Perinatal Manganese Exposure and Hydroxyl Radical Formation in Rat Brain

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.

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

“…5E and G). Oxidative stress has been implicated in Mn neurotoxicity (Milatovic et al, 2009;Herná ndez et al, 2011;Stephenson et al, 2013), and it has been reported that Mn induces production of H 2 O 2 in vitro (Posser et al, 2009) and hydroxyl radical in vivo (Bałasz et al, 2015). This result demonstrates that the hippocampus is susceptible to oxidative stress induced by perinatal Mn exposure and the effects of excessive levels of Mn in this region have consequences for the antioxidant defense system in rats that last into adulthood (PND70).…”

Influence of subchronic exposure to manganese carried by female rats during pregnancy on the behavioral and cognitive abilities of their offspring at later stages of postnatal development

“…It should be noted that disruption of the processes of barrier genesis during the development of the CNS can have a significant effect not only in the early postnatal period, but also in the long term of individual development. In one of the studies, it was shown that if this process is triggered in early ontogenesis, then it is able to persist throughout the adult life of the organism with a tendency to progress and globalize emerging disorders, even in the absence of an influencing factor (Bałasz et al, 2015).…”

The effect of manganese exposure on GnRH secretion via Nrf2/mGluR5/COX-2/PGE2/signaling pathway

“…Generally, Mn is an essential trace element that supports numerous physiological functions such as protein metabolism, energy metabolism, and the development of bone and cartilage. However, it has been noted that excessive of Mn exposure can lead to neurotoxicity and reproductive toxicity (Bałasz et al, 2015; Claus et al, 2011; Srivastava et al, 2013; Tarale et al, 2016). Williams et al (2012) reported that impaired fertility and sexual function, decreased sperm count, and viability have been found in male workers exposed to Mn dust.…”