Maternal exposure to hexachlorophene targets intermediate‐stage progenitor cells in the hippocampal neurogenesis involving myelin vacuolation of cholinergic and glutamatergic inputs in mice

Abstract

Hexachlorophene (HCP) has been shown to induce myelin vacuolation due to intramyelinic edema of the nerve fibers in animal neural tissue. We investigated the maternal exposure effect of HCP on hippocampal neurogenesis in the offspring of pregnant mice supplemented with 0 (control), 33 or 100 ppm HCP in diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, offspring as examined in males exhibited decreased granule cell lineage populations expressing paired box 6, sex-determining region Y-box 2 and eomesodermin in the hippocampal subgranular zone (SGZ) accompanied by myelin vacuolation involving white matter tracts of the hippocampal fimbria at ≥ 33 ppm. However, SGZ cellular populations expressing brain lipid binding protein and doublecortin were unchanged at any dose. Transcript expression of cholinergic receptor genes, Chrna4 and Chrnb2, and glutamate receptor genes, Grm1 and Grin2d, examined at 100 ppm, decreased in the dentate gyrus. HCP exposure did not alter the number of proliferating or apoptotic cells in the SGZ, or reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)ergic interneurons in the dentate hilus, on PND 21 and PND 77. All neurogenesis-related changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77, suggesting that maternal HCP exposure at ≥ 33 ppm reversibly decreased type 2 intermediate-stage progenitor cells in the hippocampal neurogenesis. Myelin vacuolation might be responsible for changes in neurogenesis possibly by reducing nerve conduction velocity of cholinergic inputs from the septal-hippocampal pathway to granule cell lineages and/or GABAergic interneurons, and of glutamatergic inputs to granule cell lineages.

Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene

“…With regard to the parameters of dams, no significant difference was observed in reproductive parameters, body weight and food consumption during experiment, and body and brain weights at necropsy on weaning at PND 21 between the 0 ppm controls and 100-ppm HCP-exposed group ( Supplementary Tables 5–8 ; Kato et al , 2016 ). With regard to the parameters of male offspring, body weight was significantly decreased from PND 13 to PND 21, and brain weight was also significantly decreased on PND 21 in 100-ppm HCP-exposed group compared with 0 ppm controls ( Supplementary Tables 9 and 10 ; Kato et al , 2016 ).…”

“…Experimentally, HCP can be transferred into offspring through placenta and milk ( Kennedy et al , 1977 ). In our previous study, developmental exposure of mice to HCP also induced myelin vacuolation in the brains of the offspring ( Kato et al , 2016 ).…”

“…The animal experimental protocol and samples used were identical to that previously reported ( Kato et al , 2016 ), and exposure period and number of animals per group were in accordance with the OECD test guideline for the testing chemicals (Test No. 426: Developmental Neurotoxicity Study; OECD, 2007 ).…”

“…We have recently shown that developmental exposure to glycidol, which targets axon terminals, impairs late-stage differentiation of the neurogenesis process involving density changes of interneuron subpopulations in the dentate hilus of rat offspring ( Akane et al , 2013a ). Furthermore, developmental exposure to HCP impairs intermediate-stage progenitor cells in the SGZ in rat or mouse offspring, probably by reducing nerve conduction velocity of regulatory neurons of neurogenesis ( Itahashi et al , 2015 ; Kato et al , 2016 ). In our mouse HCP developmental exposure study, however, we observed no fluctuations in the density of GABAergic interneuron subpopulations in the dentate hilus, whereas transcript downregulations of cholinergic receptors and glutamate receptors were observed in the dentate gyrus, likely related to the disruption of hippocampal neurogenesis ( Supplementary Figs.…”

“…In our mouse HCP developmental exposure study, however, we observed no fluctuations in the density of GABAergic interneuron subpopulations in the dentate hilus, whereas transcript downregulations of cholinergic receptors and glutamate receptors were observed in the dentate gyrus, likely related to the disruption of hippocampal neurogenesis ( Supplementary Figs. 1–3 ; Kato et al , 2016 ).…”