Urinary phthalate metabolites and small non-coding RNAs from seminal plasma extracellular vesicles among men undergoing infertility treatment.
Urinary phthalate metabolites and small non-coding RNAs from seminal plasma extracellular vesicles among men undergoing infertility treatment.
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DOI：
10.1016/j.envpol.2023.121529
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发表时间：
2023-03
影响因子：
8.9
通讯作者：
Oladele A. Oluwayiose;E. Houle;B. Whitcomb;A. Suvorov;T. Rahil;C. Sites;S. Krawetz;P. Visconti;J. Pilsner
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文献类型：
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作者：
Oladele A. Oluwayiose;E. Houle;B. Whitcomb;A. Suvorov;T. Rahil;C. Sites;S. Krawetz;P. Visconti;J. Pilsner
男性生殖道细胞外囊泡（EV）的非编码RNA（ncRNA）货物在精液质量中起着关键作用，新的证据表明它们对环境因素的敏感性。男性邻苯二甲酸酯暴露与精液质量差、精子DNA甲基化谱和胚胎发育有关;然而，关于其对EV ncRNA谱的潜在影响的证据有限。我们评估了接受临床不育治疗的男性中尿邻苯二甲酸酯代谢产物与精浆EV（spEV）的小ncRNA（sncRNA）之间的相关性。我们对从精子环境表观遗传学和发育研究（SEEDS）中收集的96份精浆样本中的EV进行了sncRNA测序。使用星星将测序读数映射到人转录组数据库。通过串联质谱法测定了13种邻苯二甲酸酯和2种邻苯二甲酸酯替代品DiNCH的尿液代谢物浓度。使用EdgeR（FDR <0.05）通过比重、年龄、BMI、批次和生物型特异性总计数调整尿液稀释度，评估与标准化计数的相关性。选择代谢物MEOHP、MECPP、∑ DEHP、MCPP、MCNP、MCOP与miRNA相对丰度呈负相关（p <0.05）。类似地，包括MEOHP、MECPP、MEHP、MCPP、MHBP、MHiNCH、MiBP、MEHHP、MCOP和∑ DEHP在内的9种代谢物与来自23种独特ncRNA转录物（7种miRNA（前和成熟）; 6种tRF;和10种piRNA）的标准化计数相关（q <0.05），其中大多数（78%）表现出表达模式增加。miRNA和tRFs基因靶点在囊泡介导的转运和发育相关的本体论术语中富集，例如酪氨酸激酶、头部发育和细胞形态发生。其中6个基因（MAPK1、BMPR1A/2、PTEN、TGFBR2、TP53和APP）在所有的本体中均存在，并被预测形成蛋白质关联网络。piRNA被注释为EV货物转移和胚胎发育中重要基因的假基因。这是第一项将邻苯二甲酸酯暴露与spEV sncRNA谱改变相关联的研究。未来的研究需要确定它们对生殖结果的影响。
Non-coding RNA (ncRNA) cargo of extracellular vesicles (EVs) in the male reproductive tract play critical roles in semen quality and emerging evidence suggests their susceptibility to environmental factors. Male phthalate exposures have been linked to poor semen quality, sperm DNA methylation profiles and embryo development; however, there is limited evidence on their potential impact on EV ncRNAs profiles. We evaluated the association between urinary phthalate metabolites and small ncRNAs (sncRNAs) of seminal plasma EVs (spEV) among men receiving clinical infertility care.We conducted sncRNA sequencing of EVs in 96 seminal plasma samples collected from the Sperm Environmental Epigenetics and Development Study (SEEDS). Sequencing reads were mapped to human transcriptome databases using STAR. Urinary metabolite concentrations of thirteen phthalates and two DiNCH, a phthalate alternative, were measured via tandem mass spectrometry. Associations with normalized counts were assessed using EdgeR (FDR<0.05) adjusting for urinary dilution via specific gravity, age, BMI, batch, and biotype-specific total counts.Select metabolites, MEOHP, MECPP, ∑DEHP, MCPP, MCNP, MCOP, were negatively (p < 0.05) correlated with miRNA relative abundance. Similarly, nine metabolites including MEOHP, MECPP, MEHP, MCPP, MHBP, MHiNCH, MiBP, MEHHP, MCOP and ∑DEHP were associated (q < 0.05) with normalized counts from 23 unique ncRNA transcripts (7 miRNAs (pre & mature); 6 tRFs; and 10 piRNAs), most (78%) of which displayed increased expression patterns. miRNA and tRFs gene targets were enriched in vesicle-mediated transport and developmental-related ontology terms, such as tyrosine kinase, head development, and cell morphogenesis. Six genes (MAPK1, BMPR1A/2, PTEN, TGFBR2, TP53andAPP) were present in all the ontology terms and predicted to form protein association networks. piRNAs were annotated to pseudogenes of genes important in EV cargo transfer and embryonic development.This is the first study to associate phthalate exposures to altered spEV sncRNA profiles. Future studies are needed to determine their impact on reproductive outcomes.