Transcriptomic Dose Response Changes in Female Mouse and Rat Lungs following Chloroprene Exposure

ß-chloroprene (2-chloro-1,3-butadiene), a monomer used in the production of neoprene elastomers, is of regulatory interest due to the production of multi-organ tumors in mouse and rat cancer bioassays. A significant increase in female mouse lung tumors was observed at the lowest exposure concentration of 12.8 ppm while a small, but not statistically significant, increase was observed in female rats only at the highest exposure concentration of 80 ppm. The metabolism of chloroprene results in the generation of reactive epoxides and the rate of overall chloroprene metabolism is highly species dependent. To identify potential key events in the mode-of-action of chloroprene lung tumorigenesis, dose response and time course gene expression microarray measurements were made in the lungs of female mice and female rats. The gene expression changes were analyzed using both a traditional analysis of variance approach followed by pathway enrichment analysis and a pathway-based benchmark dose (BMD) analysis approach. Pathways related to glutathione biosynthesis and metabolism were the primary pathways consistent with cross-species differences in tumor incidence and transcriptional BMD values for the pathway were more similar to differences in tumor response than were estimated target tissue dose surrogates based on the total amount of chloroprene metabolized per unit mass of lung tissue per day. The closer correspondence of the transcriptional changes with the tumor response are likely due to their reflection of the overall balance between metabolic activation and detoxication reactions whereas the current tissue dose surrogate reflects only oxidative metabolism.β-氯丁二烯（β-chloroprene，2-氯-1,3-丁二烯）是一种用于制备氯丁橡胶弹性体（neoprene elastomers）的单体。因其在小鼠和大鼠癌症生物测定中可诱发多器官肿瘤，该物质受到监管领域的广泛关注。在最低暴露浓度12.8 ppm下即可观察到雌性小鼠肺部肿瘤发生率显著升高；而仅在最高暴露浓度80 ppm时，雌性大鼠才出现肿瘤发生率小幅升高，但该差异无统计学意义。氯丁二烯的代谢过程会产生活性环氧化物，且其整体代谢速率存在显著的物种依赖性。为明确氯丁二烯致肺肿瘤发生的作用模式中潜在的关键事件，研究人员对雌性小鼠和雌性大鼠的肺部组织开展了剂量反应与时序基因表达微阵列检测。研究团队采用两种分析方法对基因表达变化进行解析：一是传统的方差分析结合通路富集分析，二是基于通路的基准剂量（benchmark dose, BMD）分析。与谷胱甘肽生物合成及代谢相关的通路是最能体现跨物种肿瘤发生率差异的核心通路；且该通路的转录基准剂量（transcriptional BMD）相较于基于"每单位肺组织每日代谢的氯丁二烯总量"计算得到的靶组织剂量替代物，与肿瘤应答差异的相关性更强。转录组变化与肿瘤应答更紧密的相关性，可能源于前者反映了代谢活化与解毒反应之间的整体平衡，而当前的组织剂量替代物仅能反映氧化代谢过程。