Printed in U.S.A. Copyright © 2001 by The Endocrine Society Targeted Disruption of the Mouse Estrogen Sulfotransferase Gene Reveals a Role of Estrogen Metabolism in Intracrine and Paracrine Estrogen Regulation
Printed in U.S.A. Copyright © 2001 by The Endocrine Society Targeted Disruption of the Mouse Estrogen Sulfotransferase Gene Reveals a Role of Estrogen Metabolism in Intracrine and Paracrine Estrogen Regulation
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DOI：
10.1210/endo.142.12.8540
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发表时间：
2001-12
期刊：
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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雌激素在靶组织中的生物反应需要雌激素和局部微环境中受体活性配体的存在。尽管对雌激素靶向组织中的受体的研究已经投入了很大的精力，但也出现了这样的概念，即组织对雌激素的敏感性也可能是通过原位代谢转化来调节配体的可用性的。在这里，我们表明，在小鼠体内，雌激素代谢酶雌激素磺基转移酶(EST)的靶向性干扰会导致男性生殖系统的结构和功能损害。EST催化雌激素的磺化结合和失活，在睾丸间质细胞中大量表达。虽然基因敲除的男性最初是生育能力和表型正常的，但他们发展成年龄依赖性的间质细胞肥大/增殖和生精小管损伤。在年轻的基因敲除小鼠中，外源性E2可以概括这些损伤在睾丸中的发展，这表明这些损伤发生在长期雌激素刺激的老年基因敲除小鼠中。研究还发现，由于组织肿胀，老年基因敲除小鼠的睾丸和附睾体重量减轻，但精囊/凝固腺重量增加。此外，与年龄匹配的野生型雄性小鼠相比，老年基因敲除小鼠的总精子活力和前向精子活力分别降低了60%和80%，并且产下的小鼠更小。这些发现确立了EST在男性生殖系统中的作用，并表明在生理环境下，内分泌和旁分泌的雌激素活性可以通过配体转换酶来调节。因此，环境化学物质对雌激素代谢酶的抑制，就像最近对人类EST所证明的那样，可能构成了体内内分泌干扰的一种新机制。
Elicitation of biological responses by estrogen in target tissues requires the presence of ER as well as receptor-active ligand in the local microenvironment. Though much attention has been devoted to the study of the receptor in estrogen target tissues, the concept is emerging that tissue estrogen sensitivity may also be regulated by ligand availability through metabolic transformation in situ. Here, we show that targeted disruption, in the mouse, of an estrogen metabolic enzyme, estrogen sulfotransferase (EST), causes structural and functional lesions in the male reproductive system. EST catalyzes the sulfoconjugation and inactivation of estrogen and is expressed abundantly in testicular Leydig cells. Although knockout males were fertile and phenotypically normal initially, they developed age-dependent Leydig cell hypertrophy/hyperplasia and seminiferous tubule damage. Development of these lesions in the testis could be recapitulated by exogenous E2 administration in younger knockout mice, suggesting that they arose in older knockout mice from chronic estrogen stimulation. Older knockout mice were also found to have reduced testis and epididymis weights but increased seminal vesicle/coagulating gland weight because of tissue swelling. Furthermore, total and forward sperm motility of older knockout mice was reduced by 60% and 80%, respectively, and these mice produced smaller litters compared with age-matched wild-type males. These findings establish a role for EST in the male reproductive system and indicate that intracrine and paracrine estrogen activity can be modulated by a ligand transformation enzyme under a physiological setting. Thus, inhibition of estrogen metabolic enzymes by environmental chemicals, as has been demonstrated recently for the human EST, may constitute a novel mechanism of endocrine disruption in vivo.