NBTS / INA 2015 Abstracts
NTX59 Solvents and Parkinson syndromes Eric Ben Brika, Vincent Bonneterreb, Jacques Reisc, Peter S. Spencerd CHU Poitiers, Poitiers, France b CHU Grenoble, Grenoble, France c Université de Strasbourg, Strasbourg, France d Oregon Health & Science University, Portland, OR, USA
a
Certain organic solvents are well known for their chronic neurotoxic potential: some aliphatic and aromatic compounds induce peripheral (axonal) neuropathy, while solvent mixtures are linked to encephalopathy. Prolonged occupational exposures to carbon disulfide or to chlorinated solvents (notably trichloroethylene) appear to be risk factors for Parkinsonism or Parkinson's disease (PD) [1, 2] but solventassociated PD mortality was not found in a recent large populationbased prospective cohort study [3]. We report 4 cases of PD related to a mixed solvent exposure in occupational settings. After clinical examination, all patients underwent neuropsychological testing, brain magnetic resonance imaging (1.5 or 3.0 Tesla) and single-photon emission computed tomography DaT SCAN. The EUROQUEST solvent questionnaire and polysomnography were administered in two cases. All 4 workers were car painters whose jobs required the use of solvent-containing paints, glues, lacquers, adhesives, and surface cleaners. Product access in one case suggested exposure to trichloroethylene, toluene, xylene and styrene. One of the major challenges in solvent neurotoxicity research is that people are exposed to mixtures of different compounds, such that it is impossible to ascribe culpability to single or multiple interacting substances. While the clinical workup of these cases is consistent with Parkinson syndrome an etiological association with solvent neurotoxicity is guarded. Solvent exposure was assessed with an occupational exposure matrix and job register, not on analysis of solvent composition, breathing zone air concentration, or absorbed dose. Our goal is to assess the link between occupational solvent exposure and Parkinson syndromes from a regulatory point of view. Scientific evidence supporting causation might lead to their recognition as an occupational disease in French Law. However, major questions remain: How can we improve assessment of cause and effect? How much weight should be placed on epidemiological association? Could some brain imaging techniques help? Are definitive controlled experimental studies needed to support clinical and epidemiologic data? 1. D.M. Gash et al., Ann. Neurol. 63:184, 2008 2. S.M. Goldman et al., Ann. Neurol. 71:776, 2012 3. M. Brouwer et al., Occup. Environ. Med. Feb 23, 2015 doi:10.1016/j.ntt.2015.04.065
NTX60 Gestation-only trichloroethylene exposure induced differential brain region-specific neurotoxicity in male offspring Sarah Blossom, Ming Li, Grant Chandler, Stepan Stepan Melnyk, Willam D. Wessinger University of Arkansas for Medical Sciences, Little Rock, AR, USA Previous studies in our lab focused on neurotoxic effects of postnatal exposure to the organic solvent and environmental pollutant, trichloroethylene (TCE) in autoimmune-prone MRL+/+ mice. The purpose of this study was to examine the neurotoxic potential of TCE during prenatal exposure in male offspring since others have shown maternal exposure to chemicals during pregnancy induced a variety of functional abnormalities in the brain of the
119
offspring. In the current study, TCE (~3 mg/kg/day) administered to the maternal drinking water during gestation increased locomotor activity and velocity (cm/s) in male offspring when evaluated at 6 weeks of age. Interestingly, these effects were not observed at the high dose (29 mg/kg/day). Glial cells from whole brain of prenatallyexposed male mice were isolated, cultured, and stimulated with LPS ex vivo. Culture supernatants from the TCE-exposed mice had significantly increased levels of the proinflammatory cytokine, IL-6, relative to controls (213 vs. 480 pg/ml, 0 and 3 mg/kg/day, respectively). Neuroinflammation, oxidative stress and loss of neurotrophic support are closely linked with adverse behavior. Thus, oxidative-stress biomarkers and neurotrophins were evaluated in cerebellum and hippocampus. There was a significant increase in oxidized glutathione (GSSG) and the ratio of reduced/oxidized glutathione (GSH/GSSG) in hippocampus but not cerebellum indicating increased hippocampal oxidative stress. The dramatic decrease in cerebellar cysteine, the precursor of GSH in cerebellum further suggested that the cerebellum was better able to regulate oxidative stress with TCE exposure. Relative mRNA expression of BDNF was also assessed in hippocampus and cerebellum. BDNF was significantly decreased in cerebellum and significantly increased in hippocampus. These findings suggested that the hippocampal region needed neurotrophic support to combat its increased vulnerability to oxidative stress. The effects of prenatal low-level TCE exposure were long lasting and altered behavior, and increased neuroinflammation and oxidative stress biomarkers in the hippocampal region. Future research will focus on epigenetic mechanisms of this transgenerational effect of TCE on hippocampal-specific behaviors. This research was supported by the National Institutes of Health and the Arkansas Biosciences Institute (SJB). doi:10.1016/j.ntt.2015.04.066
NTX61 Combined exposure to impulse noise and styrene Pierre Campo, Thomas Venet, Aurélie Thomas, Chantal Cour, Frédéric Cosnier Institut National de Recherche et de Sécurité, Vandœuvre Cedex, France The neuropharmacological (rapid) and cochleotoxic (slow) effects of styrene can exacerbate the impact of noise on the peripheral auditory receptor. The mechanisms through which coexposure to noise and styrene impairs hearing are difficult to identify particularly when the slowly developing cochleotoxic process is masked in the short-term by the rapid pharmacological effect on the central nervous system (CNS). It is clear that the neuropharmacological impact of the solvent on the acoustic (middle-ear and olivocochlear) reflexes can have a global effect on hearing. The study was designed to evaluate the effects of a noise (continuous vs. impulse), and a low or high concentration (300 ppm vs. 600 ppm) of styrene on the peripheral auditory receptor, and on the CNS, and secondly, the auditory frequency range sensitive to noise, to styrene, and to noise and styrene combined. Male Brown–Norway rats were exposed either to styrene, or to an octave band noise centered at 8 kHz, or to both noise and styrene. The noise exposure was of two different types: impulse noise with a LEX,8 h of 80 dB or continuous noise with a LEX,8 h of 85 dB SPL. Hearing was tested using distortion product oto-acoustic emissions, and the receptors were analyzed with histology. Although the LEX,8 h of the impulse noise was lower (80 dB SPL) than that of the continuous noise (85 dB SPL), it appeared more detrimental to the cochleae. Moreover, a co-exposure to styrene and continuous noise was less damaging than exposure to continuous noise alone, regardless of the concentration of styrene. In contrast,