Cholesterol is one of the essential intrauterine factors required for fetal growth and development. Maternal high cholesterol levels are known to be detrimental for offspring health. However, its long-term effect on offspring skeletal development remains to be elucidated. We performed our studies in two strains of mice (C57BL6/J and Swiss Albino) and human subjects (65 mother–female newborn dyads) to understand the regulation of offspring skeletal growth by maternal high cholesterol. We found that mice offspring from high-cholesterol-fed dams had low birth weight, smaller body length, and delayed skeletal ossification at the E18.5 embryonic stage. Moreover, we observed that the offspring did not recover from the reduced skeletal mass and exhibited a low bone mass phenotype throughout their life. We attributed this effect to reduced osteoblast cell activity with a concomitant increase in the osteoclast cell population. Our investigation of the molecular mechanism revealed that offspring from high-cholesterol-fed dams had a decrease in the expression of ligands and proteins involved in hedgehog signaling. Further, our cross-sectional study of human subjects showed a significant inverse correlation between maternal blood cholesterol levels and cord blood bone formation markers. Moreover, the bone formation markers were significantly lower in the female newborns of hypercholesterolemic mothers compared with mothers with normal cholesterolemic levels. Together, our results suggest that maternal high cholesterol levels deleteriously program offspring bone mass and bone quality and downregulate the hedgehog signaling pathway in their osteoblasts.

胆固醇是胎儿生长发育所需的重要宫内因子之一。众所周知，母体高胆固醇水平对后代健康有害。然而，其对后代骨骼发育的长期影响仍有待阐明。我们在两种小鼠品系（C57BL6/J 和 Swiss Albino）和人类受试者（65 名母-女新生儿二元组）中进行了研究，以了解母体高胆固醇对后代骨骼生长的调节作用。我们发现，来自高胆固醇喂养水坝的小鼠后代在 E18.5 胚胎期具有低出生体重、较小的体长和延迟的骨骼骨化。此外，我们观察到后代没有从减少的骨骼质量中恢复，并且在其一生中表现出低骨量表型。我们将这种效应归因于成骨细胞活性降低，同时破骨细胞群增加。我们对分子机制的研究表明，高胆固醇喂养的母鼠的后代参与刺猬信号传导的配体和蛋白质的表达减少。此外，我们对人类受试者的横断面研究表明，母体血液胆固醇水平与脐带血骨形成标志物之间存在显着的负相关。此外，与胆固醇水平正常的母亲相比，高胆固醇血症母亲的女性新生儿的骨形成标志物显着降低。一起，