Environmental Hazards and Glial Brain Tumors: Association or Causation?

Abstract

Progress in establishing environmental risk factors and, consequently, prophylactic measures for glial tumors, particularly for glioblastomas, is of utmost importance, considering the dismal prognosis and limited treatment options. This report surveyed updates on established and recently identified factors that can predispose a patient to glioma formation while highlighting possible mechanistic links and further research directions. In addition to established factors that increase the risk of glioma, i.e., brain irradiation and several genetic syndromes, another group consists of likely factors contributing to such risks, such as the use of tobacco and those yielding ambiguous results (e.g., UV exposure). Oxidative stress is a common denominator for several types of exposure, and a mechanistic background for other factors remains elusive. Nevertheless, the analysis of clinical and basic research strongly suggests that, apart from the effect of environmental stressors on DNA alterations and mutation burden, the impact of modifying the tumor microenvironment should be considered. Identifying the involvement of environmental hazards in gliomagenesis and glial tumor progression would lower overall risk by modifying clinical practice, patient management, and lifestyle choices. Further verifying the environmental hazards in glioma formation and progression would have far-reaching implications for neurologists, neurosurgeons, and patients.

Keywords: environmental hazards; glioblastoma; glioma; oxidative stress; risk of glioma.

Figure 1

Glial tumor-promoting stressors. Ionizing radiation is among the well-documented factors leading to glioma formation and is associated with oxidative stress. With less proven effects, other factors include pesticides, burn pit-derived combustion products, and vehicle exhaust fumes. Although still somewhat speculatory, viruses are widely recognized as contributing to gliomagenesis. Abbreviations: ROS, reactive oxygen species.

Figure 2

Environmental hazards can be tested in humans, laboratory animals, and cell systems, and the latter can be tested in the most controlled fashion. Upon laboratory investigations in vitro and in vivo, mutations associated with environmental stressors can be introduced with genetic engineering techniques to investigate the putative drivers of glioma phenotypes, including a multi-omics approach. Experimental systems can be subjected to artificially generated exposures to environmental mutagens, as this approach can prove causality if substantiated by demonstrating specific mutational signatures in glioma-forming cells. In glioma patients, medical history and occupational health data, imaging results, pathology reports, and lab test and multi-omics assay results should be deposited in multimodality tumor registries. The analysis of vast multimodal datasets by scientists using AI-based computing will help to pinpoint causality in glioma formation, owing to a large sample size and high power of statistical analysis.