Chandrashekar Ranjitha, Mulakala Bharath K, Gurung Manoj, Venna Geetanjali, Rearick Jolene R, Onyekweli Brenda, Ruebel Meghan L, Dada-Fox Jasmine, Zeledon Jasmina A, Talatala Rachelanne, Rodriguez Kayleigh, Osborn Laura R, Bishop Mary Grace, Smith Brenda, Stephens Kimberly E, Lucas Edralin A, Yeruva Laxmi
Nutritional Sciences Department, Oklahoma State University, Stillwater, OK, 74078, USA.
Microbiome and Metabolism Research Unit (MMRU), USDA-ARS, Arkansas Children's Nutrition Center, Southeast Area, 15 Children's Way, Little Rock, AR, 72202, USA.
Calcif Tissue Int. 2025 May 30;116(1):79. doi: 10.1007/s00223-025-01378-6.
Early-life resource limitation is one factor that could have a major impact on child health and development. Thus, using a rat model of limited bedding and nesting (LBN), we investigated the postnatal bone development, mineralization, and microarchitecture. Pregnant Sprague-Dawley rats were subjected to a LBN model to induce chronic early-life stress (CES), while a control group was maintained under standard conditions. The offspring were assessed at postnatal day (PND) 10, 21, and 35. Tibial length was measured, and tibial and lumbar vertebral bone mineral density (BMD), content (BMC), and area (BMA) were assessed using dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was examined using microcomputed tomography (μCT). Changes in gene expression from the lumbar vertebrae were analyzed by transcriptome. At PND 10, there were no significant differences in BMD and BMC between the treatment groups, but tibial length was significantly decreased by CES. By PND 21, tibial BMC and BMA were significantly reduced in the CES group, indicating impaired bone mineral accumulation. At PND 35, tibial length remained significantly reduced by CES, while BMD and BMC differences were less affected. Vertebral BMA and BMC were reduced by CES. μCT analysis of tibial cortical bone showed significant changes in cortical thickness and bone volume at PND 10 and 21, respectively. For the lumbar vertebrae, μCT data indicated significant increases in the degree of anisotropy and structural model index at PND 21 and 35, respectively. Transcriptome analyses revealed significant differential expression of genes involved in immune response, cellular repair, and stress adaptation at PND 21 but not at PND 10 and PND 35. CES significantly disrupts BMC, BMD, length, and microarchitecture differently at various stages of postnatal development. Transcriptome analyses suggest that these changes are mediated by alterations in gene expression related to immune function and cellular repair. Future research should focus on tracking the longitudinal impacts of CES on bone health from infancy into adulthood, and exploring nutritional interventions, stress reduction programs, and molecular studies that can mitigate the negative effects of CES on bone.
生命早期资源受限是一个可能对儿童健康和发育产生重大影响的因素。因此，我们使用有限垫料和筑巢（LBN）大鼠模型，研究了出生后骨骼发育、矿化和微观结构。将怀孕的斯普拉格-道利大鼠置于LBN模型中以诱导慢性生命早期应激（CES），而对照组维持在标准条件下。在出生后第10、21和35天对后代进行评估。测量胫骨长度，并使用双能X线吸收法（DXA）评估胫骨和腰椎的骨密度（BMD）、骨量（BMC）和骨面积（BMA）。使用微型计算机断层扫描（μCT）检查骨骼微观结构。通过转录组分析腰椎的基因表达变化。在出生后第10天，各治疗组之间的BMD和BMC无显著差异，但CES显著降低了胫骨长度。到出生后第21天，CES组的胫骨BMC和BMA显著降低，表明骨矿物质积累受损。在出生后第35天，CES仍显著降低胫骨长度，而BMD和BMC差异受影响较小。CES降低了椎体BMA和BMC。μCT对胫骨皮质骨的分析显示，在出生后第10天和第21天，皮质厚度和骨体积分别有显著变化。对于腰椎，μCT数据表明，在出生后第21天和第35天，各向异性程度和结构模型指数分别显著增加。转录组分析显示，在出生后第21天，参与免疫反应、细胞修复和应激适应的基因有显著差异表达，而在出生后第10天和第35天则没有。CES在出生后发育的不同阶段对BMC、BMD、长度和微观结构有不同程度的显著破坏。转录组分析表明，这些变化是由与免疫功能和细胞修复相关的基因表达改变介导的。未来的研究应集中于追踪CES从婴儿期到成年期对骨骼健康的纵向影响，并探索营养干预、减压方案以及能够减轻CES对骨骼负面影响的分子研究。
