Abstract

Tumor suppressor genes are highly affected during the development of leukemia, including circadian clock genes. Circadian rhythms constitute an evolutionary molecular machinery involving many genes, such as BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, REV-ERBa, and RORA, for tracking time and optimizing daily life during day-night cycles and seasonal changes. For circulating blood cells many of these genes coordinate their proliferation, output, and function, and therein lies their importance for the development of leukemia. Recent findings suggest that environmental pollutants may affect circadian rhythms and thus affect cancer development and treatment. Such environmental pollutants are often found in mixtures and include benzene, tobacco smoke, pesticides and microplastics. Our understanding of the molecular basis for the interaction mechanisms within complex mixtures is also growing, confirming the plausible occurrence of synergistic (superadditive effect) and antagonistic (cancellation effect) actions of pollutant cocktails. In this work, we discuss the relationship of environmental pollutants and the alteration of circadian rhythms that potentially may cause leukemia. We highlight the need of additional dimensions and perhaps a paradigm shift for future studies in relation to continuously growing magnitude of environmental pollution using multitude of disciplines such as development of high throughput reporter cell lines, other cell screening methods, contaminant measurements in leukemia patients, advanced pharmacology and toxicological measurement of mixtures and highly efficient computer analysis including artificial intelligence, among others.

摘要

肿瘤抑制基因在白血病的发展过程中受到高度影响，包括生物钟基因。昼夜节律构成了一种进化分子机制，涉及许多基因，如 BMAL1、CLOCK、CRY1、CRY2、PER1、PER2、REV-ERBa 和 RORA，用于在昼夜循环和季节变化中跟踪时间和优化日常生活。对于循环血细胞，许多这些基因协调它们的增殖、输出和功能，这就是它们对白血病发展的重要性。最近的研究结果表明，环境污染物可能会影响昼夜节律，从而影响癌症的发展和治疗。此类环境污染物通常存在于混合物中，包括苯、烟草烟雾、杀虫剂和微塑料。我们对复杂混合物中相互作用机制的分子基础的理解也在不断加深，这证实了污染物混合物的协同（超加性效应）和拮抗（消除效应）作用的合理发生。在这项工作中，我们讨论了环境污染物与可能导致白血病的昼夜节律改变之间的关系。我们强调了额外维度的必要性，也许是未来研究的范式转变，涉及使用多种学科不断增长的环境污染，例如开发高通量报告细胞系、其他细胞筛选方法、白血病患者的污染物测量、