No description available.

A recent chemical spill of 4-Methylcyclohexanemethanol (4-MCHM) in West Virginia left 300,000 people without water. Officials claimed that this compound is not lethally toxic, but potentially harmful if swallowed or inhaled, and can cause eye and skin irritation. Sittig's Handbook of Toxic and Hazardous Chemical Carcinogens reports high exposures from skin contact or inhalation may cause damage to the heart, liver, kidneys, and lungs, and may result in death. However, no quantitative data seem to exist and no references can be found on neurotoxicity. We have investigated the neurotoxicity of 4-MCHM using mammalian nerve cell networks grown on microelectrode arrays. Network spontaneous activity from multiple units (range 48 – 120 per network) were used as the primary readout. Individual units were followed based on spike waveforms digitized at 40 kHz (Plexon MNAP system). Dose response curves show the effective inhibitory concentration at 50 percent decrease (EC50) to average 27.4 microM SD±6.17. However, in the presence of 40 microM bicuculline, a competitive GABAA antagonist, the EC50 shifts to 70.63uM SD ±4.3; implying that early, low concentration exposures to 4-MCHM involve GABA activation. Initial activity loss occurs without active unit loss (defined as 10 or more template threshold crossing per min), indicating functional interference with spike production. Full recovery has not been seen at concentrations above 130 microM, unless the culture was given bicuculline. Direct exposure to 400uM results in immediate, irreversible loss of spike production, followed by necrosis of glia and neurons.

No description available.

Pesticides have been suggested to play a role in the development of many neurodegerative diseases including Parkinson's disease and Alzheimer's disease. Additionally, it has been suggested that exposure to pesticides and other environmental chemicals during the early stages of life could result in an increased vulnerability to such substances that could lead to neurotoxicity and degeneration late in life. We hypothesized that exposure to mixtures of certain pesticides could change neurotransmitter levels and cellular oxidative stress and that this would be greater in mice exposed early and later in life than mice exposed only as adults. We studied the effects of permethrin (PR) (a pyrethroid type I) and endosulfan (EN) (an organochlorine) on the levels of catecholamines, indolamines, acetylcholinesterase, lipid peroxidation and α-synuclein in the brain of mice. These pesticides have different structures but both are known to modify the kinetics of voltage-sensitive ion channels and calcium ion flux/homeostasis that could affect the release of several neurotransmitters. The study consisted of two experiments: In the first experiment, adult C57Bl/6 mice (7-9 months old) were injected, intraperitoneally, with the following treatments: EN 4.3, 2.15 mg/kg; PR 150, 15 mg/kg and their mixtures EN 4.3 + PR 150 and EN 2.15 + PR 15 mg/kg. Mice were sacrificed 24 hrs after the last injection. In the second experiment, doses consisted of EN 0.7, 1.4 mg/kg, PR 1.5, 15 mg/kg and their mixtures EN 0.7 + PR 1.5 mg/kg and EN 1.4 + PR 15 mg/kg were given to juvenile mice intraperitoneally daily during a period of two weeks from postnatal day 5 to 19. Mice were then, left undisturbed with their dams. Re-challenge was performed when mice were 7-9 months old and dosages of EN 4.3, 2.15 mg/kg, PR 150, 15 mg/kg and their mixtures, EN 4.3 + PR 150 and EN 2.15 + PR 15 mg/kg were given intraperitoneally every other day during a period of two weeks to match the treatments when pesticide exposure was only as adults. Mice were sacrificed 24 hrs after the last injection. The corpora striatum was extracted and analyzed by HPLC for catecholamines (dopamine, DOPAC, homovalinic acid and norepinephrine) and indolamines (serotonin and 5-HIAA). In general low doses of permethrin and endosulfan alone and in combination (EN 2.15 + PR 15 mg/kg) altered the levels of catecholamines and indolamines in both studies with adult mice and mice dosed as juveniles and re-challenged as adults. Catecholamine and indolamines levels were affected to a greater extent in the adult mice than in mice dosed as juveniles and re-challenged as adults, when compared to controls. Acetylcholinesterase was increased under both exposure situations but again adult mice seemed to be more affected than mice dosed as juveniles and re-challenged as adults. Because reactive oxygen species have been implicated in the development of Parkinson's disease, and are known to cause degradation of certain neurotransmitters, we monitored the levels of lipid peroxides in brain cortex as an indicator of free radical tissue damage. The peroxide levels were measured by thiobarbituric acid reactive products (TBARS). Increased levels of lipid peroxides were significant in the low dose treatment groups of the adult study. However, there seemed to be a pattern between the levels of dopamine and DOPAC in the striatum and the levels of peroxidation in cortex. The presence of dopamine metabolites appeared to be related to high levels of peroxidation within the basal ganglia and up-regulation of proteins such as α-synuclein. Western blots of α-synuclein in both experiments of the study showed intense double and triple bands that corresponded to aggregated α-synuclein. In general, when compared with controls, mice dosed as juveniles and re-challenged as adults did not alter the above parameters as much as mice dosed only as adults. Instead, the mice first dosed as juveniles seemed to develop an adaptation response to the later exposure of these pesticides. Taking all these results into account, early exposure and re-challenge with permethrin and endosulfan in this study appeared to induce a protective response against neurochemical changes in the brain of these mice. In addition, low doses of these pesticides and the low dose combination mixture seem to exert an effect on the parameters studied. Therefore, exposure to pesticides such as endosulfan and permethrin and their combinations could make a contribution towards the initiation or aggravation of biochemical neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. / Master of Science

This study examined the effects of low to moderate doses of manganese (0, 250, or 750 _g per day from PD 1-21) on a comprehensive battery of behaviors in rats during the neonatal period, preweanling period, and in adulthood.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Hydrocarbon solvents are widely used in the production of paints, adhesives, dyes, polymers, plastics, textiles, printing inks, agricultural products and pharmaceuticals. While the neuropathic potential of aliphatic solvents was shown in the 1970s, little is known about the neuropathic potential of aromatic solvents. The present study examines such solvents, 1,2-diethylbenzene (DEB) and its metabolite 1,2-diacetylbenzene (DAB), to determine (a) the neuropathological evidence for peripheral neuropathy in rodents treated with 1,2-DAB, (b) the neurochemical basis for the neurotoxic properties of this compound, and (c) the structural requirements for nerve fiber damage. The properties of 1,2-DAB and 2,5- hexanedione (HD) are also compared. A key finding of this thesis is that 1,2-DAB induces a 2,5-HD-like pattern of nerve damage of motor and sensory axons with focal swellings containing neurofilaments. Whereas nerve damage begins distally in 2,5-HD intoxication, with 1,2-DAB treatment axonal swellings begin intraspinally and in the proximal ventral roots of motor nerve fibers. A second key finding is the reactivity of 1,2-DAB with amino acids, notably lysine, a property that is shared with 2,5-HD. 1,2-DAB and 2,5-HD react with amino acids and proteins to form blue and yellow chromophores, respectively. Relative to 2,5-HD, 1,2-DAB is three orders of magnitude more reactive in forming high-molecular-weight species. 1,2-DAB treatment of spinal cord slices in vitro and intact sciatic nerve in vivo showed that neurofilament proteins react more readily than beta-tubulin. The heavy and medium subunits of neurofilament protein were more reactive than the light subunit. The reactivity of these four axonal proteins was in proportion to their lysine content. These data are consistent with selective accumulation of neurofilaments in giant axonal swellings. In summary, these studies have shown a relationship between the chromogenic and neuropathic properties of two gamma-diketones, one aliphatic (2,5-HD) the other aromatic (1,2-DAB). These studies are relevant to occupational and public health for at least two reasons. First, urinary chromogens generated by neuropathic aliphatic and aromatic hydrocarbons could serve as biological markers of exposure to solvents with neuropathic potential, and second, other chromogenic solvents (such as tetralin) should be considered for neuropathic potential. / Graduation date: 2002

Mercury (Hg) is a toxicant of global concern, but few strategies exist to evaluate its biological effects on the ecosystem. Piscivorous wildlife, such as mink (Mustela vison), are particularly at risk because they can bioaccumulate Hg to concentrations known to impair neurological systems. Given that biochemical changes in the brain precede functional and structural impairments, I evaluated the use of neurochemicals as early-warning biomarkers of Hg toxicity in mink. Initial studies demonstrated that neurochemical biomarkers could be measured from mink carcasses collected from the field, as long as factors such as storage temperature and freeze thaw cycles were accounted for. To determine if Hg could directly impair neurochemicals in mink, an in vitro study demonstrated that Hg (HgCl2 and MeHg) could inhibit radioligand binding to the muscarinic cholinergic (mACh) receptor in the cerebellum and cerebral cortex regions of the brain. By analyzing whole brains collected from wild mink, it was demonstrated that a significant positive correlation existed between concentrations of brain Hg and levels of mACh receptors. These field observations were confirmed by results from a controlled methyl Hg (MeHg) feeding trial in captive mink, whereby sub-chronic exposure of mink to 0.5 - 2 ppm MeHg (ecologically relevant levels) resulted in significant increases in acetylcholinesterase activity and mACh receptor levels in specific brain regions. Collectively, these results demonstrated that exposure of mink to environmentally realistic concentrations of Hg can be related to alterations in neurochemicals at multiple tiers of biological organization. Given the importance of a functional nervous system in wildlife health, the physiological and ecological significance of these findings need further exploration. The results demonstrate that neurochemical approaches may be novel biomarkers to assess the ecotoxicology of Hg, and by extension, other pollutants o

Thesis (Ph.D.)--Mississippi State University. College of Veterinary Medicine. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 174-200).