Burkhart Barbara A, Ivey Melissa L, Archer Trevor K
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Mol Cell Endocrinol. 2009 Jan 27;298(1-2):66-75. doi: 10.1016/j.mce.2008.10.011. Epub 2008 Oct 19.
Environmental exposure to low concentration hormones can have permanent epigenetic effects in animals and humans. The consequence of long-term low concentration glucocorticoid exposure was investigated in cell culture using glucocorticoid responsive genes organized in alternative chromatin structures. The MMTV promoter is induced by short-term glucocorticoid exposure on either an integrated (normal chromatin) or transient (unstructured chromatin) promoter. Longer hormone treatment causes a transient refractory repression of only the integrated promoter. Exposure to low concentrations of hormone for several passages persistently represses the integrated MMTV and endogenous glucocorticoid responsive promoters. The glucocorticoid receptor cannot bind to persistently repressed promoters. Induction by androgens is also inhibited on the repressed MMTV promoter. Similarly, osmotic stress induction of the endogenous Sgk gene is repressed. Persistent repression by glucocorticoids targets glucocorticoid responsive genes using a chromatin-dependent mechanism that disrupts binding of both GR-dependent and GR-independent transcription complexes.
环境中低浓度激素暴露可在动物和人类中产生永久性表观遗传效应。利用以替代染色质结构组织的糖皮质激素反应基因，在细胞培养中研究了长期低浓度糖皮质激素暴露的后果。MMTV启动子在整合型（正常染色质）或瞬时型（无结构染色质）启动子上受到短期糖皮质激素暴露的诱导。更长时间的激素处理仅导致整合型启动子的瞬时难治性抑制。在几个传代过程中暴露于低浓度激素会持续抑制整合型MMTV和内源性糖皮质激素反应启动子。糖皮质激素受体无法结合持续抑制的启动子。在受抑制的MMTV启动子上，雄激素诱导也受到抑制。同样，内源性Sgk基因的渗透压应激诱导也受到抑制。糖皮质激素的持续抑制利用一种依赖染色质的机制靶向糖皮质激素反应基因，该机制破坏了GR依赖性和GR非依赖性转录复合物的结合。
