Greathouse K L, Cook J D, Lin K, Davis B J, Berry T D, Bredfeldt T G, Walker C L
Department of Carcinogenesis, MD Anderson Cancer Center, Science Park Research Division, Smithville, Texas, USA.
Reprod Sci. 2008 Oct;15(8):765-78. doi: 10.1177/1933719108322440.
Environmental exposures during development can alter susceptibility later in life to adult diseases including uterine leiomyoma, a phenomenon termed developmental reprogramming. The goal of this study was to identify genes developmentally reprogrammed by diethylstilbestrol (DES) and aberrantly expressed in leiomyomas. Transcriptional profiling identified 171 genes differentially expressed in leiomyomas relative to normal myometrium, of which 6/18 genes with putative estrogen responsive elements and confirmed to be estrogen-responsive in neonatal uteri were reprogrammed by neonatal DES exposure. Calbindin D9k and Dio2, normally induced by estrogen, exhibited elevated expression in DES-exposed animals during both phases of the estrus cycle. Gdf10, Car8, Gria2, and Mmp3, genes normally repressed by estrogen, exhibited elevated expression in DES-exposed animals during the proliferative phase, when estrogen is highest. These data demonstrate that neonatal DES exposure causes reprogramming of estrogen-responsive genes expressed in uterine leiomyomas, leading to over-expression of these genes in the myometrium of exposed animals prior to the onset of tumorigenesis.
发育过程中的环境暴露会改变个体成年后患包括子宫平滑肌瘤在内的成人疾病的易感性,这一现象被称为发育重编程。本研究的目的是鉴定经己烯雌酚(DES)进行发育重编程且在平滑肌瘤中异常表达的基因。转录谱分析确定了171个在平滑肌瘤中相对于正常子宫肌层差异表达的基因,其中18个带有假定雌激素反应元件且在新生子宫中被证实为雌激素反应性的基因中有6个因新生期DES暴露而发生重编程。钙结合蛋白D9k和Dio2通常由雌激素诱导,在发情周期的两个阶段,DES暴露动物中它们均表现出表达升高。生长分化因子10(Gdf10)、羧酸酯酶8(Car8)、谷氨酸受体离子型AMPA2(Gria2)和基质金属蛋白酶3(Mmp3)等通常受雌激素抑制的基因,在雌激素水平最高的增殖期,DES暴露动物中表现出表达升高。这些数据表明,新生期DES暴露导致子宫平滑肌瘤中表达的雌激素反应性基因发生重编程,从而导致这些基因在暴露动物的子宫肌层中在肿瘤发生之前就过度表达。