Metabolic modeling of sex-specific tissue predicts mechanisms of differences in toxicological responses.
Metabolic modeling of sex-specific tissue predicts mechanisms of differences in toxicological responses.
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性别特异性组织的代谢模型可以预测毒理学反应差异的机制。
DOI：
10.1101/2023.02.07.527430
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Papin,JasonA
中科院分区：
文献类型：
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作者：
Moore,ConnorJ;Holstege,ChristopherP;Papin,JasonA
在动物和人类研究中，男性受试者不成比例地用于毒理学试验。这种差异在临床医学中得到了证明，其中女性比男性更有可能在对外源性物质的反应中经历肝脏相关的不良事件。虽然以前的工作已经表明性别之间的基因表达差异，但缺乏系统水平的方法来了解这些差异的直接临床影响。在这里，我们将基因表达数据与代谢网络模型相结合，以表征性别差异和药物治疗背景下代谢基因转录变化的影响。我们使用差异表达推断的任务（TIDE），一种以反应为中心的方法来分析基因表达的差异，发现雄激素，醚脂，糖皮质激素，色氨酸和异生物质代谢在男性肝脏中具有更多的活性，血清素，褪黑激素，戊糖，葡萄糖醛酸和维生素A代谢在女性肝脏中具有更多的活性。当TIDE用于比较处理和未处理的肝细胞中的表达差异时，我们在那些性别改变的子系统中几乎没有看到反应，并且最大的差异是与脂质代谢相关的子系统。最后，使用性别特异性转录组数据，我们创建了个体和平均的男性和女性肝脏模型，并发现胆汁酸和盐的输入差异。这一结果表明，肝脏的性二态行为可能是由肝肠再循环的差异引起的，我们建议对性别特异性微生物组组成进行调查，作为进一步研究的途径。
Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact effect of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that androgen, ether lipid, glucocorticoid, tryptophan, and xenobiotic metabolism have more activity in the male liver, and serotonin, melatonin, pentose, glucuronate, and vitamin A metabolism have more activity in the female liver. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we see little response in those sex-altered subsystems, and the largest differences are in subsystems related to lipid metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the import of bile acids and salts. This result suggests that the sexually dimorphic behavior of the liver may be caused by differences in enterohepatic recirculation, and we suggest an investigation into sex-specific microbiome composition as an avenue of further research.