Department of Earth and Planetary Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, 76100, Israel.
Environ Pollut. 2018 Aug;239:532-543. doi: 10.1016/j.envpol.2018.04.048. Epub 2018 Apr 21.
Obesity and exposure to particular matter (PM) have become two leading global threats to public health. However, the exact mechanisms and tissue-specificity of their health effects are largely unknown. Here we investigate whether a metabolic challenge (early nutritional obesity) synergistically interacts with an environmental challenge (PM exposure) to alter genes representing key response pathways, in a tissue-specific manner. Mice subjected to 7 weeks obesogenic nutrition were exposed every other day during the final week and a half to aqueous extracts of PM collected in the city of London (UK). The expression of 61 selected genes representing key response pathways were investigated in lung, liver, white and brown adipose tissues. Principal component analysis (PCA) revealed distinct patterns of expression changes between the 4 tissues, particularly in the lungs and the liver. Surprisingly, the lung responded to the nutrition challenge. The response of these organs to the PM challenge displayed opposite patterns for some key genes, in particular, those related to the Nrf2 pathway. While the contribution to the variance in gene expression changes in mice exposed to the combined challenge were largely similar among the tissues in PCA1, PCA2 exhibited predominant contribution of inflammatory and oxidative stress responses to the variance in the lungs, and a greater contribution of autophagy genes and MAP kinases in adipose tissues. Possible involvement of alterations in DNA methylation was demonstrated by cell-type-specific responses to a methylation inhibitor. Correspondingly, the DNA methyltransferase Dnmt3a2 increased in the lungs but decreased in the liver, demonstrating potential tissue-differential synergism between nutritional and PM exposure. The results suggest that urban PM, containing dissolved metals, interacts with obesogenic nutrition to regulate diverse response pathways including inflammation and oxidative stress, in a tissue-specific manner. Tissue-differential effects on DNA methylation may underlie tissue-specific responses to key stress-response genes such as catalase and Nrf2.
肥胖和暴露于特定物质（PM）已成为全球公共卫生的两大主要威胁。然而，它们对健康的影响的确切机制和组织特异性在很大程度上尚不清楚。在这里，我们研究了代谢挑战（早期营养肥胖）是否与环境挑战（PM 暴露）协同作用，以改变代表关键反应途径的基因，从而产生组织特异性。将接受 7 周肥胖营养的小鼠在最后一周半的每两天暴露于从英国伦敦收集的 PM 水提取物中。研究了代表关键反应途径的 61 个选定基因的表达情况，这些基因存在于肺、肝、白色和棕色脂肪组织中。主成分分析（PCA）揭示了 4 种组织之间表达变化的明显模式，特别是在肺和肝脏中。令人惊讶的是，肺部对营养挑战做出了反应。这些器官对 PM 挑战的反应显示出一些关键基因的相反模式，特别是与 Nrf2 途径相关的基因。虽然在 PCA1 中，暴露于联合挑战的小鼠中基因表达变化的方差的贡献在很大程度上相似，但在 PCA2 中，炎症和氧化应激反应对肺部方差的贡献占主导地位，而自噬基因和 MAP 激酶在脂肪组织中的贡献更大。通过细胞类型特异性对甲基化抑制剂的反应证明了 DNA 甲基化改变的可能参与。相应地，在肺部中 Dnmt3a2 增加，而在肝脏中减少，表明营养和 PM 暴露之间存在潜在的组织差异协同作用。结果表明，含有溶解金属的城市 PM 与肥胖营养相互作用，以调节包括炎症和氧化应激在内的多种反应途径，从而产生组织特异性。组织特异性对 DNA 甲基化的影响可能是对关键应激反应基因（如过氧化氢酶和 Nrf2）产生组织特异性反应的基础。
