As the sun rises and sets, a symphony of biological processes unfolds within our bodies, choreographed by internal timekeepers called circadian clocks. These circadian rhythms are important for maintaining different internal biological cycles that regulate various physiological processes, such as metabolism, immunity, and inflammation. When circadian rhythms are disrupted, it can lead to adverse health effects, including increased susceptibility to diseases.

In a recent scientific study published in Advanced Biology, scientists have gained new insights into the impact that air pollution has on the genes that control circadian rhythms, commonly called “clock genes”, and the downstream physiological effects, suggesting a relationship with inflammation that occurs in the lungs after exposure.

The study looked at ozone, a common environmental pollutant primarily produced by vehicle emissions and industrial activities, and known for its harmful effects on respiratory health, particularly in individuals with asthma.

“Understanding how the genes and proteins that regulate the circadian clock in the lungs behave might shed light on the unknown mechanism that can control environmental exposure-induced lung injury,” said Isaac Sundar, associate professor in the Department of Internal Medicine at the University of Kansas Medical Center and first author of the study.

The findings are particularly intriguing because the study found a different level of susceptibility between genders. “Our study shows for the first time that when exposed to air pollutants, such as ozone, there are changes that occur in the lungs that are quite different in female and male mice,” said Sundar. “Specifically, the changes we observed are related to circadian clock genes [suggesting] that the lung may show differential responses to environmental insults depending on the time of the day.”

Ozone and circadian rhythm

Many previous studies have shown that ozone exposure triggers inflammation in the lungs, but these recent findings have provided a crucial link that infers circadian rhythm may be involved in this mechanism. “While we do not know how these two factors affect each other, from the existing literature we know that circadian rhythms can regulate cellular processes such as inflammation [and it] has motivated us to continue this research on ozone exposure in mice,” he explained.

The researchers monitored the effect of ozone exposure on the clock genes activated or inhibited in lung cells in mice.

After both long and short term exposure, they observed changes associated with dysregulation in clock gene expression by monitoring mRNA levels in cells, which are linked to protein production and cell function. In almost every part of the lungs, ranging from structural tissues to immune cells, they observed these changes, which were surprisingly, starker in the female mice.

“Work from experimental models (rodents) has shown that female hormones make the lungs generate more inflammatory mediators in response to ozone exposure, an evolutionary adaptation to protect females from infection,” said Patricia Silveyra, a faculty member of the flagship campus of Indiana University-Bloomington at the School of Public Health, and lead author of the study. “However, pollution tends to elucidate responses that mimic what happens during infection, so it ends up damaging the lungs instead of protecting them.”

While the findings highlight the intricate possible link between ozone exposure, lung inflammation, and disruptions in clock gene expression, the experiments were conducted in mice at high exposure levels that one might not encounter on a daily basis, similar experiments could be challenging to repeat in humans.

“There are some studies done at the Environmental Protection Agency where people are placed in a chamber and asked to exercise on a treadmill or stationary bike, and controlled amounts of ozone in the air are released [and] these studies are used to set the basis for ozone environmental standards,” explained Silveyra.

“Usually, these studies look at lung function changes in subjects who volunteer to participate, and samples from their lungs are also collected,” she continued. “It is possible to access those samples with permission, so we could conduct these studies [the same conducted in mice], but we will need to make sure that subjects have been exposed to ozone at different times of the day, which is usually not the case.”

“[Moreover] future studies using preclinical models will address the reason for the observed difference in the degree of susceptibility among females vs. males to ozone exposure,” she added.

Tackling elevated levels of pollution

Analysis of air quality data from over 8600 human settlements across more than 120 countries revealed that nearly the entire global population is exposed to air pollution levels surpassing the air quality limits set by the World Health Organization, posing a significant threat to long term health.

Studies such as this highlight how important it is to push for tighter regulations and for governments to take action. For example, by increasing pedestrian and bike zones in cities and banning diesel engines, investing in public transportation, infrastructures, and promoting low-polluting forms of transportation, such as bikes or electric vehicles.

But what can we do in the short term to minimize our exposure?

“Prolonged sunlight and more vehicles on the road can cause the formation of excessive ozone, the effects are usually worse during the daytime, and based on our study, the lung could also respond differently in the morning vs. evenings,” explained Sundar.

“One way to prevent the damaging effects of ozone is to limit outdoor activities during the day,” he added, and recommended that, for example, runners with asthma or other chronic respiratory conditions that are more susceptible to ozone exposure should consider exercising in the morning before 10 AM or after 7 PM and preferably in areas away from high traffic.”

In a world where air pollution poses a significant threat to our health and well-being, understanding the cellular metabolisms that lead to lung inflammation after exposure becomes crucial. As further research unveils the complexities of these mechanisms, it is imperative that governments, policymakers, and individuals join forces to combat pollution, protect our respiratory health, and strive for a cleaner and healthier, future for all.

Reference: Isaac Sundar, et. al., Acute and Repeated Ozone Exposures Differentially Affect Circadian Clock Gene Expression in Mice, Advanced Biology (2023). DOI: 10.1002/adbi.202300045

Feature image credit: Aleksandr Popov on Unsplash