The pathogenesis of malignant brain tumors (MBTs) should be better understood due to the evident association between prolonged exposure to metals and increased risk of MBTs. The present research aimed to find trace metals that could contribute to the pathogenesis of MBTs. Essential trace elements (Mn, Co, Zn, Cu, Se) and relevant toxic metals (Al, Ni, As, Sr, Cd, Ce, Pt, Pb, U) in the serum, cell fraction (CF), cerebrospinal fluid (CSF) and cancerous tissue (CT) samples of MBT patients were analyzed. The results were compared with sex-and age-matched control groups. For the first time, this research showed that elemental profiles of serum, CF, CSF and CT samples in MBT patients were significantly altered compared to the appropriate controls, as well as that higher contents of trace elements (particularly Mn, Se, and Pb) could be involved in the pathogenesis of MBTs. However, the most noticeable change found was the elevated U content, indicating its considerable role as a major cerebral discriminator of the presence/absence of MBTs. The U/Se ratio could be considered as an appropriate blood marker in diagnostic MBT evaluation. The reported results could contribute to better understanding of the poorly understood pathogenesis of MBTs. Furthermore, the reported results could highlight a molecular basis for the pathophysiological changes caused by the hazardous effects of trace metals on brain homeostasis. The importance of trace metals in the neurosciences has become more compelling during the first decade of the 21 st century 1 , as there is considerable interest in finding the relationships between trace metals and various neurological diseases, including central nervous system (CNS) malignancies. Metals show their harmful effects at the first stage of cancerogenesis (initiation) 2. Initiation can affect normal biochemical reactions, leading to alterations in metal profiles. Considering that trace metals play a significant role in neoplastic processes, the metal contents in neoplastic samples can differ from the composition in control ones 3. Homeostasis of metals within tight physiological limits is maintained through the mechanisms of uptake, distribution, accumulation, and secretion. Each breakdown has deleterious effects on metal-regulated metabolic pathways and can be a crucial step in the pathogenesis of various diseases. The most important pathway in metal-induced cancerogenesis is the ability of a metal to modulate gene expression by interfering with signal transduction pathways, leading to the deregulation of cell proliferation, activation of numerous transcription factors, disruption of cell cycle course, and apoptosis 4. Metal homeostasis is critical for the proper functioning of the brain 5. The brain is a target organ for toxic environmental pollutants 6. The balance of metals within the brain is regulated through the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier. In physiological conditions, these barriers regulate CNS homeostasis
