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Developmental exposure to diacetoxyscirpenol reversibly disrupts hippocampal neurogenesis by inducing oxidative cellular injury and suppressed differentiation of granule cell lineages in mice.
Food and Chemical Toxicology ( IF 3.9 ) Pub Date : 2019-12-10 , DOI: 10.1016/j.fct.2019.111046
Kota Nakajima 1 , Yuko Ito 1 , Satomi Kikuchi 2 , Hiromu Okano 2 , Kazumi Takashima 2 , Gye-Hyeong Woo 3 , Toshinori Yoshida 2 , Tomoya Yoshinari 4 , Yoshiko Sugita-Konishi 5 , Makoto Shibutani 6
Affiliation  

To investigate the developmental exposure effect of diacetoxyscirpenol (DAS) on postnatal hippocampal neurogenesis, pregnant ICR mice were provided a diet containing DAS at 0, 0.6, 2.0, or 6.0 ppm from gestational day 6 to day 21 on weaning after delivery. Offspring were maintained through postnatal day (PND) 77 without DAS exposure. On PND 21, neural stem cells (NSCs) and all subpopulations of proliferating progenitor cells were suggested to decrease in number in the subgranular zone (SGZ) at ≥ 2.0 ppm. At 6.0 ppm, increases of SGZ cells showing TUNEL+, metallothionein-I/II+, γ-H2AX+ or malondialdehyde+, and transcript downregulation of Ogg1, Parp1 and Kit without changing the level of double-stranded DNA break-related genes were observed in the dentate gyrus. This suggested induction of oxidative DNA damage of NSCs and early-stage progenitor cells, which led to their apoptosis. Cdkn2a, Rb1 and Trp53 downregulated transcripts, which suggested an increased vulnerability to DNA damage. Hilar PVALB+ GABAergic interneurons decreased and Grin2a and Chrna7 were downregulated, which suggested suppression of type-2-progenitor cell differentiation. On PND 77, hilar RELN+ interneurons increased at ≥ 2.0 ppm; at 6.0 ppm, RELN-related Itsn1 transcripts were upregulated and ARC+ granule cells decreased. Increased RELN signals may ameliorate the response to the decreases of NSCs and ARC-mediated synaptic plasticity. These results suggest that DAS reversibly disrupts hippocampal neurogenesis by inducing oxidative cellular injury and suppressed differentiation of granule cell lineages. The no-observed-adverse-effect level of DAS for offspring neurogenesis was determined to be 0.6 ppm (0.09-0.29 mg/kg body weight/day).

中文翻译:

暴露于二乙酰氧基西吡醇的发育暴露可通过诱导氧化性细胞损伤并抑制小鼠颗粒细胞谱系的分化而可逆转地破坏海马神经发生。

为了研究双乙酰氧基scirpenol(DAS)对产后海马神经发生的发育暴露影响,从妊娠第6天到第21天的分娩后第6天至第21天,为怀孕的ICR小鼠提供含0、0.6、2.0或6.0 ppm的DAS的饮食。在出生后一天(PND)77维持后代,而没有DAS暴露。在PND 21上,建议神经干细胞(NSC)和所有增殖祖细胞亚群在≥2.0 ppm的亚颗粒区(SGZ)数量减少。在6.0 ppm时,在齿状体中观察到SGZ细胞增加,显示出TUNEL +,金属硫蛋白-I / II +,γ-H2AX+或丙二醛+,以及Ogg1,Parp1和Kit的转录下调,而没有改变双链DNA断裂相关基因的水平。回旋。这表明诱导了神经干细胞和早期祖细胞的氧化性DNA损伤,从而导致它们的凋亡。Cdkn2a,Rb1和Trp53下调了转录本,表明对DNA损伤的脆弱性增加。肺门PVALB + GABA能神经元减少,Grin2a和Chrna7被下调,提示抑制了2型祖细胞的分化。在PND 77上,肺门RELN +中间神经元以≥2.0 ppm的速度增加;在6.0 ppm时,RELN相关的Hisn1转录本上调,而ARC +颗粒细胞减少。RELN信号增加可能会改善对NSC和ARC介导的突触可塑性下降的反应。这些结果表明,DAS通过诱导氧化性细胞损伤和抑制颗粒细胞谱系分化,可逆性破坏海马神经发生。
更新日期:2019-12-11
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