Characterization of an animal model of pregnancy-induced vitamin D deficiency due to metabolic gene dysregulation

• Published in: American journal of physiology: endocrinology and metabolism 2014-02, Vol.306 (3), p.E256-E266
• Main Authors: Goyal, Ravi, Zhang, Lubo, Blood, Arlin B, Baylink, David J, Longo, Lawrence D, Oshiro, Bryan, Mata-Greenwood, Eugenia
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism; Animals; Disease Models, Animal; Female; Gene Expression Regulation; Male; Metabolic disorders; Metabolic Networks and Pathways - genetics; Metabolites; Polymorphism; Pregnancy; Pregnancy Complications - genetics; Pregnancy Complications - pathology; Protein expression; Rats; Rats, Inbred BN; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Vitamin D; Vitamin D - metabolism; Vitamin D Deficiency - etiology; Vitamin D3 24-Hydroxylase; Vitamin deficiency
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00528.2013

Vitamin D deficiency has been associated with pregnancy complications such as preeclampsia, gestational diabetes, and recurrent miscarriage. Therefore, we hypothesized differences in vitamin D status between healthy [Sprague-Dawley (SD) and Lewis (LW)] and complicated [Brown Norway (BN)] rat pregnancies. In SD, LW, and BN rats, we analyzed the maternal plasma levels of the vitamin D metabolites 25-OH-D and 1,25-(OH)2-D at prepregnancy, pregnancy, and postpartum. Analysis of the active metabolite 1,25-(OH)2-D showed a twofold increase in pregnant SD and LW rats but a nearly 10-fold decrease in pregnant BN rats compared with nonpregnant controls. BN rats had a pregnancy-dependent upregulation of CYP24a1 expression, a key enzyme that inactivates vitamin D metabolites. In contrast, the maternal renal expression of CYP24a1 in SD and LW rats remained constant throughout pregnancy. Analysis of the vitamin D receptor (VDR) indicated that LW and SD but not BN rats experience a pregnancy-induced 10-fold decrease in maternal renal VDR protein levels. Further analysis of bisulfite-converted and genomic DNA indicated that the observed differences in maternal renal regulation of CYP24a1 during pregnancy and lactation are not due to differences in CYP24a1 promoter methylation or single-nucleotide polymorphisms. Finally, supplementation with 1,25-(OH)2-D significantly improved the reproductive phenotype of BN rats by increasing litter size and maternal-fetal weight outcomes. We conclude that BN rats represent a novel animal model of pregnancy-specific vitamin D deficiency that is linked to pregnancy complications. Vitamin D deficiency in BN rats correlates with maternal renal CYP24a1 upregulation followed by CYP27b1 upregulation.