Current TopicVitamin D effects on pregnancy and the placenta
Introduction
The vitamin D endocrine system is pivotal for calcium homeostasis, bone mineralization, immune function, cell proliferation, and disease prevention [1]. Vitamin D is not a true vitamin because there are sources other than diet. Instead, this key nutrient is a pro-hormone, which can be synthesized from a steroid precursor if not obtained from diet. Vitamin D was discovered as a preventive treatment for rickets, a disease of children that yields bone softening, fractures, and deformity [2]. The classical actions of this hormone were first described in kidney and bone. We now know that vitamin D is also involved in many nonclassical processes [3]. Vitamin D itself is devoid of biological activity, but enzymatic conversion to 1α, 25-dihydroxyvitamin D [1,25(OH)2D] generates the hormonal form with diverse biological activities [4]. The actions of 1,25(OH)2D are mediated through specific, high affinity binding to the vitamin D receptor (VDR), which is present in multiple tissues [5], [6]. Target organs for the nonclassical actions of the vitamin D endocrine system include the adaptive and innate immune systems, pancreatic β-cells, the heart and cardiovascular system, and the brain [6]. Tissue responses include effects on hormone secretion, modulation of immune responses, and control of cellular proliferation and differentiation [3]. Vitamin D analogs may prove useful to prevent some human diseases and to treat autoimmune diseases and cancer [7], [8].
Recent work suggests important roles for the VDR and VDR signaling pathways in the placenta. Human placental trophoblasts express the VDR, and the P450 cytochromes encoded by the CYP27B1 and CYP24A1 genes. Trophoblasts both produce and respond to 1,25(OH)2D. 1,25(OH)2D regulates synthesis of hormones involved in pregnancy and influences the trophoblast anti-inflammatory and anti-microbial responses [9], [10], [11], [12], [13]. In early pregnancy, 1,25(OH)2D induces decidualization, which is key to implantation [14], [15]. Moreover, CYP27B1 modulates immune function during early gestation [16] and vitamin D deficiency associates with bacterial vaginosis, impaired calcium metabolism and fetal growth, preeclampsia, insulin resistance, gestational diabetes mellitus and primary cesarean section [17], [18], [19], [20], [21]. This review summarizes vitamin D metabolism and action, with a focus on the function of vitamin D during human pregnancy and on human placental villi and cultures of placental trophoblasts.
Section snippets
Metabolism and transport of vitamin D
Vitamin D is a general term for a chemically related family of secosteroid hormones. Vitamin D2 is produced in plants and vitamin D3 is produced in mammals (Fig. 1). In humans, vitamin D2, also called ergocholecalciferol, is one-third as potent as vitamin D3, which is also called cholecalciferol [22].
Vitamin D can be obtained from dietary sources but can also be synthesized. Ultraviolet B light induces cleavage of the B-ring of 7-dehydrocholesterol in skin to yield the secosteroid vitamin D3 [1]
Nonclassical actions of vitamin D
The classical functions of vitamin D are in the kidney, liver and intestine to regulate calcium and phosphate absorption and bone synthesis and metabolism. Recent data indicate vitamin D functions in nonclassical ways as well. Over 30 human tissues express the vitamin D receptor and are thus equipped to respond to 1,25(OH)2D [6]. Vitamin D and the VDR play a role in immune function, cell proliferation, cellular differentiation and hormone secretion.
Effects of vitamin D on the placenta and trophoblast cells
The human placenta expresses all components for vitamin D signaling, including the VDR, RXR, CYP27B1 and CYP24A1. Weisman et al. [86] found that human decidual and placental tissues synthesize 1,25(OH)2D and 24,25(OH)2D. In agreement with these findings, cultured primary human syncytiotrophoblasts and decidual cells produce 1,25(OH)2D and secrete the active form into the culture medium [86], [87], [88], [89]. Increased levels of 1,25(OH)2D reduces transcription of CYP27B1 in primary human
Conclusions
We have described the multiple effects of vitamin D in human health. The classical and nonclassical pathways of this hormone affect calcium metabolism, the immune system, cell proliferation and differentiation, infection, and cancer. The enzymes encoded by the CYP27B1 and CYP24A1 genes are local regulators of levels of 1,25(OH)2D, which binds the VDR to induce both the genomic and non-genomic responses. Importantly, vitamin D analogs offer new potentials for treatments of a variety of diseases
Acknowledgements
This work was supported by National Institutes of Health grant RO1-HD29190 to D.M.N. CHA University provided financial support for J.S. We thank Baosheng Chen for helpful discussions.
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