妊娠中のマウスにおける高用量ビタミンD補充が組織特異的なビタミンD代謝物の分布に及ぼす影響

Pregnancy is a major modifier of vitamin D metabolism, which is suggested to serve an immunomodulatory role, support placental function and aid fetal development. However, little is known about local tissue concentrations of vitamin D metabolites following supplementation during gestation.

We aimed to quantify intracellular concentrations of 25-hydroxyvitamin D (25[OH]D₃) and bioactive 1,25-dihydroxyvitamin D (1,25[OH]₂D₃) across tissues following vitamin D supplementation and to determine how this distribution is altered during gestation in mice.

Forty nulliparous female C57BL/6 (wild-type) mice were fed a semi-purified diet supplemented with either a normal (1,000 IU/kg) or high dose (6,000 IU/kg) vitamin D3 for 4 weeks. Thirty females were mated with 10 diet-matched C57BL/6 males, while 10 females were served as non-pregnant controls. Maternal serum, lung, liver, kidney and placental tissue and fetal samples were collected at gestational day 18.5. Concentrations of 25-hydroxyvitamin D (25[OH]D) and 1,25[OH]₂D₃ were measured using high-pressure liquid chromatography and tandem mass-spectrometry (LC-MS/MS) and compared between groups using t-tests in R.

High-dose vitamin D supplementation increased serum 25(OH)D across all groups, with a clear dose-response. Serum 1,25(OH)₂D concentrations were substantially increased in pregnant compared to non-pregnant females (mean difference: 74 pg/mL for control dose, p < 0.05 and 65 pg/mL for high dose, p = 0.1). Tissue analysis revealed the lungs as important targets of 25(OH)D accumulation, with significantly higher concentrations than liver tissue in non-pregnant (mean difference 27 ng/g, p < 0.05) mice. Pregnancy induced notable shifts in vitamin D metabolite distribution, including reduced serum 25(OH)D concentrations and enhanced renal conversion to serum 1,25(OH)₂D. Despite high placental accumulation of 25(OH)D, fetal 25(OH)D concentrations was significantly lower in the high-dose group (mean difference -2.6 ng/g, p < 0.05), suggesting a protective saturation mechanism. High-dose vitamin D supplementation was well tolerated without any adverse gestational events.

Our findings suggest that pregnancy results in a redistribution of vitamin D metabolites in tissues, with the kidneys and placenta playing central roles. This distribution is responsive to prenatal vitamin D supplementation; however, under supraphysiological maternal dosing fetal 25(OH)D uptake may be decreased.