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Aberration in Epigenetic Gene Regulation in Hippocampal Neurogenesis by Developmental Exposure to Manganese Chloride in Mice

Aberration in Epigenetic Gene Regulation in Hippocampal Neurogenesis by Developmental Exposure to Manganese Chloride in Mice 

Liyun Wang*, Ayako Shiraki*,‡, Hirotoshi Akane*, Hajime Abe*,‡, Kunitoshi Mitsumori* and Makoto Shibutani* 
*  Laboratory of Beterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan;
‡ Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193,  

Abstract

We have shown that maternal manganese (Mn) exposure caused sustained disruption of hippocampal neurogenesis of mouse offspring. To clarify the effects of maternal Mn exposure on epigenetic gene regulation contributing to the sustained disruption of hippocampal neurogenesis, we treated pregnant ICR mice with MnCl2 in diet from gestational day 10 through day 21 after delivery on weaning and searched epigenetically downregulated genes by global promoter methylation analysis in the hippocampal dentate gyrus of male offspring on postnatal day (PND) 21 and PND 77. By CpG promoter microarray analysis on PND 21 following 800-ppm Mn exposure, sustained promoter hypermethylation and transcript downregulation through PND 77 were confirmed with Mid1, Atp1a3, and Nr2f1, whereas Pvalb showed a transient hypermethylation only on weaning. The numbers of Pvalb+ and ATP1a3+ neurons suggestive of γ-aminobutyric acid (GABA)ergic interneurons, Mid1+ cells suggestive of late-stage granule cell lineage and GABAergic interneurons, and COUP-TF1+ cells suggestive of early-stage granule cell lineage were all reduced on PND 21, and reductions were sustained on PND 77 except for no change in Pvalb+ cells. Mid1+ cells showed asymmetric distribution with right-side predominance, and Mn exposure abolished it by promoter hypermethylation of the right side. These findings indicate epigenetic mechanisms as mediators, through which Mn exposure modulates neurogenesis involving both granule cell lineage and GABAergic interneurons with longlasting and stable repercussions. Disruption of asymmetric cellular distribution of Mid1 suggests that higher brain functions specialized in the left or right side of the brain were affected

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