Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

Abstract

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg -1 day -1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control,and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children.

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

“…In parallel with markers of dopaminergic dysfunction, Mn exposure in rats (0–50 mg/kg i.g. for 21–100 days) resulted in a significant decrease in norepinephrine levels, evoked norepinephrine release, resulting in medial prefrontal cortex catecholaminergic dysfunction and being associated with impaired attention, motor dysfunction, and altered impulse control [ 204 ]. Reversal of Mn-induced alterations of motor functions with methylphenidate treatment in Mn-exposed (0–50 mg/kg i.g.…”

Protective effect of compatible herbs in Jin-Gu-Lian formula against Alangium chinense-induced neurotoxicity via oxidative stress, neurotransmitter metabolisms, and pharmacokinetics

“…Many neurotoxicants are known to exert adverse effects in the concentration and signaling of neurotransmitters ( Stradtman and Freeman, 2021 ; Tinkov et al, 2021 ). A significant reduction in the levels of monoamine neurotransmitters, including 5-HT, DA, DOPAC and NE was reported to be associated with impaired attention, locomotor dysfunction, disrupted motor coordination, and impaired learning tasks ( Sun et al, 2018 ; Conley et al, 2020 ; Stradtman and Freeman, 2021 ). The disruption of cholinergic neurotransmission, as evidenced by upregulated AChE activity, the inhibition of choline acetyltransferase activity, cholinergic neuron death and the reduction of ACh levels is associated with oxidative damage and known to be involved in locomotor and motor deficits ( Tinkov et al, 2021 ).…”

Gut Microbiota from Short-Chain Chlorinated Paraffin-Exposed Mice Promotes Astrocyte Activation by Disrupting the Intestinal Tight Junction via Zonulin Upregulation

“…Rapid economic development has led to pollutant production, causing great harm to the environment and threats to public health. Various environmental pollutants have been reported to show neurotoxicity, including poly-L-lactic acid fibers, antimony, and manganese . Although SCCPs have been characterized as a new group of POPs, it has been unclear whether they have neurotoxic effects.…”