Methoxyacetic acid inhibits histone deacetylase and impairs axial elongation morphogenesis of mouse gastruloids in a retinoic acid signaling-dependent manner.
Methoxyacetic acid inhibits histone deacetylase and impairs axial elongation morphogenesis of mouse gastruloids in a retinoic acid signaling-dependent manner.
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DOI：
10.1002/bdr2.1712
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发表时间：
2020-08
影响因子：
2.1
通讯作者：
Marikawa Y
中科院分区：
文献类型：
--
作者：
Li ASW;Marikawa Y
致畸潜能与各种工业化合物有关。甲氧基乙酸（MAA）是广泛使用的有机溶剂和增塑剂甲氧基乙醇和邻苯二甲酸二甲氧基乙酯的主要代谢物。使用模型动物的研究表明，MAA是导致发育中的胚胎出现各种畸形的近似致畸原。然而，MAA发挥其致畸作用的分子机制尚不完全清楚。本研究以小鼠P19C5多能干细胞的原肠样细胞为体外模型，研究MAA对原肠胚期胚胎的致畸作用。通过测量类胃的形态计量参数来评估其形态发生作用，通过检测各种发育调节基因的转录水平来评估其对基因表达模式的影响。测定MAA对维甲酸（RA）信号水平和组蛋白去乙酰化酶活性的影响。MAA在与体内致畸血浆水平（5 mM）相当的浓度下降低了胃原体的轴向伸长。4 mM MAA显著改变了发育调节基因的表达谱。特别是，它上调了RA信号传导靶基因。同时使用药物抑制RA信号可以减轻MAA的形态发生作用。4 mM MAA也显著降低纯化组蛋白去乙酰化酶蛋白的活性。MAA可能通过抑制组蛋白去乙酰化酶，以RA信号依赖的方式损害小鼠类胃原体的轴向伸长形态发生。
Teratogenic potential has been linked to various industrial compounds. Methoxyacetic acid (MAA) is a primary metabolite of the widely used organic solvent and plasticizer, methoxyethanol and dimethoxyethyl phthalate, respectively. Studies using model animals have shown that MAA acts as the proximate teratogen that causes various malformations in developing embryos. Nonetheless, the molecular mechanisms by which MAA exerts its teratogenic effects are not fully understood. Gastruloids of mouse P19C5 pluripotent stem cells, which recapitulate axial elongation morphogenesis of gastrulation-stage embryos, were explored as an in vitro model to investigate the teratogenic action of MAA. Morphometric parameters of gastruloids were measured to evaluate the morphogenetic effect, and transcript levels of various developmental regulator genes were examined to assess the impact on gene expression patterns. The effects of MAA on the level of retinoic acid (RA) signaling and histone deacetylase activity were also measured. MAA reduced axial elongation of gastruloids at concentrations comparable to the teratogenic plasma level (5 mM) in vivo. MAA at 4 mM significantly altered the expression profiles of developmental regulator genes. In particular, it upregulated the RA signaling target genes. The concomitant suppression of RA signaling using a pharmacological agent alleviated the morphogenetic effect of MAA. MAA at 4 mM also significantly reduced the activity of purified histone deacetylase protein. MAA impaired axial elongation morphogenesis in a RA signaling-dependent manner in mouse gastruloids, possibly through the inhibition of histone deacetylase.
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影响因子：
30.8
作者：
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通讯作者：
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