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

Elicitation of biological responses by estrogen in target tissues requires the presence of ER as well as receptor-active ligand in the local microenvi ronment. Though much attention has been devoted to the study of the recepto r 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 mous e, of an estrogen metabolic enzyme, estrogen sulfotransferase (EST), causes structural and functional lesions in the male reproductive system. EST cat alyzes the sulfoconjugation and inactivation of estrogen and is expressed a bundantly in testicular Leydig cells. Although knockout males were fertile and phenotypically normal initially, they developed age-dependent Leydig ce ll hypertrophy/hyperplasia and seminiferous tubule damage. Development of t hese lesions in the testis could be recapitulated by exogenous E2 administr ation in younger knockout mice, suggesting that they arose in older knockou t mice from chronic estrogen stimulation. Older knockout mice were also fou nd to have reduced testis and epididymis weights but increased seminal vesi cle/coagulating gland weight because of tissue swelling. Furthermore, total and forward sperm motility of older knockout mice was reduced by 60% and 8 0%, respectively, and these mice produced smaller litters compared with age -matched wild-type males. These findings establish a role for EST in the ma le reproductive system and indicate that intracrine and paracrine estrogen activity can be modulated by a ligand transformation enzyme under a physiol ogical setting. Thus, inhibition of estrogen metabolic enzymes by environme ntal chemicals, as has been demonstrated recently for the human EST, may co nstitute a novel mechanism of endocrine disruption in vivo.