Abstract
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.
Highlights
Fluorine is one of the most abundant elements on the earth, and high fluoride concentrations can be found in soil and water; dental products; food and beverage products such as tea, soy products, and grape juice; and in fluorinated prescription drugs (Sun et al 2010)
The H19 imprint occurs during spermatogenesis, and the differentially methylated region (DMR) of H19 is methylated in mature sperm but not in oocytes (Lucifero et al 2002)
DNA methylation of H19, Peg3, and Line1 was examined in NaF-treated male, NaF-treated female, and respective control groups
Summary
Fluorine is one of the most abundant elements on the earth, and high fluoride concentrations can be found in soil and water; dental products; food and beverage products such as tea, soy products, and grape juice; and in fluorinated prescription drugs (Sun et al 2010). Imprinted genes escape reprogramming after fertilization and retain methylation differences during development. The H19 imprint occurs during spermatogenesis, and the differentially methylated region (DMR) of H19 is methylated in mature sperm but not in oocytes (Lucifero et al 2002). The DMR of Peg, a maternally imprinted gene, is unmethylated in sperm but completely methylated in mature oocytes (Lucifero et al 2002). We reported that the Peg methylation imprint can be erased and re-established during pre-implantation development (Liu et al 2008). Peg methylation may be influenced by environmental factors This leads us to speculate that NaF may change the normal DNA methylation pattern of early embryos. We investigated whether NaF interferes with DNA methylation, and we report that possible links exist between the DNA methylation and NaF reproductive toxicity
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