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Perinatal manganese exposure and hydroxyl radical formation in rat brain.

Bałasz M, Szkilnik R, Brus R, Malinowska-Borowska J, Kasperczyk S, Nowak D, Kostrzewa RM, Nowak P - Neurotox Res (2014)

Bottom Line: We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy.Also, damage to the dopaminergic system acts as a "trigger mechanism," initiating a cascade of adverse events leading to a protracted increase in HO(•) generation, and the effects of Mn and 6-OHDA are compounded.In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HO(•) formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicology and Occupational Health Protection, Public Health Faculty, Medical University of Silesia, Medykow 18, 40-752, Katowice Ligota, Poland.

ABSTRACT
The present study was designed to investigate the role of pre- and postnatal manganese (Mn) exposure on hydroxyl radical (HO(•)) formation in the brains of dopamine (DA) partially denervated rats (Parkinsonian rats). Wistar rats were given tap water containing 10,000 ppm manganese chloride during the duration of pregnancy and until the time of weaning. Control rat dams consumed tap water without added Mn. Three days after birth, rats of both groups were treated with 6-hydroxydopamine at one of three doses (15, 30, or 67 µg, intraventricular on each side), or saline vehicle. We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy. In neonates, the major organs that accumulated Mn were the femoral bone and liver. However, Mn was not elevated in tissues in adulthood. To determine the possible effect on generation of the reactive species, HO(•) in Mn-induced neurotoxicity, we analyzed the contents of 2.3- and 2.5-dihydroxybenzoic acid (spin trap products of salicylate; HO(•) being an index of in vivo HO(•) generation), as well as antioxidant enzyme activities of superoxide dismutase (SOD) isoenzymes and glutathione S-transferase (GST). 6-OHDA-depletion of DA produced enhanced HO(•) formation in the brain tissue of newborn and adulthood rats that had been exposed to Mn, and the latter effect did not depend on the extent of DA denervation. Additionally, the extraneuronal, microdialysate, content of HO(•) in neostriatum was likewise elevated in 6-OHDA-lesioned rats. Interestingly, there was no difference in extraneuronal HO(•) formation in the neostriatum of Mn-exposed versus control rats. In summary, findings in this study indicate that Mn crosses the placenta but in contrast to other heavy metals, Mn is not deposited long term in tissues. Also, damage to the dopaminergic system acts as a "trigger mechanism," initiating a cascade of adverse events leading to a protracted increase in HO(•) generation, and the effects of Mn and 6-OHDA are compounded. Moreover, HO(•) generation parallels the suppression of SOD isoenzymes and GST in the brains of rats lesioned with 6-OHDA and/or intoxicated with Mn-the most prominent impairments being in frontal cortex, striatum, and brain stem. In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HO(•) formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders.

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Striatal microdialysate 2.3-DHBA concentrations in control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 5–7). Legend: open diamond control open square manganese filled diamond control + 6-OHDA (134 µg) filled square manganese + 6-OHDA (134 µg) * p < 0.05 control versus control + 6-OHDA (134 µg) # p < 0.05 manganese versus manganese + 6-OHDA (134 µg)
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Fig6: Striatal microdialysate 2.3-DHBA concentrations in control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 5–7). Legend: open diamond control open square manganese filled diamond control + 6-OHDA (134 µg) filled square manganese + 6-OHDA (134 µg) * p < 0.05 control versus control + 6-OHDA (134 µg) # p < 0.05 manganese versus manganese + 6-OHDA (134 µg)

Mentions: After switching aCSF to aCSF with 5 mM salicylic acid (point “0” on the graph), 2.3- and 2.5-DHBA appeared in the microdialysates of the neostriatum. The formation of 2.3-DHBA stabilized at 44 min in control and Mn-exposed rats and reached a concentration of ~100 pg/20 µl in both groups. In control rats treated at P3 with 6-OHDA (134 µg) as well as in Mn-exposed rats treated at P3 with 6-OHDA (134 µg), 2.3-DHBA levels stabilized at 66 min and attained a concentration of ~180 pg/20 µl. Significant differences between control and control + 6-OHDA groups were observed at 88, 110, 132, 154, and 176 min (p < 0.05), whereas differences were observed between Mn and Mn + 6-OHDA groups at 88, 110, and 132 min of testing [Fig. 6]. With respect to the 2.5-DHBA microdialysate, significant differences between control vs. control + 6-OHDA and Mn vs. Mn + 6-OHDA were noted between 88 and 220 min of the experiment [Fig. 7].Fig. 6


Perinatal manganese exposure and hydroxyl radical formation in rat brain.

Bałasz M, Szkilnik R, Brus R, Malinowska-Borowska J, Kasperczyk S, Nowak D, Kostrzewa RM, Nowak P - Neurotox Res (2014)

Striatal microdialysate 2.3-DHBA concentrations in control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 5–7). Legend: open diamond control open square manganese filled diamond control + 6-OHDA (134 µg) filled square manganese + 6-OHDA (134 µg) * p < 0.05 control versus control + 6-OHDA (134 µg) # p < 0.05 manganese versus manganese + 6-OHDA (134 µg)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig6: Striatal microdialysate 2.3-DHBA concentrations in control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 5–7). Legend: open diamond control open square manganese filled diamond control + 6-OHDA (134 µg) filled square manganese + 6-OHDA (134 µg) * p < 0.05 control versus control + 6-OHDA (134 µg) # p < 0.05 manganese versus manganese + 6-OHDA (134 µg)
Mentions: After switching aCSF to aCSF with 5 mM salicylic acid (point “0” on the graph), 2.3- and 2.5-DHBA appeared in the microdialysates of the neostriatum. The formation of 2.3-DHBA stabilized at 44 min in control and Mn-exposed rats and reached a concentration of ~100 pg/20 µl in both groups. In control rats treated at P3 with 6-OHDA (134 µg) as well as in Mn-exposed rats treated at P3 with 6-OHDA (134 µg), 2.3-DHBA levels stabilized at 66 min and attained a concentration of ~180 pg/20 µl. Significant differences between control and control + 6-OHDA groups were observed at 88, 110, 132, 154, and 176 min (p < 0.05), whereas differences were observed between Mn and Mn + 6-OHDA groups at 88, 110, and 132 min of testing [Fig. 6]. With respect to the 2.5-DHBA microdialysate, significant differences between control vs. control + 6-OHDA and Mn vs. Mn + 6-OHDA were noted between 88 and 220 min of the experiment [Fig. 7].Fig. 6

Bottom Line: We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy.Also, damage to the dopaminergic system acts as a "trigger mechanism," initiating a cascade of adverse events leading to a protracted increase in HO(•) generation, and the effects of Mn and 6-OHDA are compounded.In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HO(•) formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicology and Occupational Health Protection, Public Health Faculty, Medical University of Silesia, Medykow 18, 40-752, Katowice Ligota, Poland.

ABSTRACT
The present study was designed to investigate the role of pre- and postnatal manganese (Mn) exposure on hydroxyl radical (HO(•)) formation in the brains of dopamine (DA) partially denervated rats (Parkinsonian rats). Wistar rats were given tap water containing 10,000 ppm manganese chloride during the duration of pregnancy and until the time of weaning. Control rat dams consumed tap water without added Mn. Three days after birth, rats of both groups were treated with 6-hydroxydopamine at one of three doses (15, 30, or 67 µg, intraventricular on each side), or saline vehicle. We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy. In neonates, the major organs that accumulated Mn were the femoral bone and liver. However, Mn was not elevated in tissues in adulthood. To determine the possible effect on generation of the reactive species, HO(•) in Mn-induced neurotoxicity, we analyzed the contents of 2.3- and 2.5-dihydroxybenzoic acid (spin trap products of salicylate; HO(•) being an index of in vivo HO(•) generation), as well as antioxidant enzyme activities of superoxide dismutase (SOD) isoenzymes and glutathione S-transferase (GST). 6-OHDA-depletion of DA produced enhanced HO(•) formation in the brain tissue of newborn and adulthood rats that had been exposed to Mn, and the latter effect did not depend on the extent of DA denervation. Additionally, the extraneuronal, microdialysate, content of HO(•) in neostriatum was likewise elevated in 6-OHDA-lesioned rats. Interestingly, there was no difference in extraneuronal HO(•) formation in the neostriatum of Mn-exposed versus control rats. In summary, findings in this study indicate that Mn crosses the placenta but in contrast to other heavy metals, Mn is not deposited long term in tissues. Also, damage to the dopaminergic system acts as a "trigger mechanism," initiating a cascade of adverse events leading to a protracted increase in HO(•) generation, and the effects of Mn and 6-OHDA are compounded. Moreover, HO(•) generation parallels the suppression of SOD isoenzymes and GST in the brains of rats lesioned with 6-OHDA and/or intoxicated with Mn-the most prominent impairments being in frontal cortex, striatum, and brain stem. In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HO(•) formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus