Maternal exposure to 3,3’‐iminodipropionitrile targets late‐stage differentiation of hippocampal granule cell lineages to affect brain‐derived neurotrophic factor signaling and interneuron subpopulations in rat offspring

Abstract

3,3'-Iminodipropionitrile (IDPN) causes neurofilament (NF)-filled swellings in the proximal segments of many large-caliber myelinated axons. This study investigated the effect of maternal exposure to IDPN on hippocampal neurogenesis in rat offspring using pregnant rats supplemented with 0 (controls), 67 or 200 ppm IDPN in drinking water from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, female offspring subjected to analysis had decreased parvalbumin(+), reelin(+) and phospho-TrkB(+) interneurons in the dentate hilus at 200 ppm and increased granule cell populations expressing immediate-early gene products, Arc or c-Fos, at ≥ 67 ppm. mRNA expression in the dentate gyrus examined at 200 ppm decreased with brain-derived neurotrophic factor (Bdnf) and very low density lipoprotein receptor. Immunoreactivity for phosphorylated NF heavy polypeptide decreased in the molecular layer of the dentate gyrus and the stratum radiatum of the cornu ammonis (CA) 3, portions showing axonal projections from mossy cells and pyramidal neurons, at 200 ppm on PND 21, whereas immunoreactivity for synaptophysin was unchanged in the dentate gyrus. Observed changes all disappeared on PND 77. There were no fluctuations in the numbers of apoptotic cells, proliferating cells and subpopulations of granule cell lineage in the subgranular zone on PND 21 and PND 77. Thus, maternal IDPN exposure may reversibly affect late-stage differentiation of granule cell lineages involving neuronal plasticity as evident by immediate-early gene responses to cause BDNF downregulation resulting in a reduction in parvalbumin(+) or reelin(+) interneurons and suppression of axonal plasticity in the mossy cells and CA3 pyramidal neurons.

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

“…Developmental exposure to IDPN has also been shown to cause morphometric changes in hippocampal structures (Zmarowski et al, 2012). With regard to the developmental neurotoxicity of IDPN, we previously found that maternal exposure to IDPN reversibly disrupted neurogenesis targeting late-stage differentiation of granule cell lineages in the dentate gyrus in rat offspring (Itahashi et al, 2015). However, we have recently found that maternal IDPN exposure in mice affected hip-pocampal neurogenesis, increasing the number of postmitotic granule cells involving glutamatergic signals at the end of maternal exposure, and then suppressing SGZ cell proliferation to result in reduction of the broad range of the granule cell lineage population in offspring (Hasegawa-Baba et al, 2017).…”

Time-Course Evaluation of Iminodipropionitrile-Induced Liver and Kidney Toxicities in Rats: A Biochemical, Molecular and Histopathological Study

“…[31][32][33] Iminodipropionitrile is also known to damage or impair the function of various sensory systems, including olfactory, 34 auditory, 35 and visual 36 systems. Subsequent researches have shown that IDPN is not only toxic to sensory, vestibular, and nervous systems but also causes reproductive, 37 developmental, 38 and hepatic 39 toxicities. The magnitude of IDPN-induced hepatotoxicity in mice was independent of the severity of vestibular epithelial damage.…”