Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men.
Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men.
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暴露于双酚 A 的男性精子 DNA 羟甲基化的全基因组改变
DOI：
10.1371/journal.pone.0178535
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Yuan W
中科院分区：
文献类型：
--
作者：
Zheng H;Zhou X;Li DK;Yang F;Pan H;Li T;Miao M;Li R;Yuan W
环境中暴露的双酚A已被证明影响人类精子的浓度和活力，以及啮齿动物的精子发生。然而，目前还不清楚双酚A暴露是否与人类精子中DNA羟甲基化的改变有关，DNA羟甲基化是表观遗传修饰的标志。对职业接触双酚A的男性的精子样本进行了全基因组DNA羟甲基化研究。与未接触双酚A的对照组相比，接触双酚A的男性总5-羟甲基胞嘧啶(5HMC)水平显著升高(增加19.37%)，其中72.69%的基因组区域含有5HMC。与对照组相比，暴露于BPA的男性共发现9,610个差异5hmc区，主要位于基因间隔区和内含子区域。这些DHMR由8,670个高HMRS和940个低HMRS组成，涉及2,008个基因和重复元件。受高HMRS影响的基因在与神经系统、发育、心血管疾病和信号转导相关的途径中丰富。此外，在暴露于双酚A的精子中，观察到8个母体表达的印记基因的启动子中有5HMC的浓缩。一些受BPA影响的基因，如MLH1、CHD2、SPATA12和SPATA20，可能参与了对BPA引起的生殖细胞DNA损伤的应答。我们的分析表明，在人类精子中检测到表达的基因中，5HMC在启动子和基因体中的浓缩程度高于那些不表达的基因。重要的是，我们观察到BPA暴露影响了这些基因中11.4%在精子中表达的5hmc水平，以及6.85%的精子基因组中的5hmc水平。最后，我们还观察到，双酚A暴露往往会改变先前报道的与三甲基化组蛋白3(H3K27me3、H3K4me2或H3K4me3)一起分布在精子中的基因的5hmc浓缩。因此，这些结果表明，BPA暴露可能通过影响DNA羟甲基化来干扰基因表达，这种影响在一定程度上依赖于人类精子发生中H3的三甲基化。我们目前的研究揭示了双酚A暴露降低人类精子质量的新机制。
Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality.