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National Toxicology Program. NTP Cancer Hazard Assessment Report on Night Shift Work and Light at Night. Research Triangle Park (NC): National Toxicology Program; 2021 Apr.
This section reviews studies that examined the effects of (1) different light-dark cycles and daytime light exposure to blue light and (2) simulated shift work or jet lag on formation and growth of tumors in mice and rats. The effects of light exposure were studied in models of spontaneous tumor formation (i.e., occurring with no co-exposure), cancer xenografts and injection of cancer cells, and chemical initiation and promotion of cancer. Melatonin was the primary biomarker of circadian disruption evaluated, but some of these studies also measured markers of circadian disruption, such as activity, body temperature, estrus cycling, and clock gene expression. Indirect measurements of the urinary metabolite 6-sulfatoxymelatonin were also monitored, and some studies looked at the effects of melatonin supplementation (see Section 6). Most of these studies examined growth of tumors after chemical or genetic initiation or after injection of tumor cells or implantation of tissue; however, they were not designed to evaluate incidences of specific tumors as would be reported in chronic cancer studies. Therefore, while these studies provide information supportive of mechanistic findings, they are not informative for reaching a level of evidence conclusion for cancer in experimental animals.
Most mice and rats used in experimental studies are nocturnal animals and thus are most active during nighttime. It is during this period that some strains of rodents produce melatonin; however, most inbred strains of mice lack melatonin due to enzyme deficiencies in melatonin synthesis (Goto et al. 1989, Jilge and Kunz 2004, Steinlechner 2012, Peirson et al. 2018). The apparent lack of melatonin detection in some inbred mouse strains does not seem to make a difference in tumor growth in response to light intensity, as melatonin supplementation or increased darkness decreases tumor growth in the absence of detectable blood levels of melatonin (Schwimmer et al. 2014). Melatonin-deficient mice are nocturnal and have a circadian pattern similar to melatonin-proficient mice (Peirson et al. 2018), which could be explained by physiologic factors that can compensate for the lack of melatonin, or by a low, but sufficient, level of endogenous melatonin in these inbred strains, as melatonin-deficient mice have intact melatonin receptors (Stehle et al. 2002, 2003). A low, but significant, level of melatonin production was noted when melatonin-deficient C57BL/6 mice were exposed to long nights or norepinephrine stimulation, which lends credence to the latter hypothesis (Haim et al. 2010). In addition, in a study using pinealectomized mice, detectable blood levels of melatonin were measured (Travlos et al. 2001). If available, information on melatonin production by the experimental animal strain is noted after the strain of experimental mouse or rat in Tables 5-1 and 5-2.
5.1. Exposure models of LAN, and simulated shift work, and chronic jet lag
The animal studies of light are a surrogate for LAN human exposure studies. Aside from red light, rodents have more absolute and spectral sensitivity than humans to visible light, and may have vision into the ultraviolet light spectrum, and thus they may respond differently or more intensely to a light source or light protocol than humans (Peirson et al. 2018).
Several models with altered lighting schedules have been used in experimental animal studies (see Figure 5-1). A light:dark cycle of 12 hours light and 12 hours dark (12:12 L:D) is commonly used as the standard or control level. One variation is to keep the lights on continuously, i.e., 24 hours light (see the model in Figure 5-1A below). The period of darkness can be replaced with dim light (usually about 0.2 lux) for 12 hours or a brief period with bright light (300 lux for 30 minutes) halfway through the dark period, or intermittent LAN (see the model in Figure 5-1B below) can be used. Another variation is to alter the length of both the light period and the dark period within a 24-hour period; this can be done by either lengthening the light period and shortening the dark period (e.g., 16:8 L:D) or shortening the period of light and increasing that of darkness (e.g., 8:16 LD) (see the model in Figure 5-1C below). Some studies have also evaluated exposure to blue light during the daytime.
Figure 5-1
Light at night models. Control groups for all models are 12:12 hour L:D cycle
The model commonly used to expose animals to the changes in light:dark patterns simulating those experienced by shift workers is to invert the light:dark cycle for a week so it is the opposite of the normal cycle and then invert it again to return to the normal cycle. This inversion can be repeated at weekly intervals for the course of an experiment (see Figure 5-2A below). The changes in the timing of light experienced by people who cross multiple time zones (transmeridian travel), which induces jet lag (see Figure 5-2B below), can be simulated by shifting the schedule forward by adding a longer light period every few days (simulating traveling across time zones from east to west) or shifting it backward by reducing the light period every few days (simulating traveling across time zones from west to east).
Figure 5-2
Simulated shift work and chronic jet lag models. Control groups for all models are 12:12 hour L:D cycle
The human exposures most relevant are those involving dim or intermittent LAN. Although some might argue that the LAN protocols used in rodent studies do not strictly apply to humans, one could also counterargue that constant exposure to artificial LAN has become pervasive in modern society due to urban light pollution filtering into bedrooms, the glow at all hours from television, computer, and mobile device screens, and indoor lights that are kept on (Bedrosian and Nelson 2013). Exposure to constant light is even more pronounced for shift workers who are exposed to constant bright lights during night shifts and sleep during daylight hours (see Figure 5-2). Simulated shift work and chronic jet lag model lighting conditions only and do not take into account other changes and experiences, such as changes in dietary and sleep patterns, that humans may experience under these type of lighting conditions.
5.2. Findings from animal models of LAN or other relevant light exposures
This section reviews LAN animal models and are organized by animal model type (Sections 5.2.1 to 5.2.3) and summarized in Table 5-1. In addition, two studies evaluated exposure to daytime blue light and tumor growth (Section 5.2.4).
5.2.1. Initiation-promotion models
This section reviews chemical initiation of tumors in animal models and the effect of various light schedules on promotion of tumor growth. For this section, more details are given on study design as the exposure protocols varied and the initiation model varied. For rat models of mammary-gland tumors, both dimethylbenzanthracene (DMBA) which results in mutations in codon 61 of H-Ras, and N-nitroso-N-methylurea (NMU), which initiates with H-Ras mutations in codon 12 are used. Although mutations in Ras are uncommon in human breast cancer, rat mammary tumors initiated with NMU have been shown to have molecular gene expression profiles similar to those in human ductal carcinoma in situ (Chan et al. 2005). In some of the studies, the animals were acclimated to a standard LD cycle, exposure groups were randomized and chemical initiator or vehicle given, followed by exposure to the test light regimens (LD, LL, or DD); in other studies, the chemical was more of a co-exposure, as it was administered after acclimatization to the test light schedules.
Mammary-gland tumors
Holtzman rats exposed from birth to LL or LD were injected with DMBA at approximately 55 days of age (Kothari et al. 1982). The incidence of DMBA-induced mammary gland tumors was significantly greater in animals maintained in continuous light as compared to control animals on a 10:14 LD schedule. In follow-up reports of additional exposure groups from the same study, co-exposure to melatonin in drinking water decreased tumor number or increased latency in the LL group (Mhatre et al. 1984, Shah et al. 1984, Kothari 1987). In another study, rats were exposed to LL or 12:12 LD from 43 days of age and DMBA was administered by gavage to female Sprague-Dawley rats at 50 days of age. Significantly more mammary fibroadenomas were identified in the LL group than in the LD control group; however, melatonin co-exposure by subcutaneous injection significantly increased mammary adenocarcinoma in the LD group with no significant effect on the LL group (Hamilton 1969). In another study (Anderson et al. 2000), Sprague-Dawley rats on a LL or 8:16 LD schedule starting at 26 days of age were injected with DMBA at 52 days of age. Significantly fewer mammary-gland tumors were observed in the LL group than in the 8:16 LD group 13 weeks after DMBA exposure; however, these rats were not exposed to experimental LAN conditions from birth. In another study, female Sprague-Dawley rats on a standard 12:12 LD schedule were exposed to DMBA at 55 days of age and palpated weekly for mammary-gland tumors (Cos et al. 2006). When mammary-gland tumors were about 1 cm in diameter, the rats were divided into one of four exposure groups for a 12-week period: (1) 12:12 LD, (2) LL (300 lux), (3) 12:12 LD with exposure to 300 lux for 30 minutes after 6 hours of dark, and (4) 12:12 LD with dim light (0.21 lux) throughout the dark phase. Rats exposed to LL, LD with intermittent light during the dark phase, and LD with dim light during the dark phase showed significantly higher rates of tumor growth than those under standard 12:12 LD conditions. The rats exposed to dim light throughout the dark period had the lowest survival of all groups and the highest rate of tumor growth.
Table 5-1
Summary of studies of LAN and cancer in experimental animals.
In a 26-week experiment, N-nitroso-N-methylurea (NMU) was given at the start of the experiment (after animals acclimated for 2 weeks to 12:12 LD photoperiod) and was used to induce mammary-gland tumors in female F344/N rats. Animals were exposed intermittently to light during the dark phase of a 12:12 LD cycle (five 1-minute exposures to light every 2 hours after start of the dark phase) or to a standard 12:12 LD cycle after NMU injection (Travlos et al. 2001). At necropsy, no significant differences were observed in mammary-gland tumor incidence, multiplicity, or average tumor weight between vehicle and NMU 12:12 LD controls, NMU-initiated intact rats, or pinealectomized rats exposed to intermittent LAN. Serum melatonin was three-fold greater in animals exposed to intermittent LAN than to those on 12:12 LD cycle. Pinealectomized rats had detectable serum levels of melatonin, suggesting that melatonin was from a secondary source. Over 90% of tumors in all treatment groups were mammary-gland adenocarcinoma.
In another experiment, rats were exposed to experimental LAN conditions from 1 month of age and NMU was administered to female rats at 55 days of age. The incidence of mammary-gland adenocarcinoma was significantly higher and the latency of mammary-gland fibroadenoma and adenocarcinoma was significantly shorter in the LL group than in the 12:12 LD group (Anisimov et al. 1994).
Other tumors
Other initiation-promotion studies in mice and rats reported that increased light exposure or short, frequent light cycling (6:6 hours LD) resulted in reduced tumor latency and increased tumor incidence.
Female adult deer mice (Peromyscus maniculatus bairdii) were exposed to either short days (8:16 LD) or long days (16:8 LD) for 8 weeks before subcutaneous injection with DMBA or dimethylsulfoxide (DMSO), examined weekly, and necropsied 8 weeks after injection (Nelson and Blom 1994). Mice exposed to long days developed squamous-cell carcinoma (89% incidence), but those exposed to short days did not.
CD-l and A/J male mice were given urethane at 5 weeks of age after seven days on either a short-day or standard-day light cycle. Those exposed to a short LD cycle (6:6 LD) developed significantly larger lung tumors (papillary adenoma) than did those exposed to 12:12 LD (Nakajima et al. 1994).
Male Wistar rats were given diethylnitrosamine (DEN) for 6 weeks under a 12:12 LD light cycle and then randomized into three exposure groups: 12:12 LD, 12:12 LD + phenobarbital, and LL. On gross examination, the percentages of rats with macroscopic nodules on the liver surface were 72% in the 12:12 LD group, 89% in the 12:12 LD + phenobarbital group, and 95% in the LL group. All of the rats died with hepatocellular carcinoma; median survival was 5 months, similar in all three groups (van den Heiligenberg et al. 1999). Conflicting results were reported in another study (Isobe et al. 2008), in which male Wistar rats were given DEN or saline injections after acclimatization to either 12:12 LD, DD, or LL conditions. The levels of preneoplastic liver foci, as measured by immunostaining for glutathione S-transferase placental form (GST-P) at 8 weeks after DEN administration, were higher in the 12:12 LD group than in the DD and LL groups.
Tumor formation in pups following exposure of pregnant Wistar dams on gestational days 18 to 19 to N-nitroso-N-ethylurea was studied under conditions of exposure of the dams and pups to LL, DD, and 12:12 LD from mating (vaginal plug) to weaning (1 month after delivery), after which the pups were exposed to 12:12 LD throughout their lifetimes (Beniashvili et al. 2001). Full necropsies of the pups revealed that continuous light exposure significantly shortened tumor latency and increased the number and types of tumors, whereas continuous dark lengthened latency and decreased the number and types of tumors. Tumors were of the peripheral nervous system and kidney, but tumor incidences were not reported.
In a model of colon cancer initiation, dimethylhydrazine was administered to male Wistar rats and the rats were then exposed for 14 days to 12:12 LD or LL (300 lux). Exposure to LL significantly increased the incidence of aberrant crypt foci in colon tissue; the LL group had significantly more pre-cancerous lesions (hyperplastic and dysplastic foci) than did the 12:12 LD group. Co-exposure to melatonin in the LL group decreased the incidence of foci as compared to LL without melatonin (Kannen et al. 2011).
5.2.2. Animal models of xenografts or injected tumor cells
Studies in which rodents were injected with human or rodent cancer cells or implanted with xenografts found that tumor growth was increased with increasing duration of light exposure or exposure to light during the dark phase of a 12:12 LD cycle. Tumor models included implantation of human breast cancer tissue or cells and cervical cancer cells into nude rats or mice and injection of rodent mammary-gland, prostate-gland, glioma, colon, and skin cancer (melanoma) tumor cells or implantation of hepatocellular carcinoma tissue into syngeneic rats or mice.
The effect of light exposure at night as a potential risk factor for human breast cancer and for rat liver cancer was investigated in several studies by Blask et al. (2003, 2005, 2014) and Dauchy et al. (2014). MCF-7 (human breast cancer) cells in tissue xenografts were implanted into female Rowett nude rats (RNU). The rate of human breast tumor growth from implanted tumor tissue was greater with continuous light exposure as compared to 12:12 LD cycle (Blask et al. 2003). In another study, beginning two weeks before tumor implantation, animals on a 12:12 LD cycle were exposed to various light intensities during the 12-hour dark phase, from total darkness to constant light (345 µW/cm2) (Blask et al. 2005). Tumor growth in response to light during the dark phase was found to depend on light intensity for estrogen- and progesterone-receptor-negative MCF-7 breast cancer tissue implants into female nude rats and also for hepatocellular carcinoma tissue implants into male Buffalo rats. In all of these studies, serum levels of melatonin were measured and showed a significant decrease with animal exposure to LAN or dim LAN. Both tissue implants exhibited decreased proliferation when perfused with venous blood from samples collected during the night from premenopausal human female volunteers; implants perfused with blood from samples collected during the daytime or following ocular exposure to LAN exhibited higher proliferation (Blask et al. 2005). Serum melatonin levels were measured in the female volunteers and were lowest in the daytime collection, intermediate following ocular exposure to LAN and highest in the night time collection (See Section 6.2.2 for further discussion).
In two additional studies, this same strain of female nude rats was exposed to a schedule of 12 hours of bright light (304 to 345 lux) and 12 hours of dim LAN (0.2 lux), compared with a 12:12 LD control group. Exposure began one week before injection of MCF-7 estrogen-receptor-positive breast tumor cells (Dauchy et al. 2014) or six weeks before implantation with estrogen- and progesterone-receptor-negative MCF-7 breast cancer tissue xenografts (Blask et al. 2014). In both cases, the dim LAN group had faster tumor growth, as measured by tumor weight, than did the 12:12 LD control group. Dim LAN was shown to suppress nocturnal melatonin but did not affect rat feeding activity (Blask et al. 2014, Dauchy et al. 2014). Dauchy et al. (2014) also demonstrated that MCF-7 tumor growth decreased with melatonin supplementation. The effect of light contaminating the dark phase was also investigated by Dauchy et al. (1997, 1999) using male Buffalo rats bearing rat hepatoma. Dim light (0.21 lux or 0.25 lux) during the dark phase increased tumor growth compared to the 12:12 LD group, with the tumor growth rate approaching that for continuous light exposure. The effect on tumor growth of dim-light contamination of animal rooms during the dark phase also was investigated in rat hepatoma and MCF-7 breast cancer tissue xenograft animal models (Dauchy et al. 2011). For both animal models, tumor latency decreased and tumor growth rates increased with increasing light contamination of the animal rooms.
HeLa (human cervical cancer) cells were injected into male nude mice exposed to continuous light or a 12:12 LD cycle (Yasuniwa et al. 2010). Tumor volume was significantly greater in the LL group than in the LD group, and tumor microvessels and stroma were more prevalent in the LL group. Subcutaneous injection of murine melanoma cells into C57BL/6 male mice under the same light exposure protocol resulted in lower survival, greater intraperitoneal dissemination, and greater tumor weight at death in the LL group than in the 12:12 LD group, and melatonin supplementation decreased tumor weight and intraperitoneal dissemination (Otálora et al. 2008).
Four studies in mice investigated the relationship between length of daily light exposure or LAN and tumor size following injection with mouse tumor cells. In one study (Waldrop et al. 1989), male mice exposed to long days (18:6 LD), short days (6:18 LD), or standard days (12:12 LD) were injected with mouse colon adenocarcinoma cells. At 22 days post-injection, tumor weight, tumor area, and mortality were significantly greater in the 12:12 LD group than in the long- or short-day groups, whereas findings for tumor incidences were inconsistent across three experiments, thus overall the results of this study are considered to be inconclusive. In another study, female mice exposed to the same light-dark cycles were injected with HFH18 melanoma cells. Although all animals developed exponentially growing tumors, the average tumor volume on day 31 post-injection was significantly smaller in the short-day group than in the long-day group, and tumor volume was intermediate in the 12:12 LD group (Lang et al. 2003). In male C57BL/6 mice injected with mouse prostate cancer cells (TRAMP-C2), tumors at 59 days post-injection were significantly larger in the long-day (18:6 LD) group than in the short-day (6:18 LD) group. Melatonin co-exposure significantly decreased tumor size in the 16:8 LD group, while the 6:18 LD group animals with 30 minutes LAN after 7 hours dark phase had significantly increased tumor size (Haim et al. 2010). In another study, mice injected with 4T1 mouse mammary-gland carcinoma cells were assigned to either a control group (8:16 LD) or to a group exposed to light for 30 minutes every night at seven hours after the start of the dark phase (Schwimmer et al. 2014). After three weeks, the light-at-night group had lower survival and significantly larger tumors than did the control group; melatonin co-exposure decreased tumor size compared to 8:16 LD group.
Growth of rat C6 glioma cells subcutaneously inoculated into male Wistar rats was increased in rats exposed to continuous light (Guerrero-Vargas et al. 2017). Tumors in LL animals were significantly larger after 13 days than tumors in rats maintained on a 12:12 LD cycle.
There is some evidence to suggest that exposure to bright light (blue light) during the daytime suppresses tumor growth, suggesting that insufficient daylight exposure (in addition to LAN) is important in carcinogenicity. Dauchy et al. (2015) reported that growth rates of human prostate cancer xenografts were delayed in nude mice exposed to blue light during the daytime (12-hour dark:12-hour light schedule using blue-tinted cages) compared to nude mice housed in clear cages (12 hour-light:12-hour dark cycle).
5.2.3. Spontaneous tumor formation
In general, four of the five studies reviewed in this section reported that exposure to LAN (continuous) light was related to carcinogenicity, e.g., increased incidence tumor incidence or multiplicity, decreased tumor latency and life span compared with exposure to a standard 12:12 LD cycle There was evidence that constant light exposure (such as irregular estrus cycling) caused circadian disruption in all these studies. However, because of poor reporting of necropsy and pathology methods, the findings for specific tumors are of limited utility. Because of these concerns, the most common tumor types as reported by the authors are noted, but the number or incidences of specific tumor types are not included.
Three studies in female mice examined the effect of continuous light exposure on the incidence and latency of spontaneous tumors and one of these studies used HER2/neu transgenic mice (which carry the HER2/neu breast-cancer oncogene). Exposures to continuous light or to 12:12 LD began at 8 weeks of age and continued until either natural death or moribund condition or, in the transgenic animals, the presence of palpable mammary-gland tumors. Popovich et al. (2013) observed mean lifespan significantly less in the LL group, but reported no significant difference in spontaneous uterine hemangioma and sarcoma or other tumor incidences between the LD and LL exposure groups. Anisimov et al. (2004) observed significant differences in spontaneous lung adenocarcinoma (P < 0.05) and lymphoma or leukemia (P < 0.02) and a non-significant increase in incidence of hepatocellular carcinoma between the LL and the LD exposure groups, with higher total and all malignant tumor incidences in the LL group. In the HER2/neu transgenic mice, the incidence and size of mammary-gland tumors did not differ between the LL and LD exposure groups; however, continuous light resulted in significantly increased mammary-gland tumor multiplicity and increased tumor latency (Baturin et al. 2001). This study also investigated the effect of melatonin supplementation on mammary-gland tumor formation. Melatonin supplementation had no effect on tumor incidence or size in the LL group, but significantly decreased tumor incidence and size in the LD group. In both groups, melatonin supplementation resulted in approximately a 60% reduction in HER2/neu mRNA expression.
In a study conducted in Russia, rats were exposed to continuous light, the natural light of northwest Russia (NL; in winter 4.5 hours maximum light, in summer 24 hours maximum light, additional information on light:dark period not reported), or 12:12 LD starting at 25 days of age (Vinogradova et al. 2009). LL or NL exposure resulted in an apparent shorter lifespan in both males and females and shorter total tumor latency in the LL and NL groups in males and in the LL group in females than in the 12:12 LD group (all values non-significant). Compared with 12:12 LD exposure, there was a significant increase in total spontaneous benign mammary-gland tumors in females in the NL group (35% vs. 56.3%) but non-significant in the LL group (35% vs. 33%); however, total tumor incidences in both sexes were not significantly different compared with the LD group (Vinogradova et al. 2009). When this experiment was repeated with both sexes of rats exposed to LL or 12:12 LD beginning at either 25 days or 14 months of age (NL exposure was not tested), the older age of exposure to the different light schedules did not affect lifespan or specific or total tumor incidence as compared to the LD group (Vinogradova et al. 2010).
5.2.4. Effects of daytime blue light exposure on tumor growth
Two studies investigated the effects of blue-enriched lighting (465 to 485 nm) during daytime on tumor growth. In the first study, groups of male nude rats were exposed to overhead cool-white fluorescent lamps on a 12:12 LD schedule and placed in either blue-tinted cages (which increased transmittance of blue light) or clear cages (Dauchy et al. 2015). In the second study, both groups of male Buffalo rats were placed in clear cages and maintained on a 12:12 LD schedule but one group was exposed to blue-enriched LED lights during the day while the second group was exposed to cool white fluorescent lights (Dauchy et al. 2018). The nude rats were implanted with human prostate cancer PC3 xenografts and the male Buffalo rats were implanted with tissue-isolated 7288CTC-Morris rat hepatomas. Both studies reported that tumor latency (i.e., time from implantation to the first palpable mass) was increased by about 50% and tumor growth rates were reduced by 50% to 55% in rats exposed to blue-enriched light during the daytime (Dauchy et al. 2015, Dauchy et al. 2018). Blue light exposure during the day was associated with increased nocturnal plasma melatonin levels and reduced uptake and metabolism of linoleic acid, aerobic glycolysis, and growth signaling activities compared to the control rats (see Sections 2.2.2, 6.2.1, and 6.3.5).
5.3. Findings from animal models of simulated shift work and chronic jet lag
This section reviews studies with animal models simulating shift work or chronic jet lag (CJL), such as weekly inversion of the light-dark cycle or weekly light-phase shifts, either forward or backward, by 8 hours (see Figure 5-2). The studies are organized by animal model (Sections 5.3.1 to 5.3.3) and summarized in Table 5-2.
5.3.1. Initiation-promotion models
Fang et al. (2017) reported that simulated jet lag (8-hour advance or delay in light onset every 3 days for 3 to 4 months) enhanced the growth of NMU-induced mammary tumors in heterozygous female c3(1)/SV40 t-antigen [C3(1)/Tag] transgenic mice. The average tumor onset was 16 days earlier and the average tumor burden (a function of both tumor number and size) was greater in CJL mice compared to controls. In a study modeling CJL, DEN was administered over a period of 46 days to male B6D2F1 mice exposed to 12:12 LD (Filipski et al. 2009). The mice were then randomized to either remain on 12:12 LD or undergo 8-hour advances of the LD cycle every 2 days (from days 46 through 297). Up to four different histologic types of liver tumors per liver (hepatocellular or cholangiocarcinoma, sarcoma, or mixed tumors) were observed in CJL-exposed mice, compared with a single histologic tumor type per liver in the 12:12 LD group. Two or more liver tumors were found in 33% of LD vs. 77% CJL-exposed mice (P = 0.026). The mean diameter of the largest tumor per liver was approximately two-fold greater in CJL-exposed mice (P = 0.027). Primary lung and kidney tumors also occurred, but their incidences were not reported.
Simulated jet lag increased lung tumor growth (as measured by area) initiated using a K-ras LSL-G12D/+; p53flox/flox mouse lung model (e.g., intratracheal administration of mice with CRE-recombinase viral vector activating K-rasG12D; p53-/- mutations). Mice that had been placed on a jet-lag schedule after tumor initiation had a significant increase in lung tumor area after 13 weeks as compared with those on 12:12 LD. In contrast, simulated jet lag did not promote lung tumor growth when given prior to tumor initiation (Papagiannakopoulos et al. 2016).
Simulated jet lag significantly increased lymphoma growth and decreased survival in animals initiated with gamma radiation; liver tumors, osteosarcoma, and ovarian tumors also occurred, but they were not significantly increased (Lee et al. 2010).
Table 5-2
Summary of cancer studies of simulated shiftwork/chronic jet lag in experimental animals.
5.3.2. Growth of injected tumor cells
All studies examining the effect of simulated CJL on growth and/or survival of tumor cells injected into rodents found that CJL exposure increased the growth rate of tumors or decreased survival.
B6D2F1 mice were exposed to 12:12 LD, LL, or DD versus 8-hour advances of a 12:12 LD cycle every two days (to mimic CJL) and were then injected with Glasgow osteosarcoma tissue (Filipski et al. 2004) or pancreatic adenocarcinoma cells (Filipski et al. 2006). Both types of tumor grew significantly faster in the CJL animals than in the 12:12 LD group, but osteosarcoma growth was not affected by exposure to continuous light or dark. In a separate study, osteosarcoma tumors grew faster in the CJL group than in the 12:12 LD synchronized animals, and the CJL effect on tumor growth was partially inhibited by feeding the mice only from the onset of activity to onset of rest (Filipski et al. 2005). In another study, C57BL/6 male mice were exposed for two weeks to 12:12 LD and then randomized into two groups: 12:12 LD and CJL (12:12 LD with light onset advanced 8 hours every 48 hours) (Wu et al. 2012). Lewis lung carcinoma cells were injected into both groups of mice on day 10 after the start of CJL exposure. Tumors grew significantly faster in the CJL mice than in the control group, and the CJL group had significantly more lung metastases.
Male Fischer rats were injected intravenously with mammary adenocarcinoma (MADB106) after being acclimatized to either a CJL protocol (6-hour LD phase advances repeated every 2 days for a total of 10 shifts followed by 5 to 7 days of continuous darkness) or a 12:12 LD control group. CJL exposure increased mammary tumor incidence and multiplicity in the lung compared to the 12:12 LD group (Logan et al. 2012). In another study, plasmacytoma cells were injected into Lou/c rats and lighting schedules were then advanced or delayed 6 hours every second day; tumor latency, size, and growth rate were greater in the CJL group than in the 12:12 LD control group (Wu et al. 1988). Mice with either Ehrlich carcinoma or sarcoma 180 tumor transplants that were shifted between 14:10 LD and 10:14 LD every three days had shorter survival and greater tumor growth than the 12:12 LD control group (Li and Xu 1997).
5.3.3. Spontaneous tumor formation
The effects of a shift-work paradigm of weekly inversion of the 12:12 LD cycle on development of mammary-gland tumors were assessed in female p53R270Ha/+ WAPCre mice (which bear a mammary-gland-specific p53 tumor-suppressor-gene mutation) (Van Dycke et al. 2015). Compared with the 12:12 LD control group, the weekly inversion group showed a 15% decrease [calculated by NTP; authors reported 17%] in mammary-gland tumor latency. Indicators of circadian disruption were body weight gain, longer period of inactivity, lower food consumption and dysregulation of core body temperature and corticosterone serum levels. The total number of tumors did not differ between the groups; mammary-gland carcinoma and fibrosarcoma or carcinosarcoma developed in both groups.
In both sexes of C57BL6/6J mice, a CJL model (weekly alternation between two rooms with light schedules offset by 8 hours, over an 86-week period) resulted in a shorter lifespan and a significantly greater incidence of hepatocellular carcinoma (8.8% vs. 0.0%) and non-alcoholic fatty liver disease than mice on an unchanging 12:12 LD cycle (Kettner et al. 2016). In addition to disruption of liver metabolism, irradiated and clock gene deficient mice (Cry1-/-, Cry2-/-, Per1-/-, Per2-/-) had greater incidences of hepatocellular carcinoma with CJL than under 12:12 LD control lighting conditions. The incidence of hepatocellular carcinoma was higher in males than in females. Other tumors reported were pancreatic cancer, ovarian cancer, and lymphoma, but tumor incidences were not reported and the primary focus of the report was on the mechanism of fatty liver disease. In p53-/- C57BL6/6J mice, CJL-exposed animals had significantly decreased survival. Lymphoma was the primary tumor type and 10% of tumors were osteosarcoma (tumor details not reported) (Lee et al. 2010). Untreated mice with deficiencies in specific clock genes (Bmal1+/-, Cry1-/- and Cry2-/-, Per1-/- and Per2m/m, Per2-/-) had similar tumor profiles as with treatment with gamma radiation or radiation plus CJL.
5.4. Summary
Constant exposure to dim artificial LAN has become pervasive in modern society due to urban and indoor light pollution. Exposure to constant light is even more pronounced for shift workers that are exposed to constant dim light during daylight hours and bright lights during night shifts.
Most studies on the growth of injected tumor cells and some initiation-promotion studies showed that light exposure at night, including chronic exposure to dim light and intermittent exposure to dim light during the dark phase, and changes in daylight length promoted the rate of tumor growth, or tumor size, incidence, or multiplicity of several types of tumors including mammary gland, human breast, liver, lung, peripheral nervous system, kidney, human cervix, skin, prostate, or glioma (see Section 5.1 and Table 5-1). In addition, tumor growth in response to intermittent light exposure during the dark phase was found to be dependent on light intensity, and co-exposure with melatonin decreased liver and human breast tumor growth. Tumors derived from human breast cancer and grown in nude rats had a greater proliferation rate when perfused in situ with human blood collected during the daytime when blood melatonin levels were low and less proliferation with blood collected at nighttime when blood melatonin levels were high. From animal studies of spontaneous cancers, exposure to continuous light decreased the latency of spontaneous tumor formation and increased tumor multiplicity as compared to 12:12 LD exposure, but incidences of spontaneous tumor types between continuous light exposure and 12:12 LD were inconclusive and of limited utility. Most of these studies assessed total tumors and had limited pathological methods for assessing specific types of tumors. As discussed in Section 2, exposure to dim LAN (0.2 lux) can reduce melatonin secretion by 65%; none of the cancer animal studies using continual bright light measured melatonin levels.
Two studies evaluated the effects of exposure to blue-enriched light during the daytime on growth of tumor xenografts (human prostate cancer or rat hepatomas) in male rats maintained on a 12:12 LD cycle. Compared to rats exposed to 12 hours of polychromatic white fluorescent lighting, rats exposed to blue-enriched light for 12 hours during the daytime had decreased growth of prostate and liver xenografts.
Tumors initiated by chemical exposure, genetic manipulation, or gamma radiation from animals exposed to a simulated CJL model were larger and more numerous than in control animals, and the CJL-exposed group had shorter survival times. This was similar in rodents injected with tumor cells and exposed to conditions to simulate CJL; faster tumor growth and lower survival were reported, and one study reported an increase in tumors in the lung in CJL-exposed mice as compared to the 12:12 LD control group after intravenous injection of mammary gland adenocarcinoma cells (see Section 5.2 and Table 5-2). Types of tumors included Ehrlich carcinoma, sarcoma 180, Glasgow osteosarcoma, pancreatic adenocarcinoma, lung carcinoma, and plasmacytoma. In initiation-promotion studies in mice, CJL increased multiplicity, tumor burden, or tumor size of liver tumors initiated with DEN or mammary-gland tumors initiated by NMU compared to 12:12 LD control mice. In a mouse model with increased susceptibility to mammary-gland cancer, exposure to light schedules simulating shift work decreased the latency of spontaneous mammary-gland tumor formation, but the final tumor incidences were similar to those of the 12:12 LD control group. In a mouse model with increased susceptibility to lung cancer, tumor initiation followed by a jet-lag exposure schedule increased tumor area. Mice exposed to CJL conditions had significantly greater spontaneous hepatocellular carcinoma incidence and shortened lifespan as compared to those on a 12:12 LD regimen and p53-/- mice exposed to CJL conditions had a shortened lifespan and increased incidence of lymphoma and osteosarcoma.
These studies provide strong evidence that LAN, CJL, or shift work can, through circadian disruption, promote tumor growth and decrease tumor latency. For most of these studies, evidence of circadian disruption was reported such as noting changes in food intake, body weight, activity, or hormone levels; however, the focus of these studies was on tumor growth and outcome, and these parameters, if noted, were not directly discussed. Therefore, although most studies reported some indication of circadian disruption, not all studies included this information and it was not possible to determine if negative tumor growth studies with light exposure were due to lack of circadian disruption. Exposure to blue light during the daytime has the opposite effect on tumor latency and growth, suggesting that total light exposure is important in circadian regulation and carcinogenicity. In the studies of light exposure (during the night or day), melatonin was shown to play a role in carcinogenicity (see Section 6.2.2). What is less certain is whether and how these factors affect spontaneous initiation of carcinogenesis. Studies of spontaneous tumor formation with LAN were of limited utility, and there were only two CJL and one shift-work study. All three of the latter studies provided data on circadian disruption affecting tumor growth. The CJL studies found significant increases in spontaneous liver tumor incidence and lymphoma, and the shift-work study found shortened tumor latency, but no change in tumor incidences. In all cases, circadian disruption outputs were measured that would affect the peripheral clock and potentially alter tumor development (see Section 6.2.3). Therefore, more carefully designed and detailed cancer studies to examine spontaneous tumor formation are needed to clearly answer whether LAN or CJL affects spontaneous cancer initiation events and which tissues may be most sensitive.
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