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Long‐lasting neurotoxic effects of exposure to methylmercury during development
Author(s) -
Ceccatelli S.,
Bose R.,
Edoff K.,
Onishchenko N.,
Spulber S.
Publication year - 2013
Publication title -
journal of internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.625
H-Index - 160
eISSN - 1365-2796
pISSN - 0954-6820
DOI - 10.1111/joim.12045
Subject(s) - dentate gyrus , neurogenesis , hippocampal formation , dna methylation , neurotrophic factors , endocrinology , epigenetics , medicine , brain derived neurotrophic factor , neural stem cell , biology , neuroscience , microbiology and biotechnology , stem cell , gene expression , genetics , receptor , gene
Amongst environmental chemical contaminants, methylmercury ( M e H g) remains a major concern because of its detrimental effects on developing organisms, which appear to be particularly susceptible to its toxicity. Here, we investigated the effects of low M e H g levels on the development of the nervous system using both in vitro and in vivo experimental models. In neural stem cells ( NSC s), M e H g decreased proliferation and neuronal differentiation and induced cellular senescence associated with impairment in mitochondrial function and a concomitant decrease in global DNA methylation. Interestingly, the effects were heritable and could be observed in daughter NSC s never directly exposed to M e H g. By chronically exposing pregnant/lactating mice to M e H g, we found persistent behavioural changes in the male offspring, which exhibited depression‐like behaviour that could be reversed by chronic treatment with the antidepressant fluoxetine. The behavioural alterations were associated with a decreased number of proliferating cells and lower expression of brain‐derived neurotrophic factor ( B dnf ) m RNA in the hippocampal dentate gyrus. M e H g exposure also induced long‐lasting DNA hypermethylation, increased histone H 3‐ K 27 tri‐methylation and decreased H 3 acetylation at the B dnf promoter IV , indicating that epigenetic mechanisms play a critical role in mediating the long‐lasting effects of perinatal exposure to M e H g. Fluoxetine treatment restored the B dnf m RNA expression levels, as well as the number of proliferating cells in the granule cell layer of the dentate gyrus, which further supports the hypothesis that links depression to impaired neurogenesis. Altogether, our findings have shown that low concentrations of M e H g induce long‐lasting effects in NSC s that can potentially predispose individuals to depression, which we have reported earlier to occur in experimental animals exposed to M e H g during prenatal and early postnatal development.