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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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Antioxidant enzymes activity in thalamus and hypothalamus of adult control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 8). Legend is the same as in Fig. 8. * p < 0.05; ** p < 0.01 control versus 6-OHDA; control versus manganese; control versus manganese + 6-OHDA
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Fig11: Antioxidant enzymes activity in thalamus and hypothalamus of adult control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 8). Legend is the same as in Fig. 8. * p < 0.05; ** p < 0.01 control versus 6-OHDA; control versus manganese; control versus manganese + 6-OHDA

Mentions: In prefrontal cortex at 8 weeks, SOD and Mn-SOD activities were decreased in rats that had been treated at P3 with 6-OHDA (134 µg) as well as in Mn and Mn + 6-OHDA groups versus control. Also, concurrently in Mn + 6-OHDA, rats activities of these enzymes were significantly elevated versus respective controls (Mn alone exposed rats). GST was decreased in Mn and Mn + 6-OHDA groups versus control, while GPx was significantly elevated in Mn + 6-OHDA rats (versus control and Mn groups). Activities of CuZn-SOD, GR, and catalase were unchanged [Fig. 8]. In hippocampus, only GPx activity was changed (elevated in 6-OHDA and Mn groups); activity of other enzymes was unchanged [Fig. 9]. In striatum SOD and CuZn-SOD, activities were decreased in 6-OHDA, Mn, and Mn + 6-OHDA groups. Significant decreases in Mn-SOD (only in Mn alone exposed rats), GST (Mn and Mn + 6-OHDA), and GR (6-OHDA) activities [Fig. 10]. In thalamus and hypothalamus, 6-OHDA (134 µg) produced significant decreases in the activities of GST and GR, Mn in GST and catalase, and Mn + 6-OHDA in GST activity [Fig. 11]. In cerebellum, CuZn-SOD activity was decreased in 6-OHDA-lesioned rats as well as in Mn alone exposed rats and Mn + 6-OHDA rats. Also, GST activity was decreased in the Mn + 6-OHDA versus control (Mn alone). Conversely, GR activity was elevated in Mn-exposed rats as compared to controls [Fig. 12]. In brain stem, 6-OHDA (134 µg) produced a decrease in the activities of SOD, Mn-SOD, CuZn-SOD, and GR; also a reduction in Mn-SOD activity was found in the Mn + 6-OHDA group. Furthermore, GST was decreased in the 6-OHDA group, Mn and Mn + 6-OHDA rats versus controls [Fig. 13].Fig. 8


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)

Antioxidant enzymes activity in thalamus and hypothalamus of adult control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 8). Legend is the same as in Fig. 8. * p < 0.05; ** p < 0.01 control versus 6-OHDA; control versus manganese; control versus manganese + 6-OHDA
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4286139&req=5

Fig11: Antioxidant enzymes activity in thalamus and hypothalamus of adult control and manganese-exposed (10,000 ppm) rats lesioned with 6-OHDA (n = 8). Legend is the same as in Fig. 8. * p < 0.05; ** p < 0.01 control versus 6-OHDA; control versus manganese; control versus manganese + 6-OHDA
Mentions: In prefrontal cortex at 8 weeks, SOD and Mn-SOD activities were decreased in rats that had been treated at P3 with 6-OHDA (134 µg) as well as in Mn and Mn + 6-OHDA groups versus control. Also, concurrently in Mn + 6-OHDA, rats activities of these enzymes were significantly elevated versus respective controls (Mn alone exposed rats). GST was decreased in Mn and Mn + 6-OHDA groups versus control, while GPx was significantly elevated in Mn + 6-OHDA rats (versus control and Mn groups). Activities of CuZn-SOD, GR, and catalase were unchanged [Fig. 8]. In hippocampus, only GPx activity was changed (elevated in 6-OHDA and Mn groups); activity of other enzymes was unchanged [Fig. 9]. In striatum SOD and CuZn-SOD, activities were decreased in 6-OHDA, Mn, and Mn + 6-OHDA groups. Significant decreases in Mn-SOD (only in Mn alone exposed rats), GST (Mn and Mn + 6-OHDA), and GR (6-OHDA) activities [Fig. 10]. In thalamus and hypothalamus, 6-OHDA (134 µg) produced significant decreases in the activities of GST and GR, Mn in GST and catalase, and Mn + 6-OHDA in GST activity [Fig. 11]. In cerebellum, CuZn-SOD activity was decreased in 6-OHDA-lesioned rats as well as in Mn alone exposed rats and Mn + 6-OHDA rats. Also, GST activity was decreased in the Mn + 6-OHDA versus control (Mn alone). Conversely, GR activity was elevated in Mn-exposed rats as compared to controls [Fig. 12]. In brain stem, 6-OHDA (134 µg) produced a decrease in the activities of SOD, Mn-SOD, CuZn-SOD, and GR; also a reduction in Mn-SOD activity was found in the Mn + 6-OHDA group. Furthermore, GST was decreased in the 6-OHDA group, Mn and Mn + 6-OHDA rats versus controls [Fig. 13].Fig. 8

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