Methylmercury Impact on Adult Neurogenesis: Is the Worst Yet to Come From Recent Brazilian Environmental Disasters?

Abstract

Worldwide environmental tragedies of anthropogenic origin causing massive release of metals and other pollutants have been increasing considerably. These pollution outbreaks affect the ecosystems and impact human health. Among those tragedies, recent large-scale environmental disasters in Brazil strongly affected riverside populations, leading to high-risk exposure to methylmercury (MeHg). MeHg is highly neurotoxic to the developing brain. This toxicant causes neural stem cell dysfunction and neurodevelopmental abnormalities. However, less is known about the effects of MeHg in the postnatal neurogenic niche, which harbors neural stem cells and their progeny, in the adult brain. Therefore, taking in consideration the impact of MeHg in human health it is urgent to clarify possible associations between exposure to mercury, accelerated cognitive decline, and neurodegenerative diseases. In this perspectives paper, we discuss the neurotoxic mechanisms of MeHg on postnatal neurogenesis and the putative implications associated with accelerated brain aging and early-onset cognitive decline in populations highly exposed to this environmental neurotoxicant.

Keywords: aging; environmental disaster; memory; methylmercury; neurogenesis; neurotoxicity.

Figure 1

Mercury (Hg): the road to the CNS: (A) small-scale and artisanal gold mining releases Hg to the environment, contaminating soil, lakes, and rivers; (B) Hg is methylated by bacteria in aquatic sediments converting to its organic form, methylmercury (MeHg); (C) this organic MeHg bioaccumulates in predatory fish, undergoing a process of biomagnification and (D) enters the human organism via contaminated seafood consumption; and (E) in the human blood stream, MeHg binds to β-chain hemoglobin in erythrocytes and forms a complex with the aminoacid cystein (complex similar to methionine, MeHg-S-Cys), which can be transported by L-aminoacid transporter (LAT-1) and easily crosses the BBB. Once in the CNS, MeHg disseminates, intoxicating all cell types and structures.

Figure 2

Cellular mechanisms in the neurogenic niche that may be affected by MeHg. Once in the CNS, MeHg reaches the hippocampus and neurogenic niche in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. There are several cellular mechanisms that are believed to be altered and impaired by MeHg in neural stem cells (NSC), causing overall poor neurogenesis. There have been observations that MeHg induces (A) impaired proliferation of NSC, with a decrease of the proliferation markers Ki67 and BrdU, and of the neural stem markers SOX2 and Nestin; (B) impairment of the migration and differentiation of NSC, confirmed by the decrease of the markers DCX, β3-Tubulin, and GFAP; (C) disruption of the maturation of new neurons and apoptosis of the existing ones (neurodegeneration), associated with elevated levels of apoptosis related proteins (Caspase-3 and ERK 1/2) and decrease of proliferation (BrdU) and neuronal markers (MAP-2); (D) increased oxidative stress, evidenced by elevation of reactive oxygen species (ROS) and decrease in NADH and Cytochrome B (Cyt B); and (E) cell cycle arrest, confirmed by the reduction in Ki67 and Cyclin A/D, and cellular senescence of NSC, concomitant with the elevation of the expression of p16 and p21.