College of Veterinary Medicine, Yangzhou University, Wenhui Rd, Yangzhou, 225009, Jiangsu, People's Republic of China.
Arch Toxicol. 2014 Feb;88(2):241-8. doi: 10.1007/s00204-013-1122-5. Epub 2013 Sep 13.
Sodium fluoride (NaF) is associated with embryonic and fetal development abnormalities, but the mechanism by which this occurs is unclear. DNA methylation, an important epigenetic reprogramming mechanism, is essential for normal embryonic development. Thus, we investigated the effect of NaF on DNA methylation in early mouse embryos, as well as mouse sperm and liver using bisulfite sequencing and ELISA. Data indicate that H19, a paternally imprinted gene, compared to control embryos, was less methylated in 8-cell embryos from pregnant mice treated with NaF (100 mg/l) in drinking water for 48 h. Peg3, a maternally imprinted gene, and the Line1 repeated sequence were similarly methylated in NaF-treated and control embryos. Oral ingestion of NaF for 35 days did not significantly change Line1 and genomic global DNA methylation in the liver. H19, Rasgrf1, Line1, and genomic global DNA methylation were also similar in NaF-treated and control sperm. Female mice mated with NaF-treated male mice (35 days) had less methylated H19, but Peg3 was significantly more methylated. Line1 was similarly methylated in treated 8-cell embryos, compared to control embryos. NaF treatment of male mice before copulation significantly increased the expression of H19 in blastocysts, whereas H19 expression was not detected in 8-cell embryos. Data suggest that NaF may interact directly with the embryo to disrupt the maintenance of normal gene imprinting during pregnancy. Long-term NaF exposure of males may not directly affect DNA methylation of the sperm and liver, but the sperm may signal to early embryos with abnormal gene imprinting.
氟化钠（NaF）与胚胎和胎儿发育异常有关，但发生这种情况的机制尚不清楚。DNA 甲基化是一种重要的表观遗传重编程机制，对于正常胚胎发育至关重要。因此，我们使用亚硫酸氢盐测序和 ELISA 法研究了 NaF 对早期小鼠胚胎以及小鼠精子和肝脏中 DNA 甲基化的影响。数据表明，与对照胚胎相比，在饮用水中接受 NaF（100mg/L）处理 48 小时的怀孕小鼠 8 细胞胚胎中，H19（一种父系印迹基因）的甲基化程度较低。印迹基因 Peg3 和 Line1 重复序列在 NaF 处理和对照胚胎中的甲基化方式相似。连续 35 天口服 NaF 不会显著改变肝脏中的 Line1 和基因组全基因组 DNA 甲基化。H19、Rasgrf1、Line1 和基因组全基因组 DNA 甲基化在 NaF 处理和对照精子中也相似。与接受 NaF 处理的雄性小鼠交配的雌性小鼠的 H19 甲基化程度降低，但 Peg3 的甲基化程度显著增加。与对照胚胎相比，处理过的 8 细胞胚胎中的 Line1 甲基化程度相似。在交配前用 NaF 处理雄性小鼠会显著增加囊胚中 H19 的表达，而在 8 细胞胚胎中未检测到 H19 的表达。数据表明，NaF 可能直接与胚胎相互作用，破坏怀孕期间正常基因印迹的维持。雄性长期暴露于 NaF 可能不会直接影响精子和肝脏的 DNA 甲基化，但精子可能会向异常基因印迹的早期胚胎发出信号。
