Trosko J E, Chang C C, Upham B, Wilson M
Department of Pediatrics and Human Development, Institute for Environmental Toxicology, College of Human Medicine, Michigan State University, East Lansing 48824, USA.
Toxicol Lett. 1998 Dec 28;102-103:71-8. doi: 10.1016/s0378-4274(98)00288-4.
Communication mechanisms [extra-, intra-, and gap junctional inter-cellular communication (GJIC)] control, from the fertilized egg, through embryogenesis to maturity and aging, whether a cell proliferates, differentiates, dies by apoptosis, or if differentiated, adaptively responds to endogenous and exogenous signals. From the egg to the 100 trillion cells in the human body, health is maintained when these communication processes between stem, progenitor and terminally differentiated cells are integrated. Each cell choice involves 'epigenetic' mechanisms to alter the expression of genes at the transcriptional, translational or post-translational levels. Disruption of the communication mechanisms can be either adaptive or maladaptive. Modulation of extra-cellular communication, either by genetic imbalances of growth factors, hormones or neurotransmitters or by environmental, exogenous chemicals can trigger signal transducing intra-cellular mechanisms. These intra-cellular signals can modulate gene expression at the transcriptional, translational or post-translational levels while also modulating GJIC. Untimely or chronic disruption of GJIC during embryonic or fetal development could lead to embryonic lethality or teratogenesis. By modulation of GJIC, homeostatic control of cell growth, differentiation or apoptosis could lead to specific diseases, such as neurological, cardiovascular, reproductive or endocrinological dysfunction. Chemical modulation or oncogene down-regulation of GJIC in initiated tissues has been shown to lead to tumor promotion. Genetic syndromes carrying a mutated gap junction gene, together with some transgenic and knock-out gap junction gene mice, provide evidence for the importance of this organelle found only in metazoans. Implications for 'thresholds' to toxicants and for risk assessment are evident.
通讯机制[细胞外、细胞内以及间隙连接细胞间通讯（GJIC）]从受精卵开始，贯穿胚胎发育、成熟直至衰老，控制着细胞是增殖、分化、通过凋亡死亡，还是在分化后对内外源信号做出适应性反应。从卵细胞到人体中的100万亿个细胞，当干细胞、祖细胞和终末分化细胞之间的这些通讯过程整合在一起时，健康得以维持。每个细胞的选择都涉及“表观遗传”机制，以在转录、翻译或翻译后水平改变基因表达。通讯机制的破坏可能是适应性的，也可能是适应不良的。细胞外通讯的调节，无论是通过生长因子、激素或神经递质的基因失衡，还是通过环境中的外源化学物质，都可以触发细胞内信号转导机制。这些细胞内信号可以在转录、翻译或翻译后水平调节基因表达，同时也调节GJIC。在胚胎或胎儿发育过程中，GJIC的过早或慢性破坏可能导致胚胎致死或致畸。通过调节GJIC，对细胞生长、分化或凋亡的稳态控制可能导致特定疾病，如神经、心血管、生殖或内分泌功能障碍。在起始组织中对GJIC进行化学调节或癌基因下调已被证明会导致肿瘤促进。携带突变间隙连接基因的遗传综合征，以及一些转基因和敲除间隙连接基因的小鼠，为仅在后生动物中发现的这种细胞器的重要性提供了证据。对毒物“阈值”和风险评估的影响是显而易见的。
