产前酒精暴露对小鼠骨骼的性别双态影响

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-06-18 DOI:10.1186/s13293-024-00626-y
Lucie E Bourne, Soher N Jayash, Lysanne V Michels, Mark Hopkinson, Fergus M Guppy, Claire E Clarkin, Paul Gard, Nigel Brissett, Katherine A Staines
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引用次数: 0

摘要

背景:产前酒精暴露(PAE)可导致终身残疾,即胎儿酒精谱系障碍(FASD),并与儿童生长缺陷和骨折风险增加有关。然而,PAE 对成人骨骼的影响仍不清楚,任何潜在的性别二形性也未确定。因此,我们利用小鼠模型来研究 PAE 对体外骨形成以及幼年和成年骨骼的性别差异:方法:妊娠期的 C57BL/6J 雌性小鼠在饮用水中加入 5% 的乙醇。方法:妊娠期的 C57BL/6J 雌性小鼠在饮用水中加入 5% 的乙醇,从新生仔鼠体内分离出原始犊骨成骨细胞,并对矿化骨结节的形成和基因表达进行评估。通过微型计算机断层扫描(μCT)、三点弯曲、生长板分析和组织学,对 4 周大和 12 周大的雄性和雌性后代进行骨骼表型分析:结果:与对照组相比,雄性和雌性 PAE 小鼠的成骨细胞显示骨形成减少(≤ 30%)。仅 PAE 雄性成骨细胞中 Vegfa、Vegfb、Bmp6、Tgfbr1、Flt1 和 Ahsg 下调,而 PAE 雌性成骨细胞中 Ahsg 上调。在 12 周大的小鼠中,µCT 分析表明性别与暴露在多个骨小梁参数上存在交互作用。与对照组相比,PAE 对雄性小鼠的骨小梁有害,而 PAE 雌性小鼠则不受影响。在 PAE 的作用下,雄性和雌性小鼠的皮质参数都显著降低。雄性小鼠的胫骨长度受到负面影响,而雌性小鼠仅在远端受到影响。只有 PAE 雌鼠后部皮质孔隙率增加。机械测试表明,与对照组相比,PAE 雄性小鼠的骨刚度明显降低;雌雄小鼠的最大负荷和屈服均降低。PAE 对雄性和雌性的总重量或胫骨长度均无影响。然而,与对照组相比,雄性 PAE 小鼠的生长板总宽度减少,而雌性 PAE 小鼠则不受影响。4周龄的小鼠没有表现出12周龄小鼠所观察到的PAE骨骼表型的改变:本文的证据首次表明 PAE 对骨骼产生了不同的性别影响,这可能受到成骨细胞潜在的性别特异性转录机制的影响。这些性别差异的确定将有助于未来针对 FASD 的政策和临床管理。
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Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton.

Background: Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton.

Methods: Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology.

Results: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals.

Conclusions: Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.

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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
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