Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Diabetologia. 2013 Sep;56(9):2059-67. doi: 10.1007/s00125-013-2944-7. Epub 2013 Jun 8.
AIMS/HYPOTHESIS: Perinatal exposure to bisphenol A (BPA), a widely distributed environmental endocrine disruptor, is associated with insulin resistance and diabetes in offspring. The underlying molecular mechanisms could involve epigenetics, as adverse effects induced by environmental exposure in early life are suggested through DNA methylation. In this study we sought to elucidate the relationship between perinatal BPA exposure and alteration of hepatic DNA methylation.
Pregnant Wistar rats were administered BPA (50 μg/kg/day) or corn oil by oral gavage throughout gestation and lactation. Variables associated with insulin resistance and hepatic DNA methylation were examined at postnatal week 3 and week 21 in male offspring.
In BPA-treated offspring, serum insulin and HOMA-insulin resistance were increased, and the insulin sensitivity index and hepatic glycogen storage were decreased compared with controls at week 21. At week 3, none of these variables were significantly changed. However, hepatic global DNA methylation was decreased, accompanied by overexpression of DNA methyltransferase 3B mRNA at week 3. Meanwhile, perinatal exposure to BPA induced promoter hypermethylation and a reduction in gene expression of hepatic glucokinase. Moreover, increased promoter hypermethylation of Gck became more pronounced in BPA-treated offspring at week 21.
CONCLUSIONS/INTERPRETATION: Abnormal DNA methylation in hepatic tissue precedes development of insulin resistance induced by perinatal BPA exposure. These findings support the potential role of epigenetics in fetal reprogramming by BPA-induced metabolic disorders.
目的/假设：围产期暴露于双酚 A（BPA），一种广泛分布的环境内分泌干扰物，与后代的胰岛素抵抗和糖尿病有关。潜在的分子机制可能涉及表观遗传学，因为早期生活中环境暴露引起的不良影响通过 DNA 甲基化得到证实。在这项研究中，我们试图阐明围产期 BPA 暴露与肝 DNA 甲基化改变之间的关系。
通过口服灌胃，给妊娠 Wistar 大鼠在整个妊娠期和哺乳期给予 BPA（50μg/kg/天）或玉米油。在雄性后代出生后第 3 周和第 21 周检查与胰岛素抵抗相关的变量和肝 DNA 甲基化改变。
与对照组相比，BPA 处理的后代在第 21 周时血清胰岛素和 HOMA-胰岛素抵抗增加，胰岛素敏感性指数和肝糖原储存减少。在第 3 周，这些变量均无明显变化。然而，肝总 DNA 甲基化减少，同时在第 3 周时 DNA 甲基转移酶 3B mRNA 表达过度。同时，围产期暴露于 BPA 诱导肝葡萄糖激酶的启动子超甲基化和基因表达减少。此外，在第 21 周时，BPA 处理的后代中 Gck 的启动子超甲基化增加更为明显。
结论/解释：肝组织中异常的 DNA 甲基化先于围产期 BPA 暴露引起的胰岛素抵抗发展。这些发现支持了表观遗传学在 BPA 诱导的代谢紊乱对胎儿重编程中的潜在作用。
