locomotor activity and the learning performances of the animals were unaffected by fluorene. In parallel, the fluorene-exposed rats showed a lower level of anxiety than controls in the open-field, but not in the elevated-plus maze, which is probably due to a possible difference in the aversive feature of the two mazes. In the same animals, increasing blood and brain levels of fluorene monohydroxylated metabolites (especially the 2-OH fluorene) were detected at both concentrations (1.5 and 150 ppb), demonstrating the exposure of the animals to the pollutant and showing the ability of this compound to be metabolized and to reach the cerebral compartment. The present study highlights the possibility for a 14-day fluorene exposure to induce some specific anxiety-related behavioral disturbances, and argues in favor of the susceptibility of the adult brain when exposed to volatile fluorene

Membrane fluidity does not explain how solvents act on the middle-ear reflex

International audienc

Identification of a Gene Signature Predicting (Nano)Particle-Induced Adverse Lung Outcome in Rats

Nanoparticles are extensively used in industrial products or as food additives. However, despite their contribution to improving our quality of life, concerns have been raised regarding their potential impact on occupational and public health. To speed up research assessing nanoparticle-related hazards, this study was undertaken to identify early markers of harmful effects on the lungs. Female Sprague Dawley rats were either exposed to crystalline silica DQ-12 with instillation, or to titanium dioxide P25, carbon black Printex-90, or multi-walled carbon nanotube Mitsui-7 with nose-only inhalation. Tissues were collected at three post-exposure time points to assess short- and long-term effects. All particles induced lung inflammation. Histopathological and biochemical analyses revealed phospholipid accumulation, lipoproteinosis, and interstitial thickening with collagen deposition after exposure to DQ-12. Exposure to the highest dose of Printex-90 and Mitsui-7, but not P25, induced some phospholipid accumulation. Comparable histopathological changes were observed following exposure to P25, Printex-90, and Mitsui-7. Comparison of overall gene expression profiles identified 15 potential early markers of adverse lung outcomes induced by spherical particles. With Mitsui-7, a distinct gene expression signature was observed, suggesting that carbon nanotubes trigger different toxicity mechanisms to spherical particles.Peer reviewe

Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

<p>1. Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK).</p> <p>2. Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated.</p> <p>3. Although the cytochrome P450 concentration was unchanged, and the activities of CYP1A2 and CYP2E1 isoforms were not additively or synergistically induced by co-exposure, TOL metabolism was inhibited by the presence of MEK (and vice versa). Depending on the relative proportions of each compound in the mixture, this sometimes resulted in a large increase in blood and brain concentrations. Apart from extreme cases (unbalanced mixtures), the amount of o-cresol and benzylmercapturic acid (and to a lesser extent 2,3-butanediols) excreted were proportional to the blood solvent concentrations.</p> <p>4. In a co-exposure context, ortho-cresol and benzylmercapturic acid can be used as urinary biomarkers in biomonitoring for employees to relatively accurately assess TOL exposure.</p

Effects of fluorene on spatial memory performances assessed in the eight-arm maze.

<p>Results are expressed as mean ± S.E.M. of n = 12 rats/group. ** <i>p</i><0.01, statistical significant variation (two-way ANOVA with repeated measures as one factor). Abbreviations: n.s., not significant.</p

Effects of fluorene on spontaneous alternation performances assessed in the Y-maze.

<p>Results are expressed as mean ± S.E.M. of n = 12 rats/group. Abbreviations: n.s., not significant.</p