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Selective vulnerability of dopaminergic systems to Manganese: Relevance to occupational exposure
M. Stanton et al. / Neurotoxicology and Teratology 30 (2008) 243–259
We have previously shown that exposure to 30 mg/kg/day of the commercial PBDE mixture DE-71 from postnatal days (PNDs) 6–12 significantly impairs learning of a visual attention task in adulthood but does not impair attention. In this study, the same behavioral tasks were administered to male Long–Evans rats exposed over the same time period, but to lower doses of DE-71 (5 or 15 mg/kg/day). DE-71 was dissolved in corn oil and administered via oral intubation. Control rats received corn oil alone. Rats were tested as adults on an automated, five-choice visual discrimination task. On each trial, the animals were food rewarded for making a nosepoke into the illuminated port. DE-71-exposed rats required a greater number of trials than controls to reach criterion (80% correct for two out of three daily sessions). The deficit in performance was due to less accurate responding and to increased omission errors (failures to respond within 30 s of cue onset). In contrast, sustained attention was unimpaired in the DE71-exposed rats. These findings suggest that brief exposure to even lower doses of DE-71 has long-lasting consequences for behavior. (Supported by CC Research and Development and Venture Grants). doi:10.1016/j.ntt.2008.03.055
NBTS53 Selective vulnerability of dopaminergic systems to Manganese: Relevance to occupational exposure Jeannette Stankowski, Duncan Leitch, Michael Aschner, BethAnn McLaughlin, Gregg D. Stanwood Vanderbilt University Medical Center, United States
Accumulating evidence supports that manganese (Mn) exposure enhances cell death associated with a host of neurological disorders including Alzheimer's and Parkinson's disease. Potential gene–environment interactions are particularly significant given the association of abnormally high brain Mn levels with Parkinson's symptoms, and that occupational exposure to Mn is common especially in welders. Inspite of epidemiological data suggesting that welders may be at high risk through occupational exposure, little is known about molecular mechanisms underlying Mn neurotoxicity. The goal of our study is to understand molecular mechanisms underlying Mn neurotoxicity using a combination of chronic in vivo and in vitro models; we detailed the damages caused by Mn exposure in cultured neurons and identify molecular signaling pathways that mediated degeneration. We found early changes in cytoskeletal structure associated with Alzheimer's-type pathology and that these changes were more strongly associated with dopaminergic neurons than other types of neurons. There also appears to be circuit level compensation for loss of dopaminergic innervation when animals were chronically exposed to Mn. Taken together, these data suggest that manganese is a potent neurotoxin to dopaminergic cells, that the primary sites of initial degeneration are in the distal cytoskeleton and that even small chronic levels of manganese (5 mg/kg/day) were capable of killing 20% of dopaminergic cells in the substantia nigra, resulting in dysfunction in the striatum and globus pallidus. (This work is supported DOD grant W81XWH-05-1-0239 and VKC P30-HD15052).
doi:10.1016/j.ntt.2008.03.056
259
NBTS54 Developmental manganese exposures produce neurobehavioral deficits associated with altered dopamine receptor/transporter expression Cynthia Kern, Donald Smith University of California, Santa Cruz, United States
Recent epidemiological reports in children reveal neurobehavioral and neurocognitive deficits associated with elevated environmental and dietary Mn exposures. Given that soy-based infant formulas and drinking water can contain naturally elevated Mn levels 100–300 times that found in breast milk, there is justified concern for neurodevelopmental deficits due to elevated Mn exposures in children. In this study we exposed neonatal rats to daily oral Mn doses of 0, 25, or 50 mg Mn/kg bw over PND 1–21. Preweaning Mn exposure resulted in hyperactivity and disinhibition in the open arena (PND23). However, Mn exposed animals showed no alteration in innate fear response in the elevated plus maze. Mn exposed animals were significantly impaired in the 8-arm radial maze learning paradigm (PND33–46) and either failed to reach learning criteria or showed a delay in learning while committing significantly more reference and total learning errors compared to controls. Interestingly, Mn exposed animals exhibited a greater frequency of stereotypic response strategies in searching for the baited arms. Finally, D1 receptor and DAT transporter levels in the Mn exposed animals were significantly decreased to ~60% of controls in the nucleus accumbens and dorsal striatum, while D2 receptor levels were significantly increased to ~500–700% of control in the pre-frontal cortex and accumbens. These data provide evidence that early Mn exposures produce behavioral hyperactivity, disinhibition, and deficits in learning, as well as significant alteration of dopamine receptor/transporter proteins in brain regions associated with attention, learning, and impulse control. doi:10.1016/j.ntt.2008.03.057
NBTS55 Developing a child-specific reference dose for manganese for use in school site risk assessment David Chan Office of Environmental Health Hazard Assessment, United States
A child-specific reference dose (chRD) for manganese has been developed to provide a means for California school districts to evaluate the potential risk of manganese found at existing or proposed school sites. The history of this State mandated program and the risk assessment process will be briefly reviewed. The application of both human and animal data in the development of this chRD will be discussed. In establishing the chRD, data from the 2002 Food and Nutrition Board study and from neonatal rat studies with neurobehavioral endpoints were analyzed and compared. The calculated reference dose values derived from these data sets fell within a narrow range. This strong agreement on the value based on a human no-observable-adverse-effect level (NOAEL) and an average of all other calculated values based on rat studies promotes confidence in the established chRD. In addition, a comparison will be made between this chRD and other existing numerical health guidance values.
doi:10.1016/j.ntt.2008.03.058
We have previously shown that exposure to 30 mg/kg/day of the commercial PBDE mixture DE-71 from postnatal days (PNDs) 6–12 significantly impairs learning of a visual attention task in adulthood but does not impair attention. In this study, the same behavioral tasks were administered to male Long–Evans rats exposed over the same time period, but to lower doses of DE-71 (5 or 15 mg/kg/day). DE-71 was dissolved in corn oil and administered via oral intubation. Control rats received corn oil alone. Rats were tested as adults on an automated, five-choice visual discrimination task. On each trial, the animals were food rewarded for making a nosepoke into the illuminated port. DE-71-exposed rats required a greater number of trials than controls to reach criterion (80% correct for two out of three daily sessions). The deficit in performance was due to less accurate responding and to increased omission errors (failures to respond within 30 s of cue onset). In contrast, sustained attention was unimpaired in the DE71-exposed rats. These findings suggest that brief exposure to even lower doses of DE-71 has long-lasting consequences for behavior. (Supported by CC Research and Development and Venture Grants). doi:10.1016/j.ntt.2008.03.055
NBTS53 Selective vulnerability of dopaminergic systems to Manganese: Relevance to occupational exposure Jeannette Stankowski, Duncan Leitch, Michael Aschner, BethAnn McLaughlin, Gregg D. Stanwood Vanderbilt University Medical Center, United States
Accumulating evidence supports that manganese (Mn) exposure enhances cell death associated with a host of neurological disorders including Alzheimer's and Parkinson's disease. Potential gene–environment interactions are particularly significant given the association of abnormally high brain Mn levels with Parkinson's symptoms, and that occupational exposure to Mn is common especially in welders. Inspite of epidemiological data suggesting that welders may be at high risk through occupational exposure, little is known about molecular mechanisms underlying Mn neurotoxicity. The goal of our study is to understand molecular mechanisms underlying Mn neurotoxicity using a combination of chronic in vivo and in vitro models; we detailed the damages caused by Mn exposure in cultured neurons and identify molecular signaling pathways that mediated degeneration. We found early changes in cytoskeletal structure associated with Alzheimer's-type pathology and that these changes were more strongly associated with dopaminergic neurons than other types of neurons. There also appears to be circuit level compensation for loss of dopaminergic innervation when animals were chronically exposed to Mn. Taken together, these data suggest that manganese is a potent neurotoxin to dopaminergic cells, that the primary sites of initial degeneration are in the distal cytoskeleton and that even small chronic levels of manganese (5 mg/kg/day) were capable of killing 20% of dopaminergic cells in the substantia nigra, resulting in dysfunction in the striatum and globus pallidus. (This work is supported DOD grant W81XWH-05-1-0239 and VKC P30-HD15052).
doi:10.1016/j.ntt.2008.03.056
259
NBTS54 Developmental manganese exposures produce neurobehavioral deficits associated with altered dopamine receptor/transporter expression Cynthia Kern, Donald Smith University of California, Santa Cruz, United States
Recent epidemiological reports in children reveal neurobehavioral and neurocognitive deficits associated with elevated environmental and dietary Mn exposures. Given that soy-based infant formulas and drinking water can contain naturally elevated Mn levels 100–300 times that found in breast milk, there is justified concern for neurodevelopmental deficits due to elevated Mn exposures in children. In this study we exposed neonatal rats to daily oral Mn doses of 0, 25, or 50 mg Mn/kg bw over PND 1–21. Preweaning Mn exposure resulted in hyperactivity and disinhibition in the open arena (PND23). However, Mn exposed animals showed no alteration in innate fear response in the elevated plus maze. Mn exposed animals were significantly impaired in the 8-arm radial maze learning paradigm (PND33–46) and either failed to reach learning criteria or showed a delay in learning while committing significantly more reference and total learning errors compared to controls. Interestingly, Mn exposed animals exhibited a greater frequency of stereotypic response strategies in searching for the baited arms. Finally, D1 receptor and DAT transporter levels in the Mn exposed animals were significantly decreased to ~60% of controls in the nucleus accumbens and dorsal striatum, while D2 receptor levels were significantly increased to ~500–700% of control in the pre-frontal cortex and accumbens. These data provide evidence that early Mn exposures produce behavioral hyperactivity, disinhibition, and deficits in learning, as well as significant alteration of dopamine receptor/transporter proteins in brain regions associated with attention, learning, and impulse control. doi:10.1016/j.ntt.2008.03.057
NBTS55 Developing a child-specific reference dose for manganese for use in school site risk assessment David Chan Office of Environmental Health Hazard Assessment, United States
A child-specific reference dose (chRD) for manganese has been developed to provide a means for California school districts to evaluate the potential risk of manganese found at existing or proposed school sites. The history of this State mandated program and the risk assessment process will be briefly reviewed. The application of both human and animal data in the development of this chRD will be discussed. In establishing the chRD, data from the 2002 Food and Nutrition Board study and from neonatal rat studies with neurobehavioral endpoints were analyzed and compared. The calculated reference dose values derived from these data sets fell within a narrow range. This strong agreement on the value based on a human no-observable-adverse-effect level (NOAEL) and an average of all other calculated values based on rat studies promotes confidence in the established chRD. In addition, a comparison will be made between this chRD and other existing numerical health guidance values.
doi:10.1016/j.ntt.2008.03.058