Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana 70803, USA.
Toxicol Sci. 2022 Jan 24;185(2):232-245. doi: 10.1093/toxsci/kfab135.
Excessive ethanol consumption is a risk factor for osteopenia. Since a previous study showed that transgenic female mice with overexpression of catalase are partially protected from ethanol-mediated trabecular bone loss, we investigated the role of endogenous catalase in skeletal ethanol toxicity comparing catalase knockout to wild-type mice. We hypothesized that catalase depletion would exacerbate ethanol effects. The mice were tested in a newly designed binge ethanol model, in which 12-week-old mice were exposed to 4 consecutive days of gavage with ethanol at 3, 3, 4, and 4.5 g ethanol/kg body weight. Binge ethanol decreased the concentration of serum osteocalcin, a marker of bone formation. The catalase genotype did not affect the osteocalcin levels. RNA sequencing of femoral shaft RNA from males was conducted. Ethanol exposure led to significant downregulation of genes expressed in cells of the osteoblastic lineage with a role in osteoblastic function and collagen synthesis, including the genes encoding major structural bone proteins. Binge ethanol further induced a smaller set of genes with a role in osteoclastic differentiation. Catalase depletion affected genes with expression in erythroblasts and erythrocytes. There was no clear interaction between binge ethanol and the catalase genotype. In an independent experiment, we confirmed that the binge ethanol effects on gene expression were reproducible and occurred throughout the skeleton in males. In conclusion, the binge ethanol exposure, independently of endogenous catalase, reduces expression of genes involved in osteoblastic function and induces expression of genes involved in osteoclast differentiation throughout the skeleton in males.
过量饮酒是导致骨质减少症的一个风险因素。由于之前的研究表明，过表达过氧化氢酶的转基因雌性小鼠部分免受乙醇介导的小梁骨丢失的影响，因此我们比较了过氧化氢酶敲除和野生型小鼠，以研究内源性过氧化氢酶在骨骼乙醇毒性中的作用。我们假设过氧化氢酶耗竭会加剧乙醇的作用。将这些小鼠在新设计的 binge 乙醇模型中进行了测试，该模型中，12 周龄的小鼠接受连续 4 天的灌胃，每次灌胃的乙醇剂量为 3、3、4 和 4.5 g/kg 体重。 binge 乙醇降低了血清骨钙素的浓度，骨钙素是骨形成的标志物。过氧化氢酶基因型不影响骨钙素水平。对雄性小鼠股骨 RNA 进行了 RNA 测序。乙醇暴露导致成骨细胞谱系中表达的基因显著下调，这些基因与成骨细胞功能和胶原合成有关，包括编码主要结构骨蛋白的基因。 binge 乙醇进一步诱导了一组数量较少的与破骨细胞分化有关的基因。过氧化氢酶耗竭影响红系细胞和红细胞中表达的基因。 binge 乙醇和过氧化氢酶基因型之间没有明显的相互作用。在一个独立的实验中，我们证实了 binge 乙醇对基因表达的影响是可重复的，并且在雄性小鼠的整个骨骼中都发生了这种影响。总之， binge 乙醇暴露，与内源性过氧化氢酶无关，会降低与成骨细胞功能有关的基因的表达，并诱导与破骨细胞分化有关的基因在整个骨骼中的表达。
