Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation

Y. M. Qian, X. J. Sun, M. H. Tong, Xiangping Li, J. Richa, W. C. Song

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5342-5350
Number of pages9
JournalEndocrinology
Volume142
Issue number12
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Estrogens
Knockout Mice
Genes
Leydig Cells
Ligands
Testis
Enzymes
Weights and Measures
Seminiferous Tubules
Seminal Vesicles
Sperm Motility
Epididymis
estrone sulfotransferase
Estrogen Receptors
Hypertrophy
Hyperplasia

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation. / Qian, Y. M.; Sun, X. J.; Tong, M. H.; Li, Xiangping; Richa, J.; Song, W. C.

In: Endocrinology, Vol. 142, No. 12, 2001, p. 5342-5350.

Research output: Contribution to journalArticle

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