Vitamin D Deficiency in Guinea Pigs: Exacerbation of Bone Phenotype During Pregnancy and Disturbed Fetal Mineralization, with Recovery by 1,25(OH)2D3 Infusion or Dietary Calcium-Phosphate Supplementation

摘要

Vitamin D (D) deficiency during human pregnancy appears to disturb fetal growth and mineralization, but fetal development is normal in D-deficient rats and vitamin D receptor gene-ablated mice. We used the guinea pig model to investigate maternal and fetal effects of D deficiency. Pregnant (Pr) and nonpregnant (NPr) animals were fed a D-replete (+D) or D-deficient diet (?D) for 8 weeks. We further studied whether the effects of a ?D diet are reversed by continuous 1,25(OH)2D3 infusion (?D+1,25) and/or by a lactose-, Ca- and P-enriched D-deficient diet (?D+Ca/P). Bone analyses included histomorphometry of the proximal tibiae, dual-energy X-ray absorptiometry (DXA), and quantitative computed tomography (QCT) of the femora. Depletion of 25(OH)D3 and 1,25(OH)2D3 levels and the D-deficiency syndrome were more severe in pregnant animals. Indeed, Pr/?D but not NPr/?D guinea pigs were hypophosphatemic, and showed robust increases in growth plate width and osteoid surface and thickness; in addition, bone mineral density on DXA was lower in Pr/?D animals only, which was exclusively in cortical bone on QCT. Bone phenotype was partly normalized in Pr/?D+1,25 and Pr/?D+Ca/P animals. Compared with +D fetuses, ?D fetuses had very low or undetectable 25(OH)D3 and 1,25(OH)2D3, were hypercalcemic and hypophosphatemic, and had lower osteocalcin levels. In addition, body weight and total body bone mineral content were 10–15% lower; histomorphometry showed hypertrophic chondrocyte zone expansion and hyperosteoidosis. 1,25(OH)2D3 levels were restored in ?D+1,25 fetuses, and the phenotype was partially corrected. Similarly, the fetal +D phenotype was rescued in large part in ?D+Ca/P fetuses, despite undetectable circulating 25(OH)D3 and 1,25(OH)2D3. We conclude that pregnancy markedly exacerbates D deficiency, and that augmenting Ca and P intake overrides the deleterious effects of D deficiency on fetal development.