Andersen M E, Barton H A
K. S. Crump Group, Inc., North Carolina 27709, USA.
Toxicol Sci. 1999 Mar;48(1):38-50. doi: 10.1093/toxsci/48.1.38.
Some endocrine-active compounds (EACs) act as agonists or antagonists of specific hormones and may interfere with cellular control processes that regulate gene transcription. Many mechanisms controlling gene expression are universal to organisms ranging from unicellular bacteria to more complex plants and animals. One mechanism, coordinated control of batteries of gene products, is critical in adaptation of bacteria to new environments and for development and tissue differentiation in multi-cellular organisms. To coordinately activate sets of genes, all living organisms have devised molecular modules to permit transitions, or switching, between different functional states over a small range of hormone concentration, and other modules to stabilize the new state through homeostatic interactions. Both switching and homeostasis are regulated by controlling concentrations of hormone-receptor complexes. Molecular control processes for switching and homeostasis are inherently nonlinear and often utilize autoregulatory feedback loops. Among the biological processes contributing to switching phenomena are receptor autoinduction, induction of enzymes for ligand synthesis, mRNA stabilization/activation, and receptor polymerization. This paper discusses a variety of molecular switches found in animal species, devises simple quantitative models illustrating roles of specific molecular interactions in creating switching modules, and outlines the impact of these switching processes and other feedback loops for risk assessments with EACs. Quantitative simulation modeling of these switching mechanisms made it apparent that highly nonlinear dose-response curves for hormones and EACs readily arise from interactions of several linear processes acting in concert on a common control point. These nonlinear mechanisms involve amplification of response, rather than multimeric molecular interactions as in conventional Hill relationships.
一些内分泌活性化合物（EACs）可作为特定激素的激动剂或拮抗剂，并可能干扰调节基因转录的细胞控制过程。许多控制基因表达的机制在从单细胞细菌到更复杂的植物和动物等生物体中是普遍存在的。一种机制，即基因产物组的协调控制，对于细菌适应新环境以及多细胞生物体的发育和组织分化至关重要。为了协调激活基因集，所有生物体都设计了分子模块，以允许在小范围的激素浓度内实现不同功能状态之间的转变或切换，以及其他模块通过稳态相互作用来稳定新状态。切换和稳态均通过控制激素 - 受体复合物的浓度来调节。切换和稳态的分子控制过程本质上是非线性的，并且经常利用自动调节反馈回路。导致切换现象的生物学过程包括受体自诱导、配体合成酶的诱导、mRNA稳定化/激活以及受体聚合。本文讨论了在动物物种中发现的各种分子开关，设计了简单的定量模型来说明特定分子相互作用在创建切换模块中的作用，并概述了这些切换过程和其他反馈回路对EACs风险评估的影响。对这些切换机制的定量模拟建模表明，激素和EACs的高度非线性剂量 - 反应曲线很容易由几个线性过程在共同控制点上协同作用的相互作用产生。这些非线性机制涉及反应的放大，而不是像传统希尔关系中那样的多聚体分子相互作用。
