Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene.
Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene.
复制标题
DOI：
10.1093/toxsci/kfx291
复制
发表时间：
2018-05-01
期刊：
影响因子：
--
通讯作者：
Shibutani M
中科院分区：
文献类型：
--
作者：
Watanabe Y;Abe H;Nakajima K;Ideta-Otsuka M;Igarashi K;Woo GH;Yoshida T;Shibutani M
母体六氯酚(HCP)暴露会导致小鼠后代海马神经发生的一过性中断。我们检查了与HCP诱导的神经发生中断相关的表观遗传高甲基化和下调基因。交配的雌性小鼠从妊娠第6天至出生后第21天断奶时，饮食中暴露于0或100 ppm的六氯酚。对雄性子代海马齿状回进行甲基捕获测序和实时逆转录聚合酶链式反应分析。甲基化验证分析确定了三个基因，Dlx4，DMRT1和Plcb4，显示出启动子区域的超甲基化。免疫组织化学显示，齿状脑门区DLX4+、DMRT1+和PLCB4+细胞共表达γ-氨基丁酸能神经元标记物GAD67。在PND 21时，HCP降低了所有三个亚群以及GAD67+细胞。PLCB4+细胞也表达代谢性谷氨酸受体GRM1。HCP还降低了突触可塑性相关基因在齿状回和突触可塑性相关ARC免疫反应颗粒细胞中的转录水平。在PND 77，所有免疫组织细胞密度的变化都被逆转，而突触可塑性相关基因的转录表达出现波动。因此，暴露于HCP的子代短暂地减少了GABA能中间神经元的数量。其中，表达DLX4、DMRT1或PLCB4的亚群数量通过表观遗传机制瞬时减少。考虑到DLX基因家族在GABA能中间神经元迁移和分化中的作用，DLX4+细胞数量的减少可能是GABA能中间神经元调节神经发生的原因之一。这种对颗粒细胞突触可塑性的影响一直持续到成年期，GRM1-PLCB4信号通路中GABA能中间神经元的减少可能是导致断奶抑制的原因之一。
Maternal hexachlorophene (HCP) exposure causes transient disruption of hippocampal neurogenesis in mouse offspring. We examined epigenetically hypermethylated and downregulated genes related to this HCP-induced disrupted neurogenesis. Mated female mice were dietary exposed to 0 or 100 ppm HCP from gestational day 6 to postnatal day (PND) 21 on weaning. The hippocampal dentate gyrus of male offspring was subjected to methyl-capture sequencing and real-time reverse transcription-polymerase chain reaction analyses on PND 21. Validation analyses on methylation identified three genes, Dlx4, Dmrt1, and Plcb4, showing promoter-region hypermethylation. Immunohistochemically, DLX4+, DMRT1+, and PLCB4+ cells in the dentate hilus co-expressed GAD67, a γ-aminobutyric acid (GABA)ergic neuron marker. HCP decreased all of three subpopulations as well as GAD67+ cells on PND 21. PLCB4+ cells also co-expressed the metabotropic glutamate receptor, GRM1. HCP also decreased transcript level of synaptic plasticity-related genes in the dentate gyrus and immunoreactive granule cells for synaptic plasticity-related ARC. On PND 77, all immunohistochemical cellular density changes were reversed, whereas the transcript expression of the synaptic plasticity-related genes fluctuated. Thus, HCP-exposed offspring transiently reduced the number of GABAergic interneurons. Among them, subpopulations expressing DLX4, DMRT1, or PLCB4 were transiently reduced in number through an epigenetic mechanism. Considering the role of the Dlx gene family in GABAergic interneuron migration and differentiation, the decreased number of DLX4+ cells may be responsible for reducing those GABAergic interneurons regulating neurogenesis. The effect on granule cell synaptic plasticity was sustained until the adult stage, and reduced GABAergic interneurons active in GRM1–PLCB4 signaling may be responsible for the suppression on weaning.
登录
查看更多内容
影响因子：
30.8
作者：
Jones, PL;Veenstra, GJC;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
15.1
作者：
Kempf SJ;Casciati A;Buratovic S;Janik D;von Toerne C;Ueffing M;Neff F;Moertl S;Stenerlöw B;Saran A;Atkinson MJ;Eriksson P;Pazzaglia S;Tapio S
通讯作者：
Tapio S
DOI：
10.1523/jneurosci.1424-08.2008
发表时间：
2008-09-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Mueller BR;Bale TL
通讯作者：
Bale TL
影响因子：
4.5
作者：
Itahashi, Megu;Abe, Hajime;Shibutani, Makoto
通讯作者：
Shibutani, Makoto
影响因子：
2
作者：
Akane, Hirotoshi;Saito, Fumiyo;Shibutani, Makoto
通讯作者：
Shibutani, Makoto