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Circadian Rhythm Disruption & the Link to Cancer Risk

Bullen Love, Danielle

doi: 10.1097/01.COT.0000524558.28851.71
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In the medical profession, working night shifts is the name of the game. Whether you are an oncology resident who drew the short straw or a nurse who is staffed to permanent night shifts, at some point you will get to know your hospital after midnight.

Beyond fatigue, is there an inherent danger to this work style? Some researchers believe when it comes to cancer risk and proliferation, the answer is yes.

In 2001, a Fred Hutchinson Cancer Research Center study showed nurses who regularly worked the night shift were more likely to be diagnosed with cancer (J Natl Cancer Inst 2001;93(20):1557-1562). Ten years ago, the International Agency for Research on Cancer identified working a night shift as a probable human carcinogenic (Lancet Oncol 2007;8(12):1065-1066). While studies have shown there is a correlation between night shift employment and cancer risk, the question remains as to why that was happening on a molecular level.

Today, another Fred Hutchinson researcher, Parveen Bhatti, PhD, Associate Member of Epidemiology, studies the potential for a correlation between working the night shift and the cellular repair process.

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Repairing DNA Damage

In the study, Bhatti's team looked at urine specimens from regular night shift hospital employees, collected both when they slept during the day and at night (Occupational and Environ Medicine 2016;73(8):537-544).

“I wanted to see if melatonin suppression among night shift workers led to a decreased ability to repair oxidative DNA damage, which is a type of damage that has been associated with an increased risk of cancer,” said Bhatti.

Melatonin regulates the body's circadian rhythms, our internal clock that plays a function in the sleep-wake cycle. Levels are lowest during the daytime hours before peaking around 1 or 2 a.m. Light exposure signals to the pineal gland to produce less of the hormone.

Sleeping in a dark environment at night, as our bodies are programmed, to do is essential for melatonin production that, in turn, improves cells' abilities to repair oxidative DNA damage. If such damage is left unrepaired, it can generate mutations that can lead to cancer. When doctors, nurses, and other hospital staff are exposed to lights when working overnight, their systems' melatonin secretion is suppressed.

In Bhatti's study, subjects who slept during the day while working at night showed lower levels of biomarker 8-hydroxydeoxyguanosine in their urine. A high presence of the compound is an indication that cells have been repairing DNA damage. The lower presence shown in these subjects is a sign their cells could be more susceptible to cancer-causing mutations.

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Stop Gap Measures

Can shift workers counteract this damage by taking melatonin supplements? Bhatti warned that over-the-counter melatonin supplements are not regulated by the FDA and may contain additives. The purpose of the hormone is to regulate sleep at night. Supplements are not sleep aids and when taken during the day, they might have no effect on sleep patterns and, therefore, DNA repair.

Bhatti, however, has applied for a grant to examine the effects of melatonin supplements in a controlled environment. Researchers would closely monitor side effects of the supplements during participants waking hours. The proposed study will look at whether such supplements can prevent or even reverse the negative effects of overnight employee's melatonin suppression and their bodies' subsequent inability to effectively repair cellular damage.

“In addition to measuring urinary levels of the DNA damage marker as was done in the recently published study, we would measure cellular levels of DNA damage,” Bhatti said.

Some 3,000 miles away, Thales Papagiannakopoulos, PhD, Assistant Professor of Pathology at NYU Langone Medical Center, is also studying the circadian rhythm disruption common to shift workers. Using mouse models, his research specifically centers on the occurrence and growth of lung cancer.

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Cancer Progression

“It is still early days but there is evidence emerging from several models that clock integrity can have effect on cancer progression,” said Papagiannakopoulos, speaking of course, of the internal clock.

In the 2016 paper, written while Papagiannakopoulos was on staff at MIT, researchers found Bmal1 and Per2, genes that control cells' circadian rhythms, also function as tumor suppressors (Cellular Metabolism 2016;24(2):324-331). Manipulate the internal clock and the genes' roles are altered, potentially leading to cancer occurrence and tumor growth.

Papagiannakopoulos and his team initiated small cell lung cancer in mice. Some of the mice were placed in light conditions that mimic shift work, where their exposure to light was altered every 2-3 days. This is similar to how clinicians who work night shift might have variable exposure to lights at night based on work schedule. After 8 weeks, those animals' tumors were larger and had grown at a faster rate. The mice in the night shift light model succumbed to the cancer quicker than the other study subjects.

Beyond the sleep-wake cycle, circadian rhythms control when immune cells are most active and control cell metabolism, a process that is necessary for tumors to grow

“Over the last 10 years, there's been a better explanation of how our bodies' clocks work genetically,” said Papagiannakopoulos.

Human cells and human tumors have their own molecular clocks. MIT researchers also examined lung human tumor samples and found lower levels of Bmal1 and Per2 gene expressions when compared to benign lung tissue samples from the same patient. Circadian rhythms were disrupted in such cases.

To tie it back to shift work: Did night shift and the subsequent variable light exposure cause the disruption? The question needs further examination but it is one that scientific community has a growing interest in answering. Some scientists who study circadian rhythms are actively working to help cancer researchers better incorporate the role of circadian rhythms into research.

“There is a gap that our research is helping to bridge,” noted Papagiannakopoulos.

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Protect Against Personal Cancer Risk

Yet with still many uncertainties surrounding the effect of working night shift on disease, including cancer, how can those on the graveyard shift protect their health?

In cancer patients, there are times of day when the circadian rhythms compel the body to produce more immune cells. Papagiannakopoulos wondered whether chemotherapy doses could be given at specific times for maximum impact. This might be especially beneficial to night shift patients whose tumor-growth mechanisms are already enhanced.

The best advice for shift workers who are concerned about their cancer risk is the same for anyone.

“Night shift workers need to be extra vigilant about living a healthy lifestyle, including trying to get enough sleep, not smoking, and drinking alcohol in moderation,” said Bhatti.

Patients cannot control all genetic factors for their personal cancer risk. And working night shift is unavoidable for certain parts of the population. Future research may suggest ways to reverse the DNA damage from altered sleep-wake cycles. Working the graveyard shift will never be fun, but perhaps one day it will not be damaging to the body's genes.

Danielle Bullen Love is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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