Supplementation with high-dose cholecalciferol throughout pregnancy induces fetal growth restriction through inhibiting placental proliferation and trophoblast epithelial-mesenchymal transition

• Published in: The Journal of nutritional biochemistry Vol. 91; p. 108601
• Main Authors: Ma, Li, Chen, Yuan-Hua, Liu, Zhi-Bing, Gao, Lan, Wang, Bo, Fu, Lin, Zhang, Shan-Yu, Chen, Wei, Wang, Hua, Xu, De-Xiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2021
• Subjects: Fetal growth restriction; HTR-8/SVneo cell; Placental proliferation; Trophoblast epithelial-mesenchymal transition; Vitamin D3 supplementation; Placental proliferation; HTR-8/SVneo cell; Trophoblast epithelial-mesenchymal transition; Vitamin D3 supplementation; Fetal growth restriction
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2021.108601

Vitamin D deficiency has been associated with adverse pregnant outcomes. Several studies investigated the effects of maternal vitamin D3 supplementation on fetal development with inconsistent results. The aim of this study was to investigate the effects of maternal supplementation with different doses of vitamin D3 on fetal development. Pregnant mice were administered with different doses of cholecalciferol (0, 2,000, 10,000, 40,000 IU/kg/day) by gavage throughout pregnancy. Fetal weight and crown-rump length were measured. Placental proliferation and mesenchymal characteristics were detected. HTR-8/SVneo cells were incubated in the absence or presence of calcitriol (500 nmol/L) to evaluate the effects of active vitamin D3 on migration and invasion of human trophoblast cells. Although a low dose of cholecalciferol was safe, fetal weight and crown-rump length were decreased in dams treated with high-dose cholecalciferol throughout pregnancy. Placental weight and labyrinth thickness were reduced in mice administered with high-dose cholecalciferol. An obvious calcification was observed in placentae of mice administered with high-dose cholecalciferol. Ki67-positive cells, a marker of placental proliferation, were reduced in mice administered with high-dose cholecalciferol. N-cadherin and vimentin, two mesenchymal markers, were decreased in cholecalciferol-treated mouse placentae and calcitriol-treated human trophoblast cells. MMP-2 and MMP-9, two matrix metalloproteinases, were downregulated in cholecalciferol-treated mouse placentae and calcitriol-treated human trophoblast cells. In addition, trophoblast migration and invasion were suppressed by calcitriol. Supplementation with high-dose cholecalciferol induces fetal growth restriction partially through inhibiting placental proliferation and trophoblast epithelial-mesenchymal transition.