title: Mechanism of testosterone deficiency in the transgenic sickle cell mouse.
abstract: Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi) exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease.
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Biljana
authors.initials: B
authors.lastname: Musicki
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Haolin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Terry R
authors.initials: TR
authors.lastname: Brown
authors.affiliation: Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Zirkin
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Burnett
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007985:Leydig Cells / Q000378:metabolism* / Q000473:pathology; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000172:deficiency*; D000094765:Glutathione Peroxidase GPX1; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D007986:Luteinizing Hormone; D005979:Glutathione Peroxidase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000094765:Glutathione Peroxidase GPX1