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首页> 外文期刊>Epigenetics & Chromatin >Differential DNA methylation at conserved non-genic elements and evidence for transgenerational inheritance following developmental exposure to mono(2-ethylhexyl) phthalate and 5-azacytidine in zebrafish
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Differential DNA methylation at conserved non-genic elements and evidence for transgenerational inheritance following developmental exposure to mono(2-ethylhexyl) phthalate and 5-azacytidine in zebrafish

机译：保守的非基因元件上的差异DNA甲基化和斑马鱼中邻苯二甲酸单（2-乙基己基）邻苯二甲酸酯和5-氮杂胞苷的发育暴露后的跨代遗传证据

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Background Exposure to environmental stressors during development may lead to latent and transgenerational adverse health effects. To understand the role of DNA methylation in these effects, we used zebrafish as a vertebrate model to investigate heritable changes in DNA methylation following chemical-induced stress during early development. We exposed zebrafish embryos to non-embryotoxic concentrations of the biologically active phthalate metabolite mono(2-ethylhexyl) phthalate (MEHP, 30?μM) and the DNA methyltransferase 1 inhibitor 5-azacytidine (5AC, 10?μM). Direct, latent and transgenerational effects on DNA methylation were assessed using global, genome-wide and locus-specific DNA methylation analyses. Results Following direct exposure in zebrafish embryos from 0 to 6?days post-fertilization, genome-wide analysis revealed a multitude of differentially methylated regions, strongly enriched at conserved non-genic elements for both compounds. Pathways involved in adipogenesis were enriched with the putative obesogenic compound MEHP. Exposure to 5AC resulted in enrichment of pathways involved in embryonic development and transgenerational effects on larval body length. Locus-specific methylation analysis of 10 differentially methylated sites revealed six of these loci differentially methylated in sperm sampled from adult zebrafish exposed during development to 5AC, and in first and second generation larvae. With MEHP, consistent changes were found at 2 specific loci in first and second generation larvae. Conclusions Our results suggest a functional role for DNA methylation on cis-regulatory conserved elements following developmental exposure to compounds. Effects on these regions are potentially transferred to subsequent generations.
机译：背景技术在开发过程中暴露于环境压力因素可能会导致潜在的和跨代不良的健康影响。为了了解DNA甲基化在这些作用中的作用，我们使用斑马鱼作为脊椎动物模型研究了在早期发育过程中化学诱导的应激后DNA甲基化的遗传变化。我们将斑马鱼胚胎暴露于非胚胎毒性浓度的生物活性邻苯二甲酸酯代谢物邻苯二甲酸单（2-乙基己基）酯（MEHP，30？μM）和DNA甲基转移酶1抑制剂5-氮杂胞苷（5AC，10？μM）。使用全局，全基因组和基因座特异性DNA甲基化分析评估了对DNA甲基化的直接，潜在和跨代影响。结果在受精后0至6天直接暴露于斑马鱼胚胎中之后，全基因组分析显示了许多差异甲基化区域，在这两种化合物的保守非基因元件上都大量富集。与脂肪形成有关的途径富含推定的致肥胖化合物MEHP。暴露于5AC会导致参与胚胎发育和对幼虫体长的跨代效应的途径丰富。对10个差异甲基化位点的基因座特异性甲基化分析显示，在发育至5AC的成年斑马鱼以及第一代和第二代幼虫中，从成年斑马鱼的精子采样中，这些基因座中有六个差异甲基化。使用MEHP，在第一代和第二代幼虫的两个特定基因座上发现了一致的变化。结论我们的研究结果表明在发育暴露于化合物后，DNA甲基化对顺式调控保守元件的功能作用。对这些区域的影响可能会转移到后代。

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