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Increased Exposure to Estrogens Disturbs Maturation, Steroidogenesis, and Cholesterol Homeostasis via Estrogen Receptor in Adult Mouse Leydig Cells

Department of Physiology (L.S., J.K., N.D., P.P., M.P.), Institute of Biomedicine, Turku Center for Disease Modeling (P.P., M.P.), and Functional Foods Forum and Department of Biochemistry and Food Chemistry (S.M.), University of Turku, 20520 Turku, Finland; Department of Medicine (T.M.), Division of Internal Medicine, University of Helsinki, 00014 Helsinki, Finland; Department of Clinical Nutrition and Department of Medicine (H.G.), University of Kuopio and Kuopio University Hospital, 70211 Kuopio, Finland; and Institute for Cell Biology (M.A., A.M.), Ludwig-Maximilians-University, 80802 Munich, Germany

Address all correspondence and requests for reprints to: Matti Poutanen, University of Turku, Institute of Biomedicine, Department of Physiology, Kiinamyllynkatu 10, 20520 Turku, Finland. E-mail: matti.poutanen{at}utu.fi.

Deteriorated male reproductive health has been connected to overexposure to estrogens or to imbalanced androgen-estrogen ratio. Transgenic male mice expressing human aromatase (AROM⁺ mice) serve as an apt model for the study of the consequences of an altered androgen-estrogen ratio. Our previous studies with AROM⁺ mice showed that low androgen levels together with high estrogen levels result in cryptorchidism and infertility. In the present study, the AROM⁺ mice were shown to have severe abnormalities in the structure and function of Leydig cells before the appearance of spermatogenic failure. Decreased expression of adult-type Leydig cell markers (Ptgds, Vcam1, Insl3, Klk21, -24 and -27, Star, Cyp17a1, and Hsd17b3) indicated an immature developmental stage of the Leydig cells, which appears to be the first estrogen-dependent alteration. Genes involved in steroidogenesis (Star, Cyp17a1, and Hsd17b3) were suppressed despite normal LH levels. The low expression level of kallikreins 21, 24, and 27 potentially further inhibited Leydig cell function via remodeling extracellular matrix composition. In connection with disrupted steroidogenesis, Leydig cells showed enlarged mitochondria, a reduced amount of smooth endoplasmic reticulum, and an accumulation of cholesterol and precursors for cholesterol synthesis. The results of studies with AROM⁺ mice crossed with estrogen receptor or β (ER and ERβ, respectively) knockout mice lead to the conclusion that the structural and functional disorders caused by estrogen exposure were mediated via ER, whereas ERβ was not involved.