Aberrant epigenetic gene regulation in hippocampal neurogenesis of mouse offspring following maternal exposure to 3,3’-iminodipropionitrile

Abstract

Maternal exposure to 3,3′-iminodipropionitrile (IDPN) affects hippocampal neurogenesis in mouse offspring, with biphasic disruption, which facilitates neurogenesis during exposure and reduces the broad range of the granule cell lineage population at the adult stage. The present study investigated the epigenetically hypermethylated and downregulated genes related to the IDPN-induced disrupted neurogenesis. Mated female mice were treated with IDPN at 0 or 1200 ppm in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning. The hippocampal dentate gyrus of male offspring on PND 21 was subjected to methyl-capture sequencing and real-time reverse transcription-PCR analyses, followed by validation analyses on DNA methylation. Three genes, Edc4, Kiss1 and Mrpl38, were identified as those showing promoter-region hypermethylation and transcript downregulation, with Mrpl38 sustaining the changes through PND 77. Immunohistochemically, MRPL38, a mitochondrial ribosomal protein, revealed an irreversible decrease in the number of immunoreactive interneurons in the dentate gyrus hilar region, suggesting a causal relationship with the long-lasting effect on neurogenesis by the impaired migration due to mitochondrial dysfunction of interneurons, which regulate the differentiation and survival of granule cell lineages. Downregulation of Edc4 may also be responsible for decreased neurogenesis on PND 77 owing to a mechanism involving interleukin-6 downregulation via processing body dysfunction. Downregulation of Kiss1 may be responsible for the facilitation of neurogenesis during IDPN-exposure due to decreased glutamatergic neurotransmission and also for suppressed neurogenesis on PND 77 due to decreased expression of immediate-early genes, which play a crucial role in the maintenance of cell differentiation or plasticity.

Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats

“…We have recently examined genes showing promoter region hypermethylation in the hippocampal dentate gyrus of mice exposed maternally to manganese, 3,3′‐iminodipropionitrile, or hexachlorophene by CpG island (CGI) microarray analysis or methyl‐capture sequencing analysis (Wang et al, 2013; Watanabe et al, 2018; Tanaka et al, 2019). Among the genes identified, a number of genes showed sustained hypermethylation and transcript downregulation after exposure to these compounds.…”