Exposure to MnCl₂ · 4H₂O during development induces activation of microglial and perivascular macrophage populations in the hippocampal dentate gyrus of rats

Abstract

Developmental exposure to Mn caused Mn accumulation in the brain tissue and transient disruption of granule cell neurogenesis, targeting the late stage differentiation of progenitor cells in the subgranular zone of the hippocampal dentate gyrus of rats. Because neurogenesis is influenced by proinflammatory responses, this study was performed to determine whether Mn exposure causes microglial activation in the dentate hilus, a region anatomically close to the subgranular zone of the dentate gyrus. Pregnant rats were treated with dietary MnCl2 · 4H2O at 32, 160 or 800 ppm from gestational day 10 to day 21 after delivery. An immunohistochemical analysis revealed increases in Iba1(+) microglia in the hilus on postnatal day 21 following exposure to MnCl2 · 4H2O in a dose-unrelated manner at 32 and at 800 ppm and an increase in CD163(+) macrophage at 800 ppm in the hilus. Real-time reverse transcription-polymerase chain reaction analysis revealed increases in the mRNA levels of Il1α, Il6, Nos2 and Tnf after 800 ppm MnCl2 · 4H2O. These results suggest that activation of microglia and perivascular macrophages occurs in the hilus after developmental exposure to MnCl2 · 4H2O at 800 ppm, and probably involves the disruption of neurogenesis through the accumulation of Mn in the brain tissue.

Subchronic Manganese Exposure Impairs Neurogenesis in the Adult Rat Hippocampus

“…Mn exposure has been suggested to cause microglial activation via various inflammatory pathways (Abe et al, 2015;Verina et al, 2011;Zhao et al, 2009). Our previous study has confirmed that Mn exposure increases the number of newly born microglial cells in the adult SVZ; however, this increase is mild but not substantial so that it does not contribute significantly to the overall cell proliferation in the SVZ under Mn influence (Fu et al, 2015a).…”

Manganese and aging

“…Using the same dosing paradigm, the same group investigated epigenetic changes relevant to neurogenesis during and after Mn exposure and found changes in genes related to neurogenesis, including Mid1, Atp1a3,Nr2f1, and Pvalb 73 . In further studies, the same group observed activation of microglia and perivascular macrophages in the hippocampal dentate hilus, adjacent to the dentate gyrus, postulating that inflammation in involved in the changes in neurogenesis observed in their previous studies 74 . In an intrapersonal injection model of Mn exposure at 6 mg/kg in adult rats, copper levels, which are normally high in the subgranular zone, were reduced, while expression of the divalent metal transporter (DMT1), which transports both copper and Mn, was increased in the region 75 .…”

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress

“…Once environmental exotoxins excessively activate microglia, the balance between its protection and pro-inflammatory effects is interrupted [12]. Significantly, excessive Mn exposure or its combination with lipopolysaccharide (LPS) may induce the activation of microglial cells, which then causes neuroinflammation via promoting the secretion of cytotoxic mediators, such as interleukin-1β (IL-1β) and reactive oxygen species (ROS) [13,14].…”