Defective female reproductive function in 1,25(OH)2D-deficient mice results from indirect effect mediated by extracellular calcium and/or phosphorus.
We used mice with targeted deletion of 25-hydroxyvitamin D 1α-hydroxylase [1α(OH)ase(-/-)] to investigate the effects of calcium and phosphorus on defects in the reproductive system of 1,25-dihydroxyvitamin D [1,25(OH)(2)D]-deficient female mice. The 1α(OH)ase(-/-) mice and their wild-type littermates were fed either a normal diet or a rescue diet (high calcium, phosphate, and lactose) starting from weaning until 3 mo of age. We then determined serum calcium and phosphorus levels, assessed gonadotropin and gonadal hormone production, and evaluated folliculogenesis, corpus luteum formation, ovarian angiogenesis, uterus development, and fertility. Results showed that hypocalcemic and hypophosphatemic female 1α(OH)ase(-/-) mice developed infertility accompanied by decreased estrogen and progestogen levels, elevated follicle-stimulating hormone and luteinizing hormone levels, defects in follicular development and corpus luteum formation, uterine hypoplasia, and decreased ovarian expression of angiogenic factors including vascular endothelial growth factor (VEGF), angiopoietin-1 and -2, and Tie-2. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the female 1α(OH)ase(-/-) mice, including the dysfunction in the hypothalamic-pituitary-ovarian axis, and ovarian angiogenesis were reversed. These results indicate that the infertility seen in 1,25(OH)(2)D-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.
Sun
Weiwei
W
Nanjing Medical Univ., Nanjing, Jiangsu, People's Republic of China.
Xie
Hui
H
Ji
Ji
J
Zhou
Xiaojie
X
Goltzman
David
D
Miao
Dengshun
D
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002136:Calcium, Dietary; D030762:Estrous Cycle / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005838:Genotype; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000378:metabolism; D010758:Phosphorus / Q000378:metabolism*; D016226:Phosphorus, Dietary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism
D002136:Calcium, Dietary; D016226:Phosphorus, Dietary; D014807:Vitamin D; D010758:Phosphorus; C097949:1,25-dihydroxyvitamin D; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002118:Calcium