Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses.
Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses.
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DOI：
10.1371/journal.pcbi.1010927
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发表时间：
2023-08
影响因子：
4.3
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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，发现几种代谢途径表现出性别差异，包括糖酵解，脂肪酸代谢，核苷酸代谢和外源性物质代谢。当TIDE用于比较处理和未处理肝细胞中的表达差异时，我们发现几个具有差异表达的子系统与性别改变的途径重叠，如脂肪酸代谢、嘌呤和嘧啶代谢以及外源性物质代谢。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，并发现戊糖磷酸途径和其他代谢途径的差异。这些结果表明戊糖磷酸途径对氧化应激的贡献存在潜在的性别差异，我们建议进一步研究这些反应对肝毒性药物的反应。在药物临床试验中存在男性偏见，女性发生肝毒性事件的数量不成比例。以前的工作使用生物性别的基因差异来解释这种差异，但很少关注这些差异的系统性相互作用。为此，我们使用基因表达数据和代谢建模的组合来比较雄性和雌性肝脏以及处理和未处理肝细胞之间的代谢活性。我们发现几个子系统在每个性别的差异活动，当这些子系统与肝毒性药物改变的途径进行比较时，我们确定了几个重叠的途径。为了在逐个反应的基础上探索这些差异，我们使用相同的性别特异性转录组数据来将先前发表的Human1代谢模型置于背景中。在这些模型中，我们发现通过戊糖磷酸途径的流量的差异，这表明在响应氧化应激的潜在差异。这些发现可以帮助指导未来的药物设计，毒理学测试和性别特异性研究，以更好地解释整个人类群体。
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 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 several metabolic pathways exhibit sex differences including glycolysis, fatty acid metabolism, nucleotide metabolism, and xenobiotics metabolism. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we find several subsystems with differential expression overlap with the sex-altered pathways such as fatty acid metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the pentose phosphate pathway and other metabolic pathways. These results suggest potential sex differences in the contribution of the pentose phosphate pathway to oxidative stress, and we recommend further research into how these reactions respond to hepatotoxic pharmaceuticals. There is a male-bias in clinical testing of drugs and a disproportionate number of hepatotoxic events occur in women. Previous work uses gene-by-gene differences in biological sex to explain this discrepancy, but there is little focus on the systematic interactions of these differences. To this end, we use a combination of gene expression data and metabolic modeling to compare metabolic activity between the male and female liver and treated and untreated hepatocytes. We find several subsystems with differential activity in each sex, and when comparing these subsystems with those pathways altered by hepatotoxic agents, we identify several pathways that overlap. To explore these differences on a reaction-by-reaction basis, we use the same sex-specific transcriptomic data to contextualize the previously published Human1 metabolic model. In these models we find a difference in flux through the pentose phosphate pathway, suggesting a potential difference in response to oxidative stress. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population.