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Anbalagan, M., Dauchy, R., Xiang, S., Robling, A., Blask, D., Rowan, B., et al. (2019). SAT-337 Disruption Of The Circadian Melatonin Signal By Dim Light At Night Promotes Bone-lytic Breast Cancer Metastases. Journal of the Endocrine Society, 3(Supplement_1).
Abstract: Breast cancer metastasis to bone is a major source of morbidity and mortality in women with advanced metastatic breast cancer. Morbidity from metastasis to bone is compounded by the fact that they cannot be surgically removed and can only be treated with chemotherapy and/or radiation therapy. Thus, there is critical need to develop new treatment strategies that kill bone metastatic tumors and reduce osteolytic lesions to improve patient quality of life and extend patient survival. Circadian rhythms are daily cycles of ~24 h that control many if not most physiologic processes and their disruption by exposure to light at night (LAN) or jet lag has been shown to be strongly associated with the development of cancer, particularly breast cancer. We have found that disruption of the anti-cancer circadian hormone melatonin (MLT) by light at night can significantly enhance the metastatic potential in breast cancer cells. Our work supports the report of the International Agency for Research on Cancer that shift work is a “probable human carcinogen” and highlights the association between exposure to light at night and invasive breast cancer. We recently reported that human breast tumor xenografts grown in athymic nude female rats housed in a photoperiod of 12h light at day: 12h dim light at night (dLAN, 0.2 lux – blocks the nighttime circadian MLT signal), display resistance to doxorubicin (Dox). More importantly, tumor growth and drug resistance could be blocked by the administration of Dox in circadian alignment with nocturnal MLT during dLAN. Our recent preliminary studies show that poorly invasive ERα positive MCF-7 breast cancer cells, when injected into the tibia (to mimic bone metastatic disease) of Foxn1nu athymic nude mice (which produce a strong circadian nighttime melatonin signal) housed in a dLAN photoperiod (suppressed nocturnal MLT production) developed full blown breast cancer tumors in bone (P<0.05) that are highly osteolytic (P<0.05). Moreover, patients with metastatic breast cancer are routinely treated with doxorubicin, which itself can promote bone damage. Our studies demonstrate that MLT slows the growth of metastatic breast cancer in bone but that the chrono-therapeutic use of doxorubicin in circadian alignment with melatonin in Foxn1nu mice with tibial breast tumors, reduced tumor growth in bone, reduced bone erosion, and promoted the formation of new bone. Successful use of this chronotherapeutic use of Dox and MLT in clinical trials increasing efficacy in preventing or suppressing breast cancer metastasis to bone while decreasing toxic side effects of doxorubicin would provide a revolutionary advancement in the treatment of bone metastatic breast cancer and decrease the morbidity and mortality associated with breast cancer metastasis to bone.
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Datta, S., Samanta, D., Tiwary, B., Chaudhuri, A. G., & Chakrabarti, N. (2019). Sex and estrous cycle dependent changes in locomotor activity, anxiety and memory performance in aged mice after exposure of light at night. Behav Brain Res, 365, 198–209.
Abstract: Light-at-night (LAN) can affect mammalian behaviour. But, the effects of LAN on aged rodents remain undefined yet. In the present investigation, aged Swiss Albino mice, habituated in regular light-dark cycle, were exposed to bright-light-pulse (1-hr) at night on the day of study followed by experimentations for assessment of locomotor activities in the open field, anxiety in the elevated plus maze and short-term memory for novel object recognition (NOR) in the habituated field. Under without-bright-light exposure, (a) aged proestrous females showed greater locomotor activities and less anxiety than in aged diestrous females, (b) aged males showed locomotor activities and anxiety level similar to aged diestrous females and aged proestrous females respectively and (c) all animals failed to retain in object discrimination memory. LAN exposure exhibited the continual failure of such retention of memory while animals showed free and spontaneous exploration with thigmotactic behaviour having no object bias and/or phobia, but time stay in objects by animals altered variably among sexes and stages of estrous cycle. Overall, the LAN caused (a) diminution in locomotor activities, rise in anxiety and failure of memory for recognition of both familiar and novel objects in aged proestrous females, (b) hyperlocomotor activities and reduction in anxiety in both males and diestrous females with the failure of memory for recognition of novel objects only in aged males while diestrous females showed enhanced exploration time to both objects during NOR. Thus, nocturnal behaviour of aged mice varies with sex and estrous cycle and light acts differentially on them.
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Fonken, L. K., Bedrosian, T. A., Zhang, N., Weil, Z. M., DeVries, A. C., & Nelson, R. J. (2019). Dim light at night impairs recovery from global cerebral ischemia. Exp Neurol, 317, 100–109.
Abstract: Nighttime lighting is one of the great conveniences of modernization; however, there is mounting evidence that inopportune light exposure can disrupt physiological and behavioral functions. Hospital patients may be particularly vulnerable to the consequences of light at night due to their compromised physiological state. Cardiac arrest/cardiopulmonary resuscitation (CA) was used to test the hypothesis in mice that exposure to dim light at night impairs central nervous system (CNS) recovery from a major pathological insult. Mice exposed to dim light at night (5lx) had higher mortality in the week following cardiac arrest compared to mice housed in dark nights (0lx). Neuronal damage was significantly greater in surviving mice exposed to dim light at night after CA versus those housed in dark nights. Dim light at night may have elevated neuronal damage by amplifying pro-inflammatory pathways in the CNS; Iba1 immunoreactivity (an indication of microglia activation) and pro-inflammatory cytokine expression were elevated in mice exposed to dim light at night post-CA. Furthermore, selective inhibition of IL-1beta or TNFalpha ameliorated damage in mice exposed to dim light at night. The effects of light at night on CA outcomes were also prevented by using a wavelength of nighttime light that has minimal impact on the endogenous circadian clock, suggesting that replacing broad-spectrum nighttime light with specific circadian-inert wavelengths could be protective. Together, these data indicate that exposure to dim light at night after global cerebral ischemia increases neuroinflammation, in turn exacerbating neurological damage and potential for mortality.
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Li, Y., Cheng, S., Li, L., Zhao, Y., Shen, W., & Sun, X. (2019). Light-exposure at night impairs mouse ovary development via cell apoptosis and DNA damage. Biosci Rep, 39, BSR20181464.
Abstract: The alternation of light and dark rhythm causes a series of physiological, biochemical and metabolic changes in animals, which also alters the growth and development of animals, and feeding, migration, reproduction and other behavioral activities. In recent years, many studies have reported the effects of long-term (more than 6 weeks) illumination on ovarian growth and development. In this study, we observed the damage, repair and apoptosis of ovarian DNA in a short period of illumination. The results showed that, in short time (less than 2 weeks) illumination conditions, the 24 hrs-light treatment caused the reduction of total ovarian follicle number and downregulation of circadian clock related genes. Furthermore, the changed levels of serum sex hormones were also detected after 24 hrs-light exposure, of which the concentrations of LH (luteinizing hormone), FSH (follicle-stimulating hormone) and E2 (estradiol) were increased, but the concentration of PROG (progesterone) was decreased. Moreover, 24 hrs-light exposure increased the expression of DNA damage and repair related genes, the number of TUNEL and RAD51 positive cells. These results indicated that 24 hrs-light exposure for 4 days, 8days and 12 days increased DNA damage and cell apoptosis, thereby affecting the development of ovary.
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Lundberg, L., Sienkiewicz, Z., Anthony, D. C., & Broom, K. A. (2019). Effects of 50 Hz magnetic fields on circadian rhythm control in mice. Bioelectromagnetics, 40(4), 250–259.
Abstract: Artificial light and power frequency magnetic fields are ubiquitous in the built environment. Light is a potent zeitgeber but it is unclear whether power frequency magnetic fields can influence circadian rhythm control. To study this possibility, 8-12-week-old male C57BL/6J mice were exposed for 30 min starting at zeitgeber time 14 (ZT14, 2 h into the dark period of the day) to 50 Hz magnetic fields at 580 muT using a pair of Helmholtz coils and/or a blue LED light at 700 lux or neither. Our experiments revealed an acute adrenal response to blue light, in terms of increased adrenal per1 gene expression, increased serum corticosterone levels, increased time spent sleeping, and decreased locomotor activity (in all cases, P < 0.0001) compared to an unexposed control group. There appeared to be no modulating effect of the magnetic fields on the response to light, and there was also no effect of the magnetic fields alone (in both cases, P > 0.05) except for a decrease in locomotor activity (P < 0.03). Gene expression of the cryptochromes cry1 and cry2 in the adrenals, liver, and hippocampus was also not affected by exposures (in all cases, P > 0.05). In conclusion, these results suggest that 50 Hz magnetic fields do not significantly affect the acute light response to a degree that can be detected in the adrenal response.
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