Copper deficiency disrupts placental development and lipid metabolism, contributing to fetal growth restriction†

To investigate how copper deficiency during pregnancy affects placental structure, metabolism, and trophoblast function, contributing to fetal growth restriction (FGR). Pregnant C57BL/6N mice were treated with ammonium tetrathiomolybdate to induce copper deficiency, with two different dosages (30 and 60 mg·kg-1·d-1) administered daily from gestational day 1 to day 14. On day 15, assessments were made on fetal growth, placental development, and spatial metabolomics. In parallel, trophoblast cells (HTR8/SVneo) were subjected to copper chelation or SLC31A1 knockdown to model copper deficiency in vitro. Cell invasiveness and proliferation were evaluated using appropriate assays, along with the measurement of molecular markers to assess the impact of copper deficiency. Copper deficiency significantly reduced maternal serum copper levels, leading to FGR, as evidenced by shorter crown-rump lengths, lower fetal weights, and altered fetal-to-placental weight ratios. Structural abnormalities in the placental junctional zone, including reduced size and altered morphology, were observed. Metabolomic analysis revealed disrupted lipid metabolism, with alterations in glycerophospholipids and fatty acids, and lipid droplet accumulation. Copper deficiency impaired trophoblast migration and invasion, linked to decreased MMP2 and MMP9 expression in vivo and in vitro. In vitro studies also showed altered lipid metabolism in SLC31A1-knockdown trophoblast cells. Copper deficiency disrupts placental structure and lipid metabolism, impairs trophoblast function, and contributes to FGR, highlighting the critical role of copper in fetal development and maternal health.