Cuscuta chinensis flavonoids down-regulate the DNA methylation of the H19/Igf2 imprinted control region and estrogen receptor alpha promoter of the testis in bisphenol A exposed mouse offspring
Cuscuta chinensis flavonoids down-regulate the DNA methylation of the H19/Igf2 imprinted control region and estrogen receptor alpha promoter of the testis in bisphenol A exposed mouse offspring
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菟丝子黄酮类化合物下调双酚 A 暴露小鼠后代 H19/Igf2 印记控制区和睾丸雌激素受体 α 启动子的 DNA 甲基化
DOI：
10.1039/c9fo02770j
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发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
Wanyu Shi
中科院分区：
文献类型：
--
作者：
Yuanyuan Wei;Chao Han;Shuying Li;Yuqing Cui;Yongzhan Bao;Wanyu Shi
暴露于新出现的污染物双酚A（BPA）是普遍存在的，并与生殖疾病有关。BPA作为一种内分泌干扰物的作用是众所周知的，但其他潜在的发育疾病机制，如表观遗传修饰，仍然不清楚。本研究的目的是通过分析BPA对睾丸发育损害的相关分子过程，探讨菟丝子黄酮类化合物（Cuscuta chinensis flavonoids，CCF）是否可以作为膳食补充剂逆转BPA诱导的表观遗传疾病。在妊娠第0.5-17.5天（GD）对母鼠给予BPA和不同浓度的CCF。分别于生后21天和56天取雄性小鼠睾丸和血清检测相关指标。结果表明，与BPA组相比，CCF组在PND 2 1和PND 5 6时血清睾酮（T）、雌二醇（E2）含量，PND 2 1时DNA甲基转移酶3A（Dnmt 3A）、Dnmt 3B含量和转录水平，PND 5 6时雌激素受体α（ERα）含量和转录水平均显著升高。不同浓度的CCF均能显著降低雄性大鼠PND 21时Dnmt 1和ERα的表达，降低PND 21和PND 56时ERβ的表达（P < 0.01或P < 0.05）。CCF还显著抑制了PND 56时BPA诱导的睾丸ERα启动子和H19/Igf 2印迹控制区（ICR）的高甲基化状态。结果表明，CCF可通过抑制DNA甲基转移酶（DNMTs）的表达，降低ERα和H19/Igf 2基因的甲基化水平，从而降低成年雄性小鼠生殖激素和受体水平，最终缓解BPA对雄性小鼠睾丸发育的不利影响。
Exposure to the emerging contaminant bisphenol A (BPA) is ubiquitous and associated with reproductive disorders. The BPA effect as an endocrine disruptor is widely known but other mechanisms underlying developmental disease, such as epigenetic modifications, still remain unclear. The objective of this study was to investigate whether Cuscuta chinensis flavonoids (CCFs) can be used as a dietary supplement to reverse BPA-induced epigenetic disorders, by analyzing the molecular processes related to BPA impair-ment of testicular development. BPA and different concentrations of CCFs were administered to the dams at gestation day (GD) 0.5–17.5. The testis and serum of male mice were collected at postnatal day (PND) 21 and PND 56 for the detection of related indicators. Our results showed that compared with the BPA group, CCFs could significantly increase the serum contents of testosterone (T), estradiol (E 2 ) in males at PND 21 and PND 56, as well as the contents and transcription levels of DNA methyltransferase3A (Dnmt3A), Dnmt3B in males at PND 21 and that of estrogen receptor alpha (ERα) at PND 56. The expressions of Dnmt1 and ERα at PND 21 and ERβ at both PND 21 and PND 56 in males were significantly decreased with the administration of different concentrations of CCFs (P < 0.01 or P < 0.05). CCFs also significantly inhibited the BPA-induced hypermethylated status of the ERα promoter and H19/Igf2 imprinting control region (ICR) in the testis at PND 56. These results indicated that CCFs could decrease the methylation levels of ERα and H19/Igf2 genes by inhibiting the expression of DNA methyltransferases(DNMTs), thereby decreasing the levels of reproductive hormones and receptors in adult males, and ulti-mately alleviating the negative effect of BPA on testicular development in male mice.