Literature Review

Air pollution in Salt Lake Valley has been directly linked to decrease the average life span of a Utah resident by 1-5+ years (Errigo et al. 2020). It has been seen through studies conducted in the World Health Organization that increasing Particulate Matter 2.5 concentration in the atmosphere is directly associated with the increasing respiratory disease rate and the hospitalization rate (Barkauskas et. al. 2018). In a study conducted at the 2014 Beijing Asia-Pacific Economic Cooperation meeting, PM 2.5 concentration was studied and lowered using a land regression model, and the results portrayed the lung cancer proportion lowered accordingly based on a toxic equivalency factor. Another study, published in Oncotarget in 2015, 2D human bronchial epithelial cells were exposed to high levels of PM 2.5. It was found in this study that two MicroRNAs are downregulated due to exposure to PM2.5. It was found that accordingly, three oncogenes found in non-small cell lung cancer cells expressions were activated. However, the specific pathogenesis of how PM2.5 induces lung cancer remains to be fully elucidated (Li et al. 2018).

Introduction

Salt Lake Valley is ranked #7 for the worst air quality cities in the United States (UDAQ 2023). Salt Lake City air pollution consists of 8 components; 4 of which are precursors to the formation of Particulate Matter 2.5 (PM2.5) (UDAQ). PM 2.5 is the most common wintertime pollutant in Salt Lake City (UDAQ). PM 2.5 is an environmental pollutant with a diameter of ≤2.5 um. PM2.5 has a large surface area and toxin absorption ability due to the small size of these particles. Due to the small size and high absorption rate, PM 2.5 can directly enter the alveolar tissue of the lung when inhaled and absorbed by alveolar macrophage (Li et. al. 2018). Alveoli are microscopic structures that are the endpoint of the respiratory system in the lung, where gas exchange between inhaled air and the blood occurs (Seadler et al. 2023). Once these particles are absorbed, they transition into the extracellular matrix and enter the systemic circulation. According to the World Health Organization, respiratory disease increased by 2.07%, and the hospitalization rate increased accordingly by 8% when PM2.5 exposure increased in the atmosphere by 10 ug/m⁴ in wintertime pollution (Barkauskas et. al. 2018). It is estimated that 75% of Utahns lose 1 or more years of life because of air pollution and 23% lose 5 or more years (Errigo et al. 2020).

PM2.5 is known to cause epigenetic and microenvironmental alterations in the pathogenesis of lung cancer (Li et al. 2018). Lung cancer has a higher mortality rate than any other type of cancer, causing 1.8 million deaths in 2020, and it is estimated that it will cause 238,240 deaths in 2024 (Errigo et. al. 2020). Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer, and has a 5-year survival rate. It has been indicated in previous studies that PM 2.5 is carcinogenic and increases the morbidity and mortality rates associated with lung cancer (Li et al. 2018). In a study conducted in Beijing during the 2014 Asia-Pacific Economic Cooperation meeting, the mean PM2.5 outdoor concentrations were obtained, and then reduced using a Land Regression Model, from the concentrations 37.5 μg/m³ to 24.0 μg/m³, which resulted in a lung cancer proportional reduction from 0.75% to 0.45%. This reduction in disease or death is modeling what would occur if exposure to the risk factor was reduced to a theoretical minimum and is based on a toxic equivalency factor (Xie et al. 2017).

Within the field of cell culture research, the aim is to culture a cell system to model complex physiological changes that occur in the body (in vivo) within the cells that are cultured. The response of the cells can be measured in the case that they are dosed with a control group exposure. Basic 2D cell culture is a type of cell culture consisting of only a single cell line and is grown and adhered on a flat surface. 2D cell culture is a simplified model that does not represent in vivo organs accurately, because an organ in vivo consists of multiple cell lines partaking in complex interactions with one another and are 3D structures. Organoids are self-organizing 3D model organ systems cultured from multiple cell lines (Kim et al.). A human lung organoid can be utilized to model how a lung functions in vivo, through creating an air-liquid interface culture where half of the lung organoid will be exposed to media and half will be exposed to air in an air sack structure. This human lung organoid can be dosed with PM 2.5 particles to observe how a lung in vivo would react to this exposure, specifically what is occurring epigenetically.

Epigenetics is the study of how environmental exposures, such as the inhalation of PM 2.5, change the way genes work through modifying how the body reads a DNA sequence (CDC). This research is important because the specific pathogenesis of how PM2.5 induces lung cancer remains to be elucidated (Li et al. 2018).

Applications

MicroRNAs are small non-coding RNAs that are primarily responsible for post-transcriptional regulation, as 50% of protein coding genes and cell metabolic processes are regulated by MicroRNAs (Papoutsidakis et al. 2013). MiRNAs can be upregulated or downregulated, meaning increased or decreased, as a response to exposure to various toxins (Papoutsidakis et al. 2013). The downregulation of miRNA is implied to affect the epigenome through elevating the expression of the genes that they control, such as oncogenes (Liu et al.

2015). Oncogenes are genes that regulate the induction of cancer, and can induce carcinogenisis when activated. In a 2015 study published in Oncotarget, which was the first study conducted examining the effects of PM2.5 exposure on MiRNA expression and the associated risk with lung cancer, 2D human bronchial epithelial cells were exposed to high levels of PM 2.5 (Lie et al. 2015). It was found in this study that two MicroRNAs, MiR-182 and MiR-185, are downregulated (decrease in production) due to exposure to PM2.5. These two MiRNAs control and suppress three targeted oncogenes (solute carrier family 30 member 1 (SLC30A1), serpin family B member 2 (SERPINB2) and aldo-keto reductase family 1 member C1 (AKR1C1)). Due to the downregulation of these two miRNAs, these three oncogenes are activated. These three oncogenes are commonly expressed in human lung adenocarcinoma and squamous cell carcinoma cells, thus when activated they can lead to non-small cell lung carcinogenesis as demonstrated in Figure 1 (Li et. al. 2018). To successfully quantify miRNA expression in the lung while under exposure to PM2.5, a 3D human lung organoid can be utilized by adding dilutions of PM 2.5 collected from the atmosphere into the organoid media to mimic an environmental change of added pollution exposure. MiRNA expression in response to this exposure is quantified within the media of the human lung organoid, as to not disturb the tissue (Haikerwal et. al. 2015). The use of a 3D human lung organoid will model a more physiologically accurate response to PM 2.5 exposure than these 2D human bronchial epithelial cells did used in the Lie et al. study.
 

Figure 1: Pathogenesis of PM 2.5 induced Carcinogenesis

A human lung organoid can be developed from isolating adult stem cells from a human lung tissue sample. Adult stem cells have the capability of differentiating into multiple tissue specific cell types when placed in the organ-specific niche environment. These adult stem cells can form organ-like cell clusters in which the cells self-organize, physiologically modeling an organ in vivo. Adult stem cell derived organoids maintain the long term functional and structural properties of the organ they were taken from, making them valuable for long term research.

There are two types of epithelia that line the inside of the human respiratory tract; the alveolar and the airway epithelium (Chiu et al. 2023). From an adult stem cell derived lung organoid, an airway organoid and an alveolar organoid can be developed through two different types of differentiation techniques. Alveolar organoids, which consist of alveolar type 1 (AV1) and alveolar type 2 (AV2) cells, can be generated through a method known as distal differentiation (Chiu et al. 2023). Alveolar organoids could prove to be useful to investigate the pathogenesis of PM2.5 induced lung cancer, seeing as PM2.5 is absorbed into the body’s systemic circulation through alveolar tissue.

Conclusion

Salt Lake City residents partake daily in the repeated inhalation of PM2.5, and this long term exposure proves to have severe epigenetic effects on the body. Throughout various research studies, it is seen that PM 2.5 is associated with the pathogenesis of lung cancer, specifically non-small cell lung cancer through the downregulation of MicroRNA’s that are in charge of silencing carcinogenesis inducing oncogenes. Still, the specific pathway for which PM2.5 induces lung cancer remains to be specifically elucidated. A human lung organoid, being a 3D air sack that physiologically models a human lung, can be utilized to pinpoint this epigenetic pathway. Locating the pathogenesis of PM 2.5-induced lung cancer will be useful within medicinal research, so that new treatments can be developed to reduce and stop this epigenetic pathway from occurring.

References

1. Li, R., Zhou, R., & Zhang, J. (2018, May). Function of PM2.5 in the pathogenesis of lung cancer and chronic airway inflammatory diseases. Oncology letters. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920433/#b30-ol-0-0-8355
2. Jmendenhall. (2023a, October 12). Understanding the sources and causes of Utah’s Air Pollution. Utah Department of Environmental Quality. https://deq.utah.gov/air-quality/understanding-utahs-air-quality
3. Salt Lake City’s air quality is nation’s 7th worst among large metro areas. The Salt Lake Tribune. (2020, January 28). https://www.sltrib.com/news/environment/2020/01/28/salt-lake-citys-air/
4. Read, 3 Min, 2:52, Read, 1 Min, Read, 2 Min, & Read, 10 Min. (n.d.). Human health and economic costs of air pollution in Utah. Plant & Wildlife Sciences. https://pws.byu.edu/ben-abbott-lab/human-health-and-economic-costs-of-air-pollution-in-utah
5. World Health Organization. (n.d.). Lung cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/lung-cancer?gclid=CjwKCAiAg9urBhB_EiwAgw88mSI_2-zrbl_MkGbHn_H9bcvnGw-9E4TrMuAnHe9KX8a8YFhnP1rpVRoCZu8QAvD_BwE
6. Barkauskas, C. E., Chung, M.-I., Fioret, B., Gao, X., Katsura, H., & Hogan, B. L. M. (2017, March 15). Lung organoids: Current uses and future promise. Development (Cambridge, England). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358104/
7. Lung organoids research - penn medicine. Lung Organoids Research - Penn Medicine. (n.d.). https://www.pennmedicine.org/news/news-releases/2018/february/lung-organoids-research
8. 1. 1. Haikerwal A. Impact of fine particulate matter (PM 2.5 ) exposure during ... [Internet]. [cited 2024 Feb 1]. Available from: https://www.ahajournals.org/doi/full/10.1161/JAHA.114.00165
9. 2. 1. Wang H. The effect of exposure time and concentration of airborne PM2.5 on lung injury in mice: A transcriptome analysis [Internet]. Elsevier; 2019 [cited 2024 Feb 1]. Available from: https://www.sciencedirect.com/science/article/pii/S2213231719304963
10. Castaneda, D. C. (2023, November 21). Protocol for establishing primary human lung organoid-derived air-liquid interface cultures from cryopreserved human lung tissue. STAR Protocols. https://www.sciencedirect.com/science/article/pii/S2666166723007025#bib9
11. Ravian L van Ineveld, Esmée J van Vliet, Ellen J Wehrens, Maria Alieva, Anne C Rios, 3D imaging for driving cancer discovery, The EMBO Journal, 10.15252/embj.2021109675, 41, 10, (2022).
12. Kim, M., Mun, H., Sung, C. O., Cho, E. J., Jeon, H.-J., Chun, S.-M., Jung, D. J., Shin, T. H., Jeong, G. S., Kim, D. K., Choi, E. K., Jeong, S.-Y., Taylor, A. M., Jain, S., Meyerson, M., & Jang, S. J. (2019, September 5). Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nature News. https://www.nature.com/articles/s41467-019-11867-6
13. Xie, Y. (2017b, March 8). Reduction in population exposure to PM2.5 and cancer risk due to PM2.5-bound pahs exposure in Beijing, China during the APEC meeting. Environmental Pollution. https://www.sciencedirect.com/science/article/pii/S0269749116328135?casa_token=y-X6p3sFyd0AAAAA%3A-PgNKpd3BOcop31TpokT3YiV4vm5XAIzNOuhjIzgZBpitSWyC4UPc9lExi51R_fIVBlM7P-jTw 
14. Centers for Disease Control and Prevention. (2022, August 15). What is epigenetics?. Centers for Disease Control and Prevention. https://www.cdc.gov/genomics/disease/epigenetics.htm#:~:text=Epigenetics%20is%20the%20study%20of,body%20reads%20a%20DNA%20sequence 
15. Papoutsidakis, N., Deftereos, S., Kaoukis, A., Bouras, G., Giannopoulos, G., Theodorakis, A., Angelidis, C., Hatzis, G., & Stefanadis, C. (1970, January 1). MicroRNAs and the heart: Small things do matter. Latest TOC RSS. https://www.ingentaconnect.com/content/ben/ctmc/2013/00000013/00000002/art00009
16. Liu, C., Guo, H., Cheng, X., Shao, M., Wu, C., Wang, S., Li, H., Wei, L., Gao, Y., Tan, W., Cheng, S., Wu, T., Yu, D., & Lin, D. (2015, October 6). Exposure to airborne PM2.5 suppresses microrna expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells. Oncotarget. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745737/
17. Seadler, B. D. (2023, May 1). Physiology, alveolar tension. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK539825/#:~:text=Alveoli%20are%20microscopic%20balloon%2Dshaped,and%20the%20blood%20takes%20place 
18. Chiu, M. C., Li, C., Yu, Y., Liu, X., Huang, J., Wan, Z., Yuen, K. Y., & Zhou, J. (2023, April 20). Establishing bipotential human lung organoid culture system and differentiation to generate mature alveolar and airway organoids. Bio-protocol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127040/ 

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Morgan graduated from Westminster University in Spring of 2024, with a Bachelor of Science in Biology, Honors College. She plans to attend Medical School (DO) in the fall of 2025, where she is interested in making advances within holistic medicine and improving the level of empathetic care patients receive. She plans to take a focus in serving the niche medically underserved population of the Deaf Community.