Li Yin, Hamilton Katherine J, Lai Anne Y, Burns Katherine A, Li Leping, Wade Paul A, Korach Kenneth S
Laboratory of Reproductive and Developmental Toxicology.
Environ Health Perspect. 2014 Mar;122(3):262-8. doi: 10.1289/ehp.1307351. Epub 2013 Dec 6.
Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor α (ERα), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes.
We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression.
We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ERα-knockout (αERKO) mice.
The DNA methylation status at four specific CpGs (-160, -237, -306, and -367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (-449 and -459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SVs, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers-DNMT3A, MBD2, and HDAC2-increased in the SV of DES-exposed WT mice.
DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ERα. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV.
Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262-268; http://dx.doi.org/10.1289/ehp.1307351.
己烯雌酚（DES）是一种合成雌激素，与对生殖器官的不良影响有关。DES诱导的小鼠精囊（SV）毒性由雌激素受体α（ERα）介导，ERα会改变精囊分泌蛋白IV（Svs4）和乳铁蛋白（Ltf）基因的表达。
我们研究了核受体活性与DNA甲基化及基因表达改变之间的关系。
我们使用新生期暴露于DES的小鼠模型，通过亚硫酸氢盐转化测序检测野生型（WT）和ERα基因敲除（αERKO）小鼠精囊中的DNA甲基化模式。
Svs4基因启动子中四个特定CpG位点（-160、-237、-306和-367）的DNA甲基化状态在小鼠发育过程中从甲基化变为未甲基化，而DES在WT精囊10周龄时阻止了这种变化。在Ltf基因启动子的两个特定CpG位点（-449和-459），DES将甲基化状态从甲基化改变为未甲基化。在αERKO精囊中未观察到Svs4和Ltf的DNA甲基化改变，这表明这些CpG位点的甲基化状态变化依赖于ERα。甲基化状态与基因表达水平相关。此外，在暴露于DES的WT小鼠精囊中，三种表观遗传修饰因子DNMT3A、MBD2和HDAC2的基因表达增加。
DES诱导的激素毒性是由Svs4和Ltf的基因表达改变引起的，这些改变与由ERα介导的DNA甲基化变化有关。暴露于DES的雄性小鼠中DNMT3A、MBD2和HDAC2基因表达的改变可能参与介导精囊中甲基化状态的变化。
Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014.己烯雌酚（DES）刺激的激素毒性由小鼠精囊中靶基因甲基化模式和表观遗传修饰因子（DNMT3A、MBD2和HDAC2）的ERα改变介导。《环境健康展望》122:262 - 268；http://dx.doi.org/10.1289/ehp.1307351
