Li S, Washburn K A, Moore R, Uno T, Teng C, Newbold R R, McLachlan J A, Negishi M
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 1997 Oct 1;57(19):4356-9.
Alteration of DNA demethylation in five CpG sites (-547, -533, -475, -464, and -454) immediately upstream from the estrogen response element of lactoferrin promoter was determined in the uteri of immature (17-day-old) and mature (21- and 30-day-old) mice treated neonatally with DES. Only the CpG/-464 was found to be abnormally demethylated by diethylstilbestrol (DES) treatment in the mature uteri. This abnormal demethylation occurred in specific response to DES in neonatal mice, because DES injected into the 30-day-old mature mice did not demethylate CpG/-464. This site, however, remained methylated in the neonatally DES-treated/ovariectomized mice, indicating that this DES-elicited demethylation is under hormonal control. Thus, neonatal DES treatment appeared to imprint an abnormal, site-specific demethylation of CpG/-464, which requires ovarian hormones to occur in adult mice. Moreover, the demethylation was maintained in uterine tumors of the neonatally DES-treated mice. This mode of demethylation is reminiscent of uterine tumor formation, which also depends on both neonatal DES exposure and ovarian hormone stimulation in adulthood. Thus, neonatal DES treatment may induce tumor formation as well as demethylation through a common cellular process.
在新生期用己烯雌酚（DES）处理的未成熟（17日龄）和成熟（21日龄和30日龄）小鼠的子宫中，测定乳铁蛋白启动子雌激素反应元件上游紧邻的5个CpG位点（-547、-533、-475、-464和-454）的DNA去甲基化变化。仅发现成熟子宫中经己烯雌酚（DES）处理后CpG/-464异常去甲基化。这种异常去甲基化是新生小鼠对DES的特异性反应，因为注射到30日龄成熟小鼠体内的DES并未使CpG/-464去甲基化。然而，该位点在新生期经DES处理/卵巢切除的小鼠中仍保持甲基化状态，表明这种DES诱导的去甲基化受激素控制。因此，新生期DES处理似乎印记了CpG/-464的异常、位点特异性去甲基化，而这在成年小鼠中需要卵巢激素才能发生。此外，这种去甲基化在新生期经DES处理的小鼠的子宫肿瘤中得以维持。这种去甲基化模式让人联想到子宫肿瘤的形成，其也依赖于新生期DES暴露和成年期卵巢激素刺激。因此，新生期DES处理可能通过共同的细胞过程诱导肿瘤形成以及去甲基化。
