Hippocampal developmental vulnerability to methylmercury extends into prepubescence

Abstract

The developing brain is sensitive to environmental toxicants such as methylmercury (MeHg), to which humans are exposed via contaminated seafood. Prenatal exposure in children is associated with learning, memory and IQ deficits, which can result from hippocampal dysfunction. To explore underlying mechanisms, we have used the postnatal day (P7) rat to model the third trimester of human gestation. We previously showed that a single low exposure (0.6 μg/gbw) that approaches human exposure reduced hippocampal neurogenesis in the dentate gyrus (DG) 24 h later, producing later proliferation and memory deficits in adolescence. Yet, the vulnerable stem cell population and period of developmental vulnerability remain undefined. In this study, we find that P7 exposure of stem cells has long-term consequences for adolescent neurogenesis. It reduced the number of mitotic S-phase cells (BrdU), especially those in the highly proliferative Tbr2+ population, and immature neurons (Doublecortin) in adolescence, suggesting partial depletion of the later stem cell pool. To define developmental vulnerability to MeHg in prepubescent (P14) and adolescent (P21) rats, we examined acute 24 h effects of MeHg exposure on mitosis and apoptosis. We found that low exposure did not adversely impact neurogenesis at either age, but that a higher exposure (5 μg/gbw) at P14 reduced the total number of neural stem cells (Sox2+) by 23% and BrdU+ cells by 26% in the DG hilus, suggesting that vulnerability diminishes with age. To determine whether these effects reflect changes in MeHg transfer across the blood brain barrier (BBB), we assessed Hg content in the hippocampus after peripheral injection and found that similar levels (~800 ng/gm) were obtained at 24 h at both P14 and P21, declining in parallel, suggesting that changes in vulnerability depend more on local tissue and cellular mechanisms. Together, we show that MeHg vulnerability declines with age, and that early exposure impairs later neurogenesis in older juveniles.

Unveiling the neurotoxicity of methylmercury in fish ( Diplodus sargus ) through a regional morphometric analysis of brain and swimming behavior assessment

“…Alternatively, the loss of cells in medial pallium and optic tectum may also be related to an inhibition of cell proliferation promoted by MeHg, as previously hypothesized in D. sargus exposed to iHg (Pereira et al, 2016) and as observed in the hippocampus and cerebellum of rats exposed to MeHg (Burke et al, 2006;Falluel-Morel et al, 2007;Sokolowski et al, 2013;Obiorah et al, 2015). Studies with MeHg have indicated that the decreased number of brain cells in mammals is a result of the inhibition of proliferation rather than cell death (Lewandowski et al, 2003 and references herein).…”

“…Such evidence is in line with several studies in rodents (Nagashima, 1997) and humans (Sanfeliu et al, 2001;Ceccatelli et al, 2010) that have described the occurrence of neuronal damage upon MeHg exposure. In order to unveil the neurotoxic effects of MeHg, rodent brain has been scrutinized by stereological methods comprising an evaluation of cell numbers and volumes (Sager et al, 1984;Larsen and Braendgaard, 1995;Roegge et al, 2006;Falluel-Morel et al, 2007;Sokolowski et al, 2013;Obiorah et al, 2015). This methodology has provided clarification about the localized effects of MeHg in the nervous system of rodents.…”

“…Indeed, a pronounced axonal degeneration occurred in the peripheral nervous system of rats exposed to MeHg (Larsen and Braendgaard, 1995;Schiønning et al, 1998). Moreover, adverse effects in cell populations within the hippocampus and cerebellum have also been found in rodents exposed to MeHg (Sager et al, 1984;Roegge et al, 2006;Falluel-Morel et al, 2007;Sokolowski et al, 2013;Obiorah et al, 2015). Unfortunately, this is a time consuming method, which has mostly been used for toxicology purposes to assess the neurotoxicity of contaminants in humans.…”

Age‐related changes in Ki‐67 and DCX expression in the BALB/ c mouse (Mus Musculus) brain

“…Ki-67 and DCX-ir cells were quantified in 6 corresponding sections/ per animal (approximately 250 μm apart) containing the dentate gyrus following a method modified from Obiorah et al (2015). The first section was situated at a level corresponding to sagittal level 12 (lateral 1.725 mm) of Allen's reference atlas of the mouse brain (Dong, 2008) and the rest were placed medial to the first one.…”

Effects of Gintonin-Enriched Fraction on Methylmercury-Induced Neurotoxicity and Organ Methylmercury Elimination

“…Although it is well known that prenatal exposure to MeHg induces abnormal brain development, recent study shows that MeHg vulnerability declines with age, and that early exposure impairs later neurogenesis in older juveniles [29]. Interestingly, in vitro study also showed that co-culture of astrocytes with neurons was less vulnerable to MeHg assaults than neuron alone.…”