National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079, United States.
ApconiX Ltd, Alderley Park, Alderley Edge SK10 4TG, United Kingdom.
Chem Res Toxicol. 2023 Jun 19;36(6):916-925. doi: 10.1021/acs.chemrestox.3c00037. Epub 2023 May 18.
Animal studies are required for the evaluation of candidate drugs to ensure patient and volunteer safety. Toxicogenomics is often applied in these studies to gain understanding of the underlying mechanisms of toxicity, which is usually focused on critical organs such as the liver or kidney in young male rats. There is a strong ethical reason to reduce, refine and replace animal use (the 3Rs), where the mapping of data between organs, sexes and ages could reduce the cost and time of drug development. Herein, we proposed a generative adversarial network (GAN)-based framework entitled TransOrGAN that allowed the molecular mapping of gene expression profiles in different rodent organ systems and across sex and age groups. We carried out a proof-of-concept study based on rat RNA-seq data from 288 samples in 9 different organs of both sexes and 4 developmental stages. First, we demonstrated that TransOrGAN could infer transcriptomic profiles between any 2 of the 9 organs studied, yielding an average cosine similarity of 0.984 between synthetic transcriptomic profiles and their corresponding real profiles. Second, we found that TransOrGAN could infer transcriptomic profiles observed in females from males, with an average cosine similarity of 0.984. Third, we found that TransOrGAN could infer transcriptomic profiles in juvenile, adult, and aged animals from adolescent animals with an average cosine similarity of 0.981, 0.983, and 0.989, respectively. Altogether, TransOrGAN is an innovative approach to infer transcriptomic profiles between ages, sexes, and organ systems, offering the opportunity to reduce animal usage and to provide an integrated assessment of toxicity in the whole organism irrespective of sex or age.
动物研究对于评估候选药物是必需的，以确保患者和志愿者的安全。毒理基因组学通常应用于这些研究中，以了解毒性的潜在机制，这些研究通常集中在年轻雄性大鼠的关键器官，如肝脏或肾脏。有强烈的伦理理由来减少、优化和替代动物使用（3Rs），其中器官、性别和年龄之间的数据映射可以降低药物开发的成本和时间。在此，我们提出了一个基于生成对抗网络（GAN）的框架，称为 TransOrGAN，它允许在不同的啮齿动物器官系统和性别和年龄组之间进行基因表达谱的分子映射。我们进行了一项概念验证研究，基于 288 个样本的大鼠 RNA-seq 数据，这些样本来自 9 种不同器官的雌雄两性和 4 个发育阶段。首先，我们证明了 TransOrGAN 可以在研究的 9 个器官中的任意两个之间推断转录组谱，生成的合成转录组谱与真实谱之间的余弦相似度平均为 0.984。其次，我们发现 TransOrGAN 可以从雄性推断雌性的转录组谱，平均余弦相似度为 0.984。第三，我们发现 TransOrGAN 可以从青少年推断出幼年、成年和老年动物的转录组谱，平均余弦相似度分别为 0.981、0.983 和 0.989。总之，TransOrGAN 是一种在年龄、性别和器官系统之间推断转录组谱的创新方法，它提供了减少动物使用的机会，并提供了对整个生物体的毒性进行综合评估的机会，而不受性别或年龄的影响。
