Vitamin D-deficiency and sex-specific dysregulation of placental inflammation

Abstract

To investigate an immunomodulatory role for vitamin D in pregnancy we used mice raised on vitamin D-sufficient (SUFF), or -deficient (DEF) diets. At embryonic day 14, pregnant mice received intraperitoneal injection of lipopolysaccharide (LPS) or vehicle for 24h, with age-matched non-pregnant mice as controls. In non-pregnant mice, 6 serum analytes (IL-1β, IL-18, MDC/CCL22, MIP-1α/CCL3, EGF, IgA) were lower in DEF mice. In pregnant DEF mice only GH was higher. In non-pregnant mice LPS induced 28 analytes, with 5 (IL-18, IP-10/CXCL10, MCP-1/CCL2, MIP-1β/CCL4, MIP-3β/CCL19) being highest in DEF mice. In pregnant SUFF mice 16 serum analytes increased with LPS, and 6 of these (IP-10/CXCL10, MCP-1/CCL2, SAP, TIMP-1, VCAM-1, vWF) were higher and 1 (GCP-2/CXCL6) lower in DEF mice. Parallel analysis of placental mRNAs showed elevated mRNA for Il-6, Ccl2 and Cxcl10 in placentae from male and female fetuses in LPS-DEF mice. However, LPS-induced expression of Ifnγ, Tnfα, and Cxcl6 was only observed in female placentae from DEF mice. LPS-DEF mice also showed smaller litter sizes relative to control SUFF mice. Numbers of female fetuses per dam were significantly lower for DEF mice with or without LPS challenge. LPS had no effect on numbers of male fetuses from DEF mothers, but significantly decreased male fetuses from SUFF mothers. These data indicate that vitamin D is an important component of anti-inflammatory immune responses during pregnancy, with the placenta and fetal sex playing pivotal roles in this process.

Maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio through alterations in the one‐carbon cycle in Wistar rats

“…Earlier reports in humans indicate that increase in the plasma AA levels is associated with an increase in the activity of COX and increase in the synthesis of TXB 2 . In a condition of placental ischemia and oxidative stress, vitamin D is known to have protective anti‐inflammatory effect in the placenta and its deficiency is associated with increased inflammation during pregnancy . One limitation of the present study is that we could not estimate the inflammatory markers like tumor necrosis factor‐α (TNF‐α).…”

“…Earlier reports in humans indicate that increase in the plasma FIG 4 Effect of vitamin D deficiency on fatty acid metabolism through one-carbon cycle; AA: arachidonic acid; sPLA 2 : secreted phospholipase A 2 ; PG: prostaglandin; TX: thromboxane; COX: cyclooxygenase; CBS: cystathionine-β-synthase; THF: tetrahydrofolate; 5-MTHF: 5-methyltetrahydrofolate; ROS: reactive oxygen species AA levels is associated with an increase in the activity of COX and increase in the synthesis of TXB 2 [61]. In a condition of placental ischemia and oxidative stress, vitamin D is known to have protective anti-inflammatory effect in the placenta [62] and its deficiency is associated with increased inflammation during pregnancy [10,63,64]. One limitation of the present study is that we could not estimate the inflammatory markers like tumor necrosis factor-α (TNF-α).…”

Evidence of an Association Between Vitamin D Deficiency and Preterm Birth and Preeclampsia: A Critical Review

“…In a recent RCT with a sample of 57 women at less than 20 weeks’ gestation, women who received 2000 units per day of vitamin D 3 supplement had increased regulatory T cell immunity, increased production of anti‐inflammatory cytokine IL‐10, and decreased levels of proinflammatory cytokine TNFα compared with women who were in the control group who received a placebo dose of 400 units per day . The effects of vitamin D status are the greatest early in pregnancy during placentation . Thus, it is possible that vitamin D supplementation in the late second or third trimester may not decrease the risk for preeclampsia because of the inflammatory effects that maternal vitamin D deficiency could have on the placental trophoblasts …”

“…The effects of vitamin D status are the greatest early in pregnancy during placentation . Thus, it is possible that vitamin D supplementation in the late second or third trimester may not decrease the risk for preeclampsia because of the inflammatory effects that maternal vitamin D deficiency could have on the placental trophoblasts …”

“…Education related to adequate vitamin D status may be best initiated during preconception visits, as evidence suggests maternal vitamin D deficiency can have detrimental effects on the fetus beginning with the development of the placenta . 5 One group of researchers found that placentas from pregnant women with serum 25(OH)D concentrations higher than 40 ng/mL had significant messenger RNA downregulation of some angiogenic factors associated with preeclampsia compared with those who had deficient levels of vitamin D .…”