title: Active vitamin D deficiency mediated by extracellular calcium and phosphorus results in male infertility in young mice.
abstract: We used mice with targeted deletion of 25-hydroxyvitamin D-1 α-hydroxylase [1α(OH)ase(-/-)] to investigate whether 1,25(OH)2D3 deficiency results in male infertility mediated by 1,25(OH)2D3 or extracellular calcium and phosphorus. Male 1α(OH)ase(-/-) and their wild-type littermates fed either a normal diet or a rescue diet from weaning were mated at 6-14 wk of age with female wild-type mice on the same diet. The fertility efficiency of females was analyzed, and the reproductive phenotypes of males were evaluated by histopathological and molecular techniques. Hypocalcemic and hypophosphatemic male 1α(OH)ase(-/-) mice on a normal diet developed infertility characterized by hypergonadotropic hypogonadism, with downregulation of testicular calcium channels, lower intracellular calcium levels, decreased sperm count and motility, and histological abnormalities of the testes. The proliferation of spermatogenic cells was decreased with downregulation of cyclin E and CDK2 and upregulation of p53 and p21 expression, whereas apoptosis of spermatogenic cells was increased with upregulation of Bax and p-caspase 3 expression and downregulation of Bcl-xl expression. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the male 1α(OH)ase(-/-) mice, including the hypergonadotropic hypogonadism, decreased sperm count and motility, histological abnormalities of testis, and defective spermatogenesis, was reversed. These results indicate that the infertility seen in male 1,25(OH)2D3-deficient mice is not a direct effect of active vitamin D deficiency on the reproductive system but is an indirect effect mediated by extracellular calcium and phosphorus.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Jiangsu, China; and.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Jiangsu, China; and.
authors.forename: Lulu
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Jiangsu, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Jiangsu, China; and.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Departments of Medicine and Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Jiangsu, China; and dsmiao@njmu.edu.cn.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D002136:Calcium, Dietary / Q000009:adverse effects*; D004032:Diet / Q000009:adverse effects; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000150:complications* / Q000209:etiology; D005260:Female; D007248:Infertility, Male / Q000097:blood / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008903:Minerals / Q000494:pharmacology; D010758:Phosphorus / Q000097:blood; D016226:Phosphorus, Dietary / Q000009:adverse effects*; D014808:Vitamin D Deficiency / Q000097:blood / Q000150:complications / Q000378:metabolism*
chemical_list: D002136:Calcium, Dietary; D008903:Minerals; D016226:Phosphorus, Dietary; D010758:Phosphorus; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium
keywords: male infertility; spermatogenesis; vitamin D