Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Israel.
Department of Environmental Health Sciences, Columbia University, Mailman School of Public Health, New York City, New York, USA.
Toxicol Sci. 2018 May 1;163(1):116-122. doi: 10.1093/toxsci/kfy013.
Phthalates are endocrine-disrupting chemicals that can cross the placenta and affect the fetal epigenome. Among various epigenetic regulators of gene expression, long noncoding RNAs (lncRNAs) are important players that may also be involved in the manifestation of endocrine-disrupting chemical toxicity. We sought to explore the association between maternal urinary phthalate metabolite concentrations and lncRNA expression in human placenta to better understand potential mechanisms through which lncRNAs participate in mediating phthalate toxicity. Ten patients with uncomplicated dichorionic diamniotic twin pregnancies at term were included in this study. Urinary (n = 10) and placenta samples (n = 20) were collected for all participants. Urinary samples were analyzed for 15 phthalate metabolites and 2 phthalate alternative metabolites. Real-time PCR arrays were used to identify and quantify 87 lncRNAs from the placental samples. We tested the Spearman correlation matrix to compare prenatal phthalate measures against placental lncRNA levels. lncRNA levels showed large variations across samples, with no significant differences in lncRNA expression within twin pairs. Mono-(carboxynonyl) phthalate demonstrated consistently strong correlations with most lncRNAs. The strongest correlation was observed between mono-hydroxyisobutyl phthalate and LOC91450 (Rspearman = 0.88, p < .001). This correlation remained significant after Bonferroni adjustment. Other strong correlations were observed between mono-isobutyl phthalate, DPP10 and HOTTIP (Rspearman = -0.91, p < .001). AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 were strongly correlated with the greatest number of phthalate metabolites. Further studies are needed to validate these results and understand if the altered expression of lncRNAs in human placenta has clinical significance.
邻苯二甲酸酯是一种内分泌干扰化学物质,可以穿过胎盘并影响胎儿的表观基因组。在各种基因表达的表观遗传调控因子中,长非编码 RNA(lncRNA)是重要的参与者,它们也可能参与内分泌干扰化学毒性的表现。我们试图探讨母体尿液邻苯二甲酸酯代谢物浓度与人类胎盘 lncRNA 表达之间的关联,以更好地了解 lncRNA 参与介导邻苯二甲酸酯毒性的潜在机制。本研究纳入了 10 名足月单纯双绒毛膜双羊膜妊娠的患者。所有参与者均采集了尿液(n = 10)和胎盘样本(n = 20)。对尿液样本进行了 15 种邻苯二甲酸酯代谢物和 2 种邻苯二甲酸酯替代代谢物的分析。实时 PCR 阵列用于鉴定和量化胎盘样本中的 87 个 lncRNA。我们测试了 Spearman 相关矩阵,以比较产前邻苯二甲酸测量值与胎盘 lncRNA 水平。lncRNA 水平在样本中差异较大,双胞胎内的 lncRNA 表达无显著差异。单-(羧基壬基)邻苯二甲酸酯与大多数 lncRNA 表现出一致的强相关性。单-羟基异丁基邻苯二甲酸酯与 LOC91450 之间的相关性最强(Rspearman = 0.88,p <.001)。经 Bonferroni 调整后,这种相关性仍然显著。在单-异丁基邻苯二甲酸酯、DPP10 和 HOTTIP 之间也观察到了其他强相关性(Rspearman = -0.91,p <.001)。AIRN、DACT3.AS1、DLX6、DPP10、HOTTIP、LOC143666 和 LOC91450 与最多数量的邻苯二甲酸酯代谢物强烈相关。需要进一步的研究来验证这些结果,并了解人类胎盘 lncRNA 表达的改变是否具有临床意义。