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.
Highlights
Manganese (Mn) is an enzymatic cofactor that plays an important role in a number of physiologic processes
Rats were weaned on postnatal day 21 (P21), at which time Mn was discontinued, and male offspring was group housed until experimentation
We demonstrated that Mn content in the brain, kidney, liver, and bone was significantly elevated in rat dams exposed to this metal during pregnancy
Summary
Manganese (Mn) is an enzymatic cofactor that plays an important role in a number of physiologic processes. Occupational exposure (miners, smelters, welders, and workers in dry-cell battery factories; inhalation of Mn in aerosols/dusts) accounts for the major source of Mn intoxication in humans. An important but non-occupational source of Mn is methylcyclopentadienyl manganese tricarbonyl (MMT), the antiknock agent in gasoline. Another source is potassium permanganate, a powerful oxidizing agent for purifying drinking water, treating waste water, and as an agricultural fungicidal and bactericidal agent (Huang 2007). Manganism has been observed recently in intravenous methcathinone abusers because this substance is illicitly produced by a potassium permanganate oxidation process (Stepens et al 2008). There are numerous reports of Mn intoxication related to long-term total parenteral nutrition (Reynolds et al 1994; Reimund et al 2000)
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