Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0645, USA.
J Steroid Biochem Mol Biol. 2011 Oct;127(1-2):44-50. doi: 10.1016/j.jsbmb.2011.01.015. Epub 2011 Feb 12.
When inappropriate (non-physiologic) estrogens affect organisms at critical times of estrogen sensitivity, disruption of normal endocrine functions can result. Non-physiologic estrogen mimetics (environmental, dietary, and pharmaceutical) can signal rapidly and potently via the membrane versions of estrogen receptors, as can physiologic estrogens. Both physiologic and non-physiologic estrogens activate multiple signaling pathways, leading to altered cellular functions (e.g. peptide release, cell proliferation or death, transport). Xenoestrogens' mimicry of physiologic estrogens is imperfect. When superimposed, xenoestrogens can alter endogenous estrogens' signaling and thereby disrupt normal signaling pathways, leading to malfunctions in many tissue types. Though these xenoestrogen actions occur rapidly via nongenomic signaling pathways, they can be sustained with continuing ligand stimulation, combinations of ligands, and signaling that perpetuates downstream, eventually also impinging on genomic regulation by controlling the activation state of transcription factors. Because via these pathways estrogens and xenoestrogens cause nonmonotonic stimulation patterns, they must be carefully tested for activity and toxicity over wide dose ranges. Nongenomic actions of xenoestrogens in combination with each other, and with physiologic estrogens, are still largely unexplored from these mechanistic perspectives.
当不适当的（非生理性）雌激素在雌激素敏感的关键时期影响生物体时，正常的内分泌功能可能会受到干扰。非生理性雌激素模拟物（环境、饮食和药物）可以通过雌激素受体的膜形式快速而有效地发出信号，生理性雌激素也可以。生理性和非生理性雌激素都可以激活多种信号通路，导致细胞功能改变（例如肽释放、细胞增殖或死亡、运输）。外源性雌激素对生理性雌激素的模拟是不完善的。当外源性雌激素叠加时，它们可以改变内源性雌激素的信号，从而破坏正常的信号通路，导致许多组织类型的功能障碍。尽管这些外源性雌激素通过非基因组信号通路迅速发挥作用，但它们可以通过持续的配体刺激、配体组合以及下游的持续信号传递来维持，最终也会通过控制转录因子的激活状态来影响基因组调节。由于通过这些途径，雌激素和外源性雌激素引起非单调刺激模式，因此必须在广泛的剂量范围内仔细测试它们的活性和毒性。从这些机制角度来看，外源性雌激素的非基因组作用与其相互作用以及与生理性雌激素的相互作用在很大程度上仍未得到探索。
