Air Pollution as a brain tumor risk factor

Air pollution is linked to brain inflammation, which accelerates tumorigenesis and neurodegeneration. The molecular mechanisms that connect air pollution with brain pathology are largely unknown but seem to depend on the chemical composition of airborne particulate matter (PM).

Outdoor air pollution is a global public health problem, particularly prevalent in megalopoles and southern countries but also important in developed European countries [43]. It results from multiple sources including transport, industrial activity and power generation, biomass burning, and domestic heating, lighting, and cooking based on solid fuel [44]. Outdoor air varies substantially both in space and time because of the mix of sources and the external effects, including oxidation and weather. 9 In 2013, members from the IARC unanimously classified outdoor air pollution as carcinogenic, with a strong causal association with lung cancer in particular [45]. Several diseases of the CNS, including ischemic stroke [46–48] and Parkinson disease, were linked to pollution exposure [49]. Outdoor air pollution comprises several potentially carcinogenic factors: particulate matter (PM), black carbon, heavy metals (e.g., vanadium, nickel, and manganese), environmental tobacco smoke, organic compounds (e.g., polycyclic aromatic hydrocarbons and endotoxins) and gaseous pollutants (e.g., O3, NO2, SO2, CO). PM and O3 are thought to be the 2 most important dangers to public health [50,51]. However, data regarding brain tumors are scarce. In addition to biological and animal models, only a few epidemiological studies exist: 2 ecological studies [52,53], 4 cohort studies [54– 57] and 1 case–control study [58] (Table 3). Studies of animals argue for the penetrance of particles and mineral magnetite into the CNS, which causes neuroinflammation [59,60]. Brain inflammation within a tumor microenvironment is thought to increase oxidative stress and DNA damage, thus stimulating both genetic and epigenetic changes that occur during glioma evolution [61]. Conflicting results arise from epidemiological studies. The European Study of Cohorts for Air Pollution Effects [57] reported evidence of an association between traffic-related air pollution, using PM2.5 (PM with a diameter of less than 2.5 micrometers) absorbance as a proxy, and brain tumors. However, McKean-Cowdin et al. and Valberg et al. found a negative association between sulfur dioxide, nitrogen dioxide, and carbon monoxide exposure and nervous system cancer mortality or incidence [52,62]. The authors proposed that the protective effect is induced by chronic immune stimulation. Indeed, immune hyperactivity is characteristic of allergies and asthma, both conditions inversely correlated with brain cancer risk in most studies [63–67] if not all [68]. Another incoherence was found in the Danish population: in a first nationwide cohort study [55], Poulsen et al. identified an exposureresponse linear association between nitrogen oxides at the residence – as a proxy of outdoor pollution – and risk for brain cancer. They found contradicting evidence in another nationwide case–control study [58], where they could not replicate this association. Still, this second study highlighted an increased risk of non-glioma tumours with high exposures (nitrogen oxides concentration ≥100µg/m3 ) with an OR of 2.3 (95% CI 1.2-4.6). 10 As a whole, data for the effect of outdoor air pollution on brain cancerogenesis mostly rely on a small number of studies that are exploratory in nature. Thus, to date, we lack evidence to incriminate air pollution in the development of brain tumors 1).

used kriging interpolation and land use regression models to estimate long-term air pollutant exposures of oxides of nitrogen (NOx, NO2), kriging interpolation for ozone (O3), carbon monoxide, and particulate matter (PM2.5, PM10), and nearest monitoring station measurements for benzene for 103 308 men and women from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2013. We used Cox proportional hazards models to examine the associations between time-varying pollutants and risk of malignant brain cancer (94 men, 116 women) and meningioma (130 men, 425 women) with adjustment for sex, race and ethnicity, neighborhood socioeconomic status, smoking, occupation, and other covariates. Stratified analyses were conducted by sex and race and ethnicity.

Results: Brain cancer risk in men increased in association with exposure to benzene (hazard ratio [HR] = 3.52, 95% confidence interval [CI] = 1.55 to 7.55) and PM10 (HR = 1.80, 95% CI = 1.00 to 3.23). Stronger associations with PM10 (HR = 3.02, 95% CI = 1.26 to 7.23), O3 (HR = 2.93, 95% CI = 1.09 to 7.88), and benzene (HR = 4.06, 95% CI = 1.17 to 18.2) were observed among Latino men. Air pollution was unrelated to risk of meningioma except that O3 exposure was associated with risk in men (HR = 1.77, 95% CI = 1.02 to 3.06). Brain cancer risk in women was unrelated to air pollution exposures.

Conclusions: Confirmation of these sex differences in air pollution-brain cancer associations and the stronger findings in Latino men in additional diverse populations is warranted 2).

The global incidence of brain tumors varies substantially without explanation. Studies correlating radon exposure and incidence are inconclusive. Particulate pollution has been linked to increased tumor incidence. Particulates may disrupt the blood-brain barrier allowing intracranial exposure to oncogenic radon. Palmer et al. investigated the relationship between exposure to residential radon, particulate pollution, and brain tumor incidence in the United States (US).

County-level median radon testing results and annual air quality index values were obtained and divided into tertiles. Counties without both values were excluded. Four groups of counties were generated: high particulate/high radon (high/high), high/low, low/high, and low/low. Using incidence data from the Central Brain Tumor Registry of the US (provided by CDC's National Program of Cancer Registries and NCI's SEER), annual age-adjusted incidence rates (AAAIRs) by the group were generated by behavior. Incidence rate ratios were calculated to examine for significant differences (α=0.05). Poisson regression accounting for possible confounders was conducted.

Counties with available data included 83% of the US population. High/high exposure was significantly associated with increased AAAIR of all non-malignant tumors (up to 26% higher, including most meningiomas) even after accounting for potential confounders. An increased AAAIR was noted for all malignant tumors (up to 10% higher), including glioblastoma, but was negated after accounting for demographic/socioeconomic differences.

They present the first report suggesting increased non-malignant brain tumor incidence in regions with high particulate and radon exposure. These findings provide insight into unexplained variation in tumor incidence. Future studies are needed to validate these findings in other populations 3).

Ljubimova et al., sourced ambient PM from Riverside, California, and selectively exposed rats to coarse (PM2.5-10: 2.5-10 µm), fine (PM<2.5: <2.5 µm), or ultrafine particles (UFPM: <0.15 µm). They characterized each PM type via atomic emission spectroscopy and detected nickel, cobalt and zinc within them. They then exposed rats separately to each PM type for short (2 weeks), intermediate (1-3 months) and long durations (1 year). All three metals accumulated in rat brains during intermediate-length PM exposures. Via RNAseq analysis we then determined that intermediate-length PM2.5-10 exposures triggered the expression of the early growth response gene 2 (EGR2), genes encoding inflammatory cytokine pathways (IL13-Rα1 and IL-16) and the oncogene RAC1. Gene upregulation occurred only in brains of rats exposed to PM2.5-10 and correlated with cerebral nickel accumulation. We hypothesize that the expression of inflammation and oncogenesis-related genes is triggered by the combinatorial exposure to certain metals and toxins in Los Angeles Basin PM2.5-10 4).

Negatively impacts pulmonary, cardiovascular, and central nervous systems. Although its influence on brain cancer is unclear, toxic pollutants can cause blood-brain barrier disruption, enabling them to reach the brain and cause alterations leading to tumor development. By gene microarray analysis validated by quantitative RT-PCR and immunostaining Ljubimova et al, examined whether rat (n=104) inhalation exposure to air pollution particulate matter (PM) resulted in brain molecular changes similar to those associated with human brain tumors. Global brain gene expression was analyzed after exposure to PM (coarse, 2.5-10μm; fine, <2.5μm; or ultrafine, <0.15μm) and purified air for different times, short (0.5, 1, and 3 months) and chronic (10 months), for 5h per day, four days per week. Expression of select gene products was also studied in human brain (n=7) and in tumors (n=83). Arc/Arg3.1 and Rac1 genes, and their protein products were selected for further examination. Arc was elevated upon two-week to three-month exposure to coarse PM and declined after 10-month exposure. Rac1 was significantly elevated upon 10-month coarse PM exposure. On human brain tumor sections, Arc was expressed in benign meningiomas and low-grade gliomas but was much lower in high-grade tumors. Conversely, Rac1 was elevated in high-grade vs. low-grade gliomas. Arc is thus associated with early brain changes and low-grade tumors, whereas Rac1 is associated with long-term PM exposure and highly aggressive tumors. In summary, exposure to air PM leads to distinct changes in rodent brain gene expression similar to those observed in human brain tumors 5).

A. Vienne-Jumeau, C. Tafani, D. Ricard. Environmental risk factors of primary brain tumors: A review. Revue Neurologique, Elsevier Masson, 2019, 175, pp.664 - 678. ff10.1016/j.neurol.2019.08.004ff. ffhal-03488519f
Wu AH, Wu J, Tseng C, Yang J, Shariff-Marco S, Fruin S, Larson T, Setiawan VW, Masri S, Porcel J, Jain J, Chen TC, Stram DO, Marchand LL, Ritz B, Cheng I. Association Between Outdoor Air Pollution and Risk of Malignant and Benign Brain Tumors: The Multiethnic Cohort Study. JNCI Cancer Spectr. 2020 Jan 3;4(2):pkz107. doi: 10.1093/jncics/pkz107. PMID: 32211584; PMCID: PMC7083235.
Palmer JD, Prasad RN, Cioffi G, Kruchtko C, Zaorsky NG, Trifiletti DM, Gondi V, Brown PD, Perlow HK, Mishra MV, Chakravarti A, Barnholtz-Sloan JS, Ostrom QT. Exposure to Radon and Heavy Particulate Pollution and Incidence of Brain Tumors. Neuro Oncol. 2022 Jun 28:noac163. doi: 10.1093/neuonc/noac163. Epub ahead of print. PMID: 35762336.
Ljubimova JY, Braubach O, Patil R, Chiechi A, Tang J, Galstyan A, Shatalova ES, Kleinman MT, Black KL, Holler E. Coarse particulate matter (PM(2.5-10) in Los Angeles Basin air induces expression of inflammation and cancer biomarkers in rat brains. Sci Rep. 2018 Apr 9;8(1):5708. doi: 10.1038/s41598-018-23885-3. PubMed PMID: 29632393; PubMed Central PMCID: PMC5890281.
Ljubimova JY, Kleinman MT, Karabalin NM, Inoue S, Konda B, Gangalum P, Markman JL, Ljubimov AV, Black KL. Gene expression changes in rat brain after short and long exposures to particulate matter in Los Angeles basin air: Comparison with human brain tumors. Exp Toxicol Pathol. 2013 Nov;65(7-8):1063-71. doi: 10.1016/j.etp.2013.04.002. Epub 2013 May 18. PubMed PMID: 23688656.
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